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Defamie V, Aliar K, Sarkar S, Vyas F, Shetty R, Reddy Narala S, Fang H, Saw S, Tharmapalan P, Sanchez O, Knox JJ, Waterhouse PD, Khokha R. Metalloproteinase inhibitors regulate biliary progenitor cells through sDLK1 in organoid models of liver injury. J Clin Invest 2024; 135:e164997. [PMID: 39699962 PMCID: PMC11785925 DOI: 10.1172/jci164997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
Understanding cell fate regulation in the liver is necessary to advance cell therapies for hepatic disease. Liver progenitor cells (LPCs) contribute to tissue regeneration after severe hepatic injury, yet signals instructing progenitor cell dynamics and fate are largely unknown. Tissue inhibitor of metalloproteinases 1 (TIMP1) and TIMP3 control the sheddases ADAM10 and ADAM17, key for NOTCH activation. Here we uncover the role of the TIMP/ADAM/NOTCH/DLK1 axis in LPC maintenance and cholangiocyte specification. Combined TIMP1/TIMP3 loss in vivo caused abnormal portal triad stoichiometry accompanied by collagen deposits, dysregulated Notch signaling, and increased soluble DLK1. The MIC1-1C3+CD133+CD26- biliary progenitor population was reduced following acute CCl4 or chronic DDC liver injury and in aged TIMP-deficient livers. Single-cell RNA sequencing data interrogation and RNAscope identified portal mesenchymal cells coexpressing ADAM17/DLK1 as enzymatically equipped to process DLK1 and direct LPC differentiation. Specifically, TIMP-deficient biliary fragment-derived organoids displayed increased propensity for cholangiocyte differentiation. ADAM17 inhibition reduced Sox9-mediated cholangiocyte differentiation, prolonging organoid growth and survival, whereas WT organoids treated with soluble DLK1 triggered Sox9 expression and cholangiocyte specification in mouse and patient-derived liver organoids. Thus, metalloproteinase inhibitors regulate instructive signals for biliary cell differentiation and LPC preservation within the portal niche, providing a new basis for cell therapy strategies.
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Affiliation(s)
- Virginie Defamie
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Kazeera Aliar
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Soumili Sarkar
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Foram Vyas
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Ronak Shetty
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Swami Reddy Narala
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Hui Fang
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Sanjay Saw
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Otto Sanchez
- Ontario Tech University, Oshawa, Ontario, Canada
| | - Jennifer J. Knox
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Paul D. Waterhouse
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Rama Khokha
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Nam YW, Shin JH, Kim S, Hwang CH, Lee CS, Hwang G, Kim HR, Roe JS, Song J. EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401. Cell Death Differ 2024; 31:1318-1332. [PMID: 38789573 PMCID: PMC11445491 DOI: 10.1038/s41418-024-01316-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
Tumour necrosis factor receptor 1 (TNFR1) induces the nuclear factor kappa-B (NF-κB) signalling pathway and regulated cell death processes when TNF-α ligates with it. Although mechanisms regulating the downstream pathways of TNFR1 have been elucidated, the direct regulation of TNFR1 itself is not well known. In this study, we showed that the kinase domain of the epidermal growth factor receptor (EGFR) regulates NF-κB signalling and TNF-α-induced cell death by directly phosphorylating TNFR1 at Tyr 360 and 401 in its death domain. In contrast, EGFR inhibition by EGFR inhibitors, such as erlotinib and gefitinib, prevented their interaction. Once TNFR1 is phosphorylated, its death domain induces the suppression of the NF-κB pathways, complex II-mediated apoptosis, or necrosome-dependent necroptosis. Physiologically, in mouse models, EGF treatment mitigates TNF-α-dependent necroptotic skin inflammation induced by treatment with IAP and caspase inhibitors. Our study revealed a novel role for EGFR in directly regulating TNF-α-related pathways.
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Affiliation(s)
- Young Woo Nam
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - June-Ha Shin
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Seongmi Kim
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Chi Hyun Hwang
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Choong-Sil Lee
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Gyuho Hwang
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Hwa-Ryeon Kim
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Jae-Seok Roe
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Jaewhan Song
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea.
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Chen M, Chen W, Sun S, Lu Y, Wu G, Xu H, Yang H, Li C, He W, Xu M, Li X, Jiang D, Cai Y, Liu C, Zhang W, He Z. CDK4/6 inhibitor PD-0332991 suppresses hepatocarcinogenesis by inducing senescence of hepatic tumor-initiating cells. J Adv Res 2024:S2090-1232(24)00374-6. [PMID: 39218249 DOI: 10.1016/j.jare.2024.08.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
INTRODUCTION Owing to the limited treatment options for hepatocellular carcinoma (HCC), interventions targeting pre-HCC stages have attracted increasing attention. In the pre-HCC stage, hepatic tumor-initiating cells (hTICs) proliferate abnormally and contribute to hepatocarcinogenesis. Numerous studies have investigated targeted senescence induction as an HCC intervention. However, it remains to be clarified whether senescence induction of hTICs could serve as a pre-HCC intervention. OBJECTIVES This study was designed to investigate whether senescence induction of hTICs in the precancerous stage inhibit HCC initiation. METHODS AND RESULTS HCC models developed from chronic liver injury (CLI) were established by using Fah-/- mice and N-Ras + AKT mice. PD-0332991, a selective CDK4/6 inhibitor that blocks the G1/S transition in proliferating cells, was used to induce senescence during the pre-HCC stage. Upon administration of PD-0332991, we observed a significant reduction in HCC incidence following selective senescence induction in hTICs, and an alleviation liver injury in the CLI-HCC models. PD-0332991 also induced senescence in vitro in cultured hTICs isolated from CLI-HCC models. Moreover, RNA sequencing (RNA-seq) analysis delineated that the "Cyclin D-CDK4/6-INK4-Rb" pathway was activated in both mouse and human liver samples during the pre-HCC stage, while PD-0332991 exhibited substantial inhibition of this pathway, thereby inducing cellular senescence in hTICs. Regarding the immune microenvironment, we demonstrated that senescent hTICs secrete key senescence-associated secretory phenotypic (SASP) factors, CXCL10 and CCL2, to activate and recruit macrophages, and contribute to immune surveillance. CONCLUSION We found that hTICs can be targeted and induced into a senescent state during the pre-HCC stage. The SASP factors released by senescent hTICs further activate the immune response, facilitating the clearance of hTICs, and consequently suppressing HCC occurrence. We highlight the importance of pre-HCC interventions and propose that senescence-inducing drugs hold promise for preventing HCC initiation under CLI.
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Affiliation(s)
- Miaomiao Chen
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Wenjian Chen
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Shiwen Sun
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Yanli Lu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Guoxiu Wu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Hongyu Xu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Huiru Yang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Chong Li
- Zhoupu Community Health Service Center of Pudong New Area, Shanghai, China
| | - Weizhi He
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Mingyang Xu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Xiuhua Li
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Dong Jiang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Yongchao Cai
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Changcheng Liu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Zhiying He
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China.
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Sperrhacke M, Leitzke S, Ahrens B, Reiss K. Breakdown of Phospholipid Asymmetry Triggers ADAM17-Mediated Rescue Events in Cells Undergoing Apoptosis. MEMBRANES 2023; 13:720. [PMID: 37623781 PMCID: PMC10456294 DOI: 10.3390/membranes13080720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/27/2023] [Accepted: 08/03/2023] [Indexed: 08/26/2023]
Abstract
ADAM17, a prominent member of the "Disintegrin and Metalloproteinase" (ADAM) family, controls vital cellular functions through the cleavage of transmembrane substrates, including epidermal growth factor receptor (EGFR) ligands such as transforming growth factor (TGF)-alpha and Epiregulin (EREG). Several ADAM17 substrates are relevant to oncogenesis and tumor growth. We have presented evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. The scramblase Xkr8 is instrumental for calcium-independent exposure of PS in apoptotic cells. Xkr8 can be dually activated by caspase-3 and by kinases. In this investigation, we examined whether Xkr8 would modulate ADAM17 activity under apoptotic and non-apoptotic conditions. Overexpression of Xkr8 in HEK293T cells led to significantly increased caspase-dependent as well as PMA-induced release of EREG and TGF-alpha. Conversely, siRNA-mediated downregulation of Xkr8 in colorectal Caco-2 cancer cells led to decreased PS externalization upon induction of apoptosis, which was accompanied by reduced shedding of endogenously expressed EREG and reduced cell survival. We conclude that Xkr8 shares with conventional scramblases the propensity to upmodulate the ADAM-sheddase function. Liberation of growth factors could serve a rescue function in cells on the pathway to apoptotic death.
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Affiliation(s)
| | | | | | - Karina Reiss
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany (B.A.)
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5
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Wang K, Xuan Z, Liu X, Zheng M, Yang C, Wang H. Immunomodulatory role of metalloproteinase ADAM17 in tumor development. Front Immunol 2022; 13:1059376. [PMID: 36466812 PMCID: PMC9715963 DOI: 10.3389/fimmu.2022.1059376] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/03/2022] [Indexed: 12/25/2023] Open
Abstract
ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.
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Affiliation(s)
- Kai Wang
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Zixue Xuan
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xiaoyan Liu
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Meiling Zheng
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Chao Yang
- National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, China
| | - Haiyong Wang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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Matched Paired Primary and Recurrent Meningiomas Points to Cell-Death Program Contributions to Genomic and Epigenomic Instability along Tumor Progression. Cancers (Basel) 2022; 14:cancers14164008. [PMID: 36011000 PMCID: PMC9406329 DOI: 10.3390/cancers14164008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/08/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
Meningioma (MN) is an important cause of disability, and predictive tools for estimating the risk of recurrence are still scarce. The need for objective and cost-effective techniques addressed to this purpose is well known. In this study, we present methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a friendly method for deepening the understanding of the mechanisms underlying meningioma progression. A large follow-up allowed us to obtain 50 samples, which included the primary tumor of 20 patients in which half of them are suffering one recurrence and the other half are suffering more than one. We histologically characterized the samples and performed MS-MLPA assays validated by FISH to assess their copy number alterations (CNA) and epigenetic status. Interestingly, we determined the increase in tumor instability with higher values of CNA during the progression accompanied by an increase in epigenetic damage. We also found a loss of HIC1 and the hypermethylation of CDKN2B and PTEN as independent prognostic markers. Comparison between grade 1 and higher primary MN's self-evolution pointed to a central role of GSTP1 in the first stages of the disease. Finally, a high rate of alterations in genes that are related to apoptosis and autophagy, such as DAPK1, PARK2, BCL2, FHIT, or VHL, underlines an important influence on cell-death programs through different pathways.
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Tissue Inhibitor of Metalloproteases 3 (TIMP-3): In Vivo Analysis Underpins Its Role as a Master Regulator of Ectodomain Shedding. MEMBRANES 2022; 12:membranes12020211. [PMID: 35207132 PMCID: PMC8878240 DOI: 10.3390/membranes12020211] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/29/2022] [Accepted: 02/03/2022] [Indexed: 01/06/2023]
Abstract
The proteolytical cleavage of transmembrane proteins with subsequent release of their extracellular domain, so-called ectodomain shedding, is a post-translational modification that plays an essential role in several biological processes, such as cell communication, adhesion and migration. Metalloproteases are major proteases in ectodomain shedding, especially the disintegrin metalloproteases (ADAMs) and the membrane-type matrix metalloproteases (MT-MMPs), which are considered to be canonical sheddases for their membrane-anchored topology and for the large number of proteins that they can release. The unique ability of TIMP-3 to inhibit different families of metalloproteases, including the canonical sheddases (ADAMs and MT-MMPs), renders it a master regulator of ectodomain shedding. This review provides an overview of the different functions of TIMP-3 in health and disease, with a major focus on the functional consequences in vivo related to its ability to control ectodomain shedding. Furthermore, herein we describe a collection of mass spectrometry-based approaches that have been used in recent years to identify new functions of sheddases and TIMP-3. These methods may be used in the future to elucidate the pathological mechanisms triggered by the Sorsby’s fundus dystrophy variants of TIMP-3 or to identify proteins released by less well characterized TIMP-3 target sheddases whose substrate repertoire is still limited, thus providing novel insights into the physiological and pathological functions of the inhibitor.
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Al-Salihi M, Bornikoel A, Zhuang Y, Stachura P, Scheller J, Lang KS, Lang PA. The role of ADAM17 during liver damage. Biol Chem 2021; 402:1115-1128. [PMID: 34192832 DOI: 10.1515/hsz-2021-0149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/02/2021] [Indexed: 12/14/2022]
Abstract
A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.
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Affiliation(s)
- Mazin Al-Salihi
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
- School of Medicine, University of Central Lancashire, Preston, PR1 2HE, UK
| | - Anna Bornikoel
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Yuan Zhuang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Pawel Stachura
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Jürgen Scheller
- Department of Biochemistry and Molecular Biology II, Medical Faculty, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Karl S Lang
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, D-45147 Essen, Germany
| | - Philipp A Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
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Implications of ADAM17 activation for hyperglycaemia, obesity and type 2 diabetes. Biosci Rep 2021; 41:228464. [PMID: 33904577 PMCID: PMC8128101 DOI: 10.1042/bsr20210029] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
In this review, we focus specifically on the role that the metalloproteinase, A Disintegrin and Metalloproteinase 17 [ADAM17] plays in the development and progression of the metabolic syndrome. There is a well-recognised link between the ADAM17 substrate tumour necrosis factor α (TNF-α) and obesity, inflammation and diabetes. In addition, knocking out ADAM17 in mice leads to an extremely lean phenotype. Importantly, ADAM17-deficient mice exhibit one of the most pronounced examples of hypermetabolism in rodents to date. It is vital to further understand the mechanistic role that ADAM17 plays in the metabolic syndrome. Such studies will demonstrate that ADAM17 is a valuable therapeutic target to treat obesity and diabetes.
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Kawai T, Elliott KJ, Scalia R, Eguchi S. Contribution of ADAM17 and related ADAMs in cardiovascular diseases. Cell Mol Life Sci 2021; 78:4161-4187. [PMID: 33575814 PMCID: PMC9301870 DOI: 10.1007/s00018-021-03779-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/23/2020] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Abstract
A disintegrin and metalloproteases (ADAMs) are key mediators of cell signaling by ectodomain shedding of various growth factors, cytokines, receptors and adhesion molecules at the cellular membrane. ADAMs regulate cell proliferation, cell growth, inflammation, and other regular cellular processes. ADAM17, the most extensively studied ADAM family member, is also known as tumor necrosis factor (TNF)-α converting enzyme (TACE). ADAMs-mediated shedding of cytokines such as TNF-α orchestrates immune system or inflammatory cascades and ADAMs-mediated shedding of growth factors causes cell growth or proliferation by transactivation of the growth factor receptors including epidermal growth factor receptor. Therefore, increased ADAMs-mediated shedding can induce inflammation, tissue remodeling and dysfunction associated with various cardiovascular diseases such as hypertension and atherosclerosis, and ADAMs can be a potential therapeutic target in these diseases. In this review, we focus on the role of ADAMs in cardiovascular pathophysiology and cardiovascular diseases. The main aim of this review is to stimulate new interest in this area by highlighting remarkable evidence.
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Affiliation(s)
- Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Katherine J Elliott
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA.
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Seidel J, Leitzke S, Ahrens B, Sperrhacke M, Bhakdi S, Reiss K. Role of ADAM10 and ADAM17 in Regulating CD137 Function. Int J Mol Sci 2021; 22:2730. [PMID: 33800462 PMCID: PMC7962946 DOI: 10.3390/ijms22052730] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/01/2021] [Accepted: 03/05/2021] [Indexed: 12/20/2022] Open
Abstract
Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137.
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Affiliation(s)
- Jana Seidel
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany; (J.S.); (S.L.); (B.A.); (M.S.)
| | - Sinje Leitzke
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany; (J.S.); (S.L.); (B.A.); (M.S.)
| | - Björn Ahrens
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany; (J.S.); (S.L.); (B.A.); (M.S.)
| | - Maria Sperrhacke
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany; (J.S.); (S.L.); (B.A.); (M.S.)
| | | | - Karina Reiss
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany; (J.S.); (S.L.); (B.A.); (M.S.)
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12
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Hu C, Zuo Y, Ren Q, Sun X, Zhou S, Liao J, Hong X, Miao J, Zhou L, Liu Y. Matrix metalloproteinase-10 protects against acute kidney injury by augmenting epidermal growth factor receptor signaling. Cell Death Dis 2021; 12:70. [PMID: 33436543 PMCID: PMC7803968 DOI: 10.1038/s41419-020-03301-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022]
Abstract
Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase involved in regulating a wide range of biologic processes, such as apoptosis, cell proliferation, and tissue remodeling. However, the role of MMP-10 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we show that MMP-10 was upregulated in the kidneys and predominantly localized in the tubular epithelium in various models of AKI induced by ischemia/reperfusion (IR) or cisplatin. Overexpression of exogenous MMP-10 ameliorated AKI, manifested by decreased serum creatinine, blood urea nitrogen, tubular injury and apoptosis, and increased tubular regeneration. Conversely, knockdown of endogenous MMP-10 expression aggravated kidney injury. Interestingly, alleviation of AKI by MMP-10 in vivo was associated with the activation of epidermal growth factor receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase-1 and 2 (ERK1/2) signaling. Blockade of EGFR signaling by erlotinib abolished the MMP-10-mediated renal protection after AKI. In vitro, MMP-10 potentiated EGFR activation and protected kidney tubular cells against apoptosis induced by hypoxia/reoxygenation or cisplatin. MMP-10 was colocalized with heparin-binding EGF-like growth factor (HB-EGF) in vivo and activated it by a process of proteolytical cleavage in vitro. These studies identify HB-EGF as a previously unrecognized substrate of MMP-10. Our findings also underscore that MMP-10 can protect against AKI by augmenting EGFR signaling, leading to promotion of tubular cell survival and proliferation after injury.
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Affiliation(s)
- Chengxiao Hu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yangyang Zuo
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Ren
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoli Sun
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shan Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Liao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue Hong
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinhua Miao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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13
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Mao X, Tey SK, Yeung CLS, Kwong EML, Fung YME, Chung CYS, Mak L, Wong DKH, Yuen M, Ho JCM, Pang H, Wong MP, Leung CO, Lee TKW, Ma V, Cho WC, Cao P, Xu X, Gao Y, Yam JWP. Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2002157. [PMID: 33173740 PMCID: PMC7640351 DOI: 10.1002/advs.202002157] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/15/2020] [Indexed: 05/24/2023]
Abstract
In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in metastatic HCC cell-derived extracellular vesicles (EVs) promotes pre-metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV-NID1 also activates fibroblasts, which secrete tumor necrosis factor receptor 1 (TNFR1), facilitate lung colonization of tumor cells, and augment HCC cell growth and motility. Administration of anti-TNFR1 antibody effectively diminishes lung metastasis induced by the metastatic HCC cell-derived EVs in mice. In the clinical perspective, analysis of serum EV-NID1 and TNFR1 in HCC patients reveals their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. In conclusion, these results demonstrate the interplay of HCC EVs and activated fibroblasts in pre-metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.
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Affiliation(s)
- Xiaowen Mao
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Sze Keong Tey
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Cherlie Lot Sum Yeung
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Ernest Man Lok Kwong
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Yi Man Eva Fung
- Department of Chemistry, State Key Laboratory of Synthetic ChemistryThe University of Hong KongPokfulamHong Kong
| | - Clive Yik Sham Chung
- School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Lung‐Yi Mak
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Danny Ka Ho Wong
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Man‐Fung Yuen
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - James Chung Man Ho
- Department of Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Herbert Pang
- School of Public Health, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Maria Pik Wong
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Carmen Oi‐Ning Leung
- Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityKowloonHong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityKowloonHong Kong
| | - Victor Ma
- Department of Clinical OncologyQueen Elizabeth HospitalKowloonHong Kong
| | | | - Peihua Cao
- Department of Hepatobiliary Surgery II, Zhujiang HospitalSouthern Medical UniversityGuangzhou510280China
- Clinical Research CenterZhujiang HospitalSouthern Medical UniversityGuangzhou510280China
| | - Xiaoping Xu
- Department of Hepatobiliary Surgery II, Zhujiang HospitalSouthern Medical UniversityGuangzhou510280China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Zhujiang HospitalSouthern Medical UniversityGuangzhou510280China
- Guangdong Provincial Research Center of Artificial Organ and Tissue Engineering, Zhujiang HospitalSouthern Medical UniversityGuangzhou510280China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
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14
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Heib M, Rose-John S, Adam D. Necroptosis, ADAM proteases and intestinal (dys)function. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 353:83-152. [PMID: 32381179 DOI: 10.1016/bs.ircmb.2020.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Recently, an unexpected connection between necroptosis and members of the a disintegrin and metalloproteinase (ADAM) protease family has been reported. Necroptosis represents an important cell death routine which helps to protect from viral, bacterial, fungal and parasitic infections, maintains adult T cell homeostasis and contributes to the elimination of potentially defective organisms before parturition. Equally important for organismal homeostasis, ADAM proteases control cellular processes such as development and differentiation, immune responses or tissue regeneration. Notably, necroptosis as well as ADAM proteases have been implicated in the control of inflammatory responses in the intestine. In this review, we therefore provide an overview of the physiology and pathophysiology of necroptosis, ADAM proteases and intestinal (dys)function, discuss the contribution of necroptosis and ADAMs to intestinal (dys)function, and review the current knowledge on the role of ADAMs in necroptotic signaling.
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Affiliation(s)
- Michelle Heib
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Dieter Adam
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
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15
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Markotic A, Flegar D, Grcevic D, Sucur A, Lalic H, Turcic P, Kovacic N, Lukac N, Pravdic D, Vukojevic K, Cavar I, Kelava T. LPS-induced inflammation desensitizes hepatocytes to Fas-induced apoptosis through Stat3 activation-The effect can be reversed by ruxolitinib. J Cell Mol Med 2020; 24:2981-2992. [PMID: 32022429 PMCID: PMC7077556 DOI: 10.1111/jcmm.14930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/05/2019] [Accepted: 12/15/2019] [Indexed: 12/12/2022] Open
Abstract
Recent studies have established a concept of tumour necrosis factor‐α (TNF‐α)/Fas signalling crosstalk, highlighting TNF‐α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF‐α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS‐induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase‐8 level. Analysis of molecular mechanisms revealed an increased expression of various pro‐inflammatory cytokines in non‐parenchymal liver cells and hepatocyte‐specific increase in Bcl‐xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre‐treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS‐induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas‐mediated apoptosis. Furthermore, ruxolitinib pre‐treatment diminished the LPS‐induced Bcl‐xL up‐regulation without an inhibitory effect on LPS‐induced expression of pro‐inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro‐inflammatory mediators, such as TNF‐α or neutrophils, are pro‐apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3‐dependent desensitization to Fas‐mediated apoptosis.
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Affiliation(s)
- Antonio Markotic
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Center for Clinical Pharmacology, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Darja Flegar
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Danka Grcevic
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alan Sucur
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Lalic
- Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Petra Turcic
- Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Natasa Kovacic
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Anatomy, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nina Lukac
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Anatomy, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Danijel Pravdic
- Department of Physiology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina.,University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Katarina Vukojevic
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Split, Croatia.,Department of Medical Genetics, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
| | - Ivan Cavar
- Department of Physiology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina.,University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Tomislav Kelava
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
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16
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Sundaram B, Behnke K, Belancic A, Al-Salihi MA, Thabet Y, Polz R, Pellegrino R, Zhuang Y, Shinde PV, Xu HC, Vasilevska J, Longerich T, Herebian D, Mayatepek E, Bock HH, May P, Kordes C, Aghaeepour N, Mak TW, Keitel V, Häussinger D, Scheller J, Pandyra AA, Lang KS, Lang PA. iRhom2 inhibits bile duct obstruction-induced liver fibrosis. Sci Signal 2019; 12:12/605/eaax1194. [PMID: 31662486 DOI: 10.1126/scisignal.aax1194] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor-α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2-/- ) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2-/- mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.
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Affiliation(s)
- Balamurugan Sundaram
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Kristina Behnke
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Andrea Belancic
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Mazin A Al-Salihi
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Yasser Thabet
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Robin Polz
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Rossella Pellegrino
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
| | - Yuan Zhuang
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Prashant V Shinde
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Haifeng C Xu
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Jelena Vasilevska
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Hans H Bock
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Petra May
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Claus Kordes
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.,Institute for Experimental Regenerative Hepatology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Nima Aghaeepour
- Stanford University, 300 Pasteur Drive, Grant S280, Stanford, CA 94305-5117, USA
| | - Tak W Mak
- Department of Medical Biophysics, University of Toronto, 1 King's Circle, Toronto, ON M5S 1A8, Canada.,Department of Pathology, University of Hong Kong, Hong Kong
| | - Verena Keitel
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.,Institute for Experimental Regenerative Hepatology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Aleksandra A Pandyra
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Karl S Lang
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany
| | - Philipp A Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
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17
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Duan B, Liu Y, Hu H, Shi FG, Liu YL, Xue H, Yun XY, Yan MY, Han XR, Chen AF, Wang Y, Li ZH. Notch1-ADAM8 positive feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression. Cell Commun Signal 2019; 17:134. [PMID: 31640732 PMCID: PMC6805603 DOI: 10.1186/s12964-019-0443-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 09/20/2019] [Indexed: 12/14/2022] Open
Abstract
Background Osteoarthritis (OA) is one of the most prevalent joint disease, and there are still no effective therapeutic agents or clinical methods for the cure of this disease to date. The degradation of cartilage extracellular matrix (ECM) is a major cause of OA. Method IL-1β was used to induce chondrogenic degradation. Q-PCR and Western blotting were used to detect mRNA and protein level, respectively. ELISA was used to detect the secreted TNF-α and IL-6 level. Immunofluorescence was used to detect the protein level of Aggrecan, Collagen II and ki67. TUNEL and flow cytometry were used to examine cell apoptosis of chondrocytes. ChIP and luciferase assay were used to study molecular gene regulation. Osteoarthritic animal model and Safranin-O staining were used to determine the in vivo OA phenotype. Results The expression of ADAM8 was up-regulated in osteoarthritic chondrocytes. Knockdown of ADAM8 suppressed the OA phenotype in the in vitro OA cell model. ADAM8 regulated OA progression through the activation of EGFR/ERK/NF-κB signaling pathway. Inhibition of Notch signaling suppressed OA phenotype in the in vitro OA cell model. Notch signaling regulated the gene expression of ADAM8 directly via Hes1. Notch1-ADAM8 positive feedback loop promoted the progression of OA in vivo. Conclusion Notch1-ADAM8 feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression.
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Affiliation(s)
- Biao Duan
- Reproductive Center, Ganzhou People's Hospital, No.17 Hongqi Avenue, Zhanggong District, Ganzhou, 314000, People's Republic of China.,Inner Mongolia Medical University, Jinshan District, Hohhot, 010110, People's Republic of China
| | - Yan Liu
- Department of Orthopedics, Inner Mongolia Medical University Third Affiliated Hospital, No.20 Shaoxian Road, Kundulun District, Baotou, 014000, People's Republic of China
| | - He Hu
- Department of Orthopedics, Inner Mongolia People's Hospital, No.20 Zhaowuda Road, Saihan District, Hohhot, 010017, People's Republic of China
| | - Fu-Guo Shi
- Department of Chinese medicine, Preventive health center of Baotou steel group, Aerding Street, Kundulun District, Baotou, 014000, People's Republic of China
| | - Ya-Long Liu
- Department of Orthopedics, Yangling Demonstration District Hospital, No.8 Houji Road, Yangling District, Xianyan, 712100, People's Republic of China
| | - Hao Xue
- Department of Pediatric Orthopedics, Fourth Hospital of Baotou, Aogen Road, Qingshan District, Baotou, 014010, People's Republic of China
| | - Xin-Yu Yun
- Department of Orthopedics, Inner Mongolia Medical University Third Affiliated Hospital, No.20 Shaoxian Road, Kundulun District, Baotou, 014000, People's Republic of China
| | - Ming-Yu Yan
- Department of Orthopedics, Inner Mongolia Medical University Third Affiliated Hospital, No.20 Shaoxian Road, Kundulun District, Baotou, 014000, People's Republic of China
| | - Xi-Rui Han
- Department of Orthopedics, Peking University Third Hospital, No.10 Courtyard, Chedaogou, Haidian District, Beijing, 100083, People's Republic of China
| | - An-Fu Chen
- Department of Orthopedics, Peking University Third Hospital, No.10 Courtyard, Chedaogou, Haidian District, Beijing, 100083, People's Republic of China
| | - Yong Wang
- Department of Orthopedics, Peking University Third Hospital, No.10 Courtyard, Chedaogou, Haidian District, Beijing, 100083, People's Republic of China
| | - Zhe-Hai Li
- Inner Mongolia Medical University, Jinshan District, Hohhot, 010110, People's Republic of China. .,Department of Orthopedics, Peking University Third Hospital, No.10 Courtyard, Chedaogou, Haidian District, Beijing, 100083, People's Republic of China.
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18
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Abstract
Eicosanoids are bioactive lipids that play crucial roles in various pathophysiological conditions, including inflammation and cancer. They include both the COX-derived prostaglandins and the LOX-derived leukotrienes. Furthermore, the epidermal growth factor receptor (EGFR) pathways family of receptor tyrosine kinases also are known to play a central role in the tumorigenesis. Various antitumor modalities have been approved cancer treatments that target therapeutically the COX-2 and EGFR pathways; these include selective COX-2 inhibitors and EGFR monoclonal antibodies. Research has shown that the COX-2 and epidermal growth factor receptor pathways actively interact with each other in order to orchestrate carcinogenesis. This has been used to justify a targeted combinatorial approach aimed at these two pathways. Although combined therapies have been found to have a greater antitumor effect than the administration of single agent, this does not exempt them from the possible fatal cardiac effects that are associated with COX-2 inhibition. In this review, we delineate the contribution of HB-EGF, an important EGFR ligand, to the cardiac dysfunction related to decreased shedding of HB-EGF after COX-2/PGE2 inhibition. A better understanding of the molecular mechanisms underlying these cardiac side effects will make possible more effective regimens that use the dual-targeting approach.
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Affiliation(s)
- Cheng-Chieh Yang
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
- School of Dentistry, National Yang-Ming University, Taipei, Taiwan
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuo-Wei Chang
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
- School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
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Dreschers S, Platen C, Ludwig A, Gille C, Köstlin N, Orlikowsky TW. Metalloproteinases TACE and MMP-9 Differentially Regulate Death Factors on Adult and Neonatal Monocytes After Infection with Escherichia coli. Int J Mol Sci 2019; 20:ijms20061399. [PMID: 30897723 PMCID: PMC6471605 DOI: 10.3390/ijms20061399] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 01/22/2019] [Accepted: 02/28/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Cleaving ligands and receptors of the tumor necrosis factor (TNF) superfamily can critically regulate the induction of apoptosis. Matrix metalloproteinases (MMPs) such as MMP-9 and tumor necrosis factor-α-converting enzyme (TACE) have been shown to cleave CD95-Ligand (CD95L) and TNF/(TNF receptor-1) TNFR1 which induce phagocytosis induced cell death (PICD) in adult monocytes. This process is reduced in neonatal monocytes. Methods: Here we tested in vitro, whether Escherichia coli infection mounts for activation of MMP-9 and TACE in monocytes and whether this process regulates PICD. Results: The surface expression of TACE was most prominent on infected adult monocytes. In contrast, surface presentation of MMP-9 was highest on infected neonatal monocytes. Selective blocking of MMP-9 decreased CD95L secretion, while inhibition of TACE left CD95L secretion unaltered. Blocking of MMP-9 increased surface CD95L (memCD95L) expression on infected neonatal monocytes to levels comparable to infected adult monocytes. Moreover, MMP-9 inhibition raised PICD of infected neonatal monocytes to levels observed for infected adult monocytes. In contrast, TACE inhibition decreased PICD in infected monocytes. Addition of extracellular TNF effectively induced memCD95L presentation and PICD of adult monocytes and less of neonatal monocytes. Conclusion: MMP-9 activity is crucial for downregulating cell-contact dependent PICD in E. coli infected neonatal monocytes. By this mechanism, MMP-9 could contribute to reducing sustained inflammation in neonates.
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Affiliation(s)
- Stephan Dreschers
- Department of Neonatology, University Children's Hospital, Aachen 52074, Germany.
| | - Christopher Platen
- Department of Neonatology, University Children's Hospital, Aachen 52074, Germany.
| | - Andreas Ludwig
- Department of Pharmacology and Toxicology, University Hospital, Aachen 52074, Germany.
| | - Christian Gille
- Department of Neonatology, University Children's Hospital, Tuebingen 72074, Germany.
| | - Natascha Köstlin
- Department of Pharmacology and Toxicology, University Hospital, Aachen 52074, Germany.
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20
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Liang XQ, Liang J, Zhao XF, Wang XY, Deng X. Integrated network analysis of transcriptomic and protein-protein interaction data in taurine-treated hepatic stellate cells. World J Gastroenterol 2019; 25:1067-1079. [PMID: 30862995 PMCID: PMC6406182 DOI: 10.3748/wjg.v25.i9.1067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/24/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Studies show that the antifibrotic mechanism of taurine may involve its inhibition of the activation and proliferation of hepatic stellate cells (HSCs). Since the molecular mechanism of taurine-mediated antifibrotic activity has not been fully unveiled and is little studied, it is imperative to use “omics” methods to systematically investigate the molecular mechanism by which taurine inhibits liver fibrosis.
AIM To establish a network including transcriptomic and protein-protein interaction data to elucidate the molecular mechanism of taurine-induced HSC apoptosis.
METHODS We used microarrays, bioinformatics, protein-protein interaction (PPI) network, and sub-modules to investigate taurine-induced changes in gene expression in human HSCs (LX-2). Subsequently, all of the differentially expressed genes (DEGs) were subjected to gene ontology function and Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Furthermore, the interactions of DEGs were explored in a human PPI network, and sub-modules of the DEGs interaction network were analyzed using Cytoscape software.
RESULTS A total of 635 DEGs were identified in taurine-treated HSCs when compared with the controls. Of these, 304 genes were statistically significantly up-regulated, and 331 down-regulated. Most of these DEGs were mainly located on the membrane and extracellular region, and are involved in the biological processes of signal transduction, cell proliferation, positive regulation of extracellular regulated protein kinases 1 (ERK1) and ERK2 cascade, extrinsic apoptotic signaling pathway and so on. Fifteen significantly enriched pathways with DEGs were identified, including mitogen-activated protein kinase (MAPK) signaling pathway, peroxisome proliferators-activated receptor signaling pathway, estrogen signaling pathway, Th1 and Th2 cell differentiation, cyclic adenosine monophosphate signaling pathway and so on. By integrating the transcriptomics and human PPI data, nine critical genes, including MMP2, MMP9, MMP21, TIMP3, KLF10, CX3CR1, TGFB1, VEGFB, and EGF, were identified in the PPI network analysis.
CONCLUSION Taurine promotes the apoptosis of HSCs via up-regulating TGFB1 and then activating the p38 MAPK-JNK-Caspase9/8/3 pathway. These findings enhance the understanding of the molecular mechanism of taurine-induced HSC apoptosis and provide references for liver disorder therapy.
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Affiliation(s)
- Xing-Qiu Liang
- Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - Jian Liang
- College of Medical, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Fang Zhao
- Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - Xin-Yuan Wang
- School of Basic Sciences, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Xin Deng
- School of Basic Sciences, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
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21
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Chen Y, Aiken A, Saw S, Weiss A, Fang H, Khokha R. TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass. J Bone Miner Res 2019; 34:182-194. [PMID: 30216540 DOI: 10.1002/jbmr.3585] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/17/2018] [Accepted: 08/25/2018] [Indexed: 12/17/2022]
Abstract
Deregulated proteolysis invariably underlies most human diseases including bone pathologies. Metalloproteinases constitute the largest of the five protease families, and the metzincin metalloproteinases are inhibited by the four tissue inhibitors of metalloproteinase called TIMPs. We hypothesized that Timp genes are essential for skeletal homeostasis. We bred individual Timp knockout mice to generate unique mouse models, the quadruple Timp null strain (QT) as well as mice harboring only a single Timp3 allele (QT3+/- ). QT mice are grossly smaller and exhibit a dramatic reduction of trabeculae in long bones by μCT imaging with a corresponding increase in metalloproteinase activity. At the cellular level, Timp deficiency compromised differentiation markers, matrix deposition and mineralization in neonatal osteoblasts from calvariae, as well as the fibroblastic colony-forming unit (CFU-F) capacity of bone marrow-derived stromal cells. In contrast, we observed that osteoclasts were overactive in the Timp null state, consistent with the noted excessive bone resorption of QT bones. Immunohistochemistry (IHC) and immunofluorescence (IF) analyses of bone sections revealed higher Cathepsin K and RANKL signals upon Timp loss. Seeking the molecular mechanism, we identified abnormal TNFα bioactivity to be a central event in Timp-deficient mice. Specifically, TNFα triggered induction of the Wnt signaling inhibitor Dkk1 in the osteoblasts at the mRNA and protein levels, with a simultaneous increase in RANKL. Neutralizing TNFα antibody was capable of rescuing the induction of Dkk1 as well as RANKL. Therefore, the generation of novel Timp-deficient systems allowed us to uncover the essential and collective function of TIMP proteins in mammalian long-bone homeostasis. Moreover, our study discovers a functional TIMP/metalloproteinase-TNFα-Dkk1/RANKL nexus for optimal control of the bone microenvironment, which dictates coexistence of the osteoblast and osteoclast lineages. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Yan Chen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Alison Aiken
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Sanjay Saw
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Ashley Weiss
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Hui Fang
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Rama Khokha
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
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22
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Veit M, Koyro KI, Ahrens B, Bleibaum F, Munz M, Rövekamp H, Andrä J, Schreiber R, Kunzelmann K, Sommer A, Bhakdi S, Reiss K. Anoctamin-6 regulates ADAM sheddase function. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2018; 1865:1598-1610. [PMID: 30327201 DOI: 10.1016/j.bbamcr.2018.08.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 08/17/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023]
Abstract
ADAM17, a prominent member of the "Disintegrin and Metalloproteinase" (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates including TGF-alpha, Amphiregulin (AREG) and TNF-Receptor 1 (TNFR1). We recently presented evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. Anoctamin-6 (ANO6) has Ca2+-dependent phospholipid scramblase activity and it followed that the functions of ANO6 and ADAM17 might be linked. We report that overexpression of ANO6 in HEK293T cells led to increased Ca2+-mediated PS-exposure that was indeed accompanied by enhanced release of AREG and TGF-alpha. The effect was not observed when cells were treated with the PKC-dependent ADAM17 activator PMA. Transformation of cells with a constitutively active ANO6 mutant led to spontaneous PS-exposure and to the release of ADAM17-substrates in the absence of any stimuli. Inhibitor experiments indicated that ANO6-mediated enhancement of substrate cleavage simultaneously broadened the spectrum of participating metalloproteinases. In complementary experiments, siRNA-mediated downregulation of ANO6 was shown to decrease ionophore-mediated release of TNFR1 in human umbilical vein endothelial cells (HUVECs). We conclude that ANO6, by virtue of its scramblase activity, may play a role as an important regulator of the ADAM-network in the plasma membrane.
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Affiliation(s)
- Martin Veit
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany
| | | | - Björn Ahrens
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany
| | | | - Martin Munz
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Hagen Rövekamp
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Jörg Andrä
- Hamburg University of Applied Science, Ulmenliet 20, 21033 Hamburg, Germany
| | - Rainer Schreiber
- Physiological Institute, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany
| | - Karl Kunzelmann
- Physiological Institute, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany
| | - Anselm Sommer
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Sucharit Bhakdi
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Karina Reiss
- Dept. of Dermatology, University of Kiel, 24105 Kiel, Germany.
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23
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Inhibition of miR-21 ameliorates excessive astrocyte activation and promotes axon regeneration following optic nerve crush. Neuropharmacology 2018; 137:33-49. [PMID: 29709341 DOI: 10.1016/j.neuropharm.2018.04.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/18/2018] [Accepted: 04/26/2018] [Indexed: 12/15/2022]
Abstract
Optic nerve injury is a leading cause of irreversible visual impairment worldwide and can even cause blindness. Excessive activation of astrocytes has negative effects on the repair and recovery of retinal ganglion cells following optic nerve injury. However, the molecular and cellular mechanisms underlying astrocyte activation after optic nerve injury remain largely unknown. In the present study, we explored the effects of microRNA-21 (miR-21) on axon regeneration and flash visual evoked potential (F-VEP) and the underlying mechanisms of these effects based on astrocyte activation in the rat model of optic nerve crush (ONC). To the best of our knowledge, this article is the first to report that inhibition of miR-21 enhances axonal regeneration and promotes functional recovery in F-VEP in the rat model of ONC. Furthermore, inhibition of miR-21 attenuates excessive astrocyte activation and glial scar formation, thereby promoting axonal regeneration by regulating the epidermal growth factor receptor (EGFR) pathway. In addition, we observed that the expression of tissue inhibitor of metalloproteinase-3, a target gene of miR-21, was inhibited during this process. Taken together, these findings demonstrate that inhibition of miR-21 regulates the EGFR pathway, ameliorating excessive astrocyte activation and glial scar progression and promoting axonal regeneration and alleviating impairment in F-VEP function in a model of ONC. This study's results suggest that miR-21 may represent a therapeutic target for optic nerve injury.
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24
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Liang D, Chen H, Zhao L, Zhang W, Hu J, Liu Z, Zhong P, Wang W, Wang J, Liang G. Inhibition of EGFR attenuates fibrosis and stellate cell activation in diet-induced model of nonalcoholic fatty liver disease. Biochim Biophys Acta Mol Basis Dis 2018; 1864:133-142. [PMID: 29038049 DOI: 10.1016/j.bbadis.2017.10.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 09/27/2017] [Accepted: 10/11/2017] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD begins with steatosis and advances to nonalcoholic steatohepatitis (NASH) and cirrhosis. The molecular mechanisms involved in NAFLD progression are not understood. Based on recent studies showing dysregulation of epidermal growth factor receptor (EGFR) in animal models of liver injury, we sought to determine if inhibition of EGFR mitigates liver fibrosis and HSC activation in NAFLD. We utilized the high fat diet (HFD)-induced murine model of liver injury to study the role of EGFR in NAFLD. The lipid accumulation, oxidative stress, hepatic stellate cell (HSC) activation and matrix deposition were examined in the liver tissues. We also evaluated the EGFR signaling pathway, ROS activation and pro-fibrogenic phenotype in oxidized low density lipoproteins (ox-LDL) challenged cultured HSCs. We demonstrate that EGFR was phosphorylated in liver tissues of HFD murine model of NAFLD. Inhibition of EGFR prevented diet-induced lipid accumulation, oxidative stress, and HSC activation and matrix deposition. In cultured HSCs, we show that ox-LDL caused rapid activation of the EGFR signaling pathway and induce the production of reactive oxygen species. EGFR also mediated HSC activation and promoted a pro-fibrogenic phenotype. In conclusion, our data demonstrate that EGFR plays an important role in NAFLD and is an attractive target for NAFLD therapy.
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Affiliation(s)
- Dandan Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hongjin Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou 325000, China
| | - Leping Zhao
- Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou 325000, China
| | - Wenxin Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jie Hu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhiguo Liu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Peng Zhong
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei Wang
- School of Medicine, Qingdao University, Qingdao, Shandong 266071, China
| | - Jingying Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou 325000, China.
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25
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Nam EJ, Hayashida K, Aquino RS, Couchman JR, Kozar RA, Liu J, Park PW. Syndecan-1 limits the progression of liver injury and promotes liver repair in acetaminophen-induced liver injury in mice. Hepatology 2017; 66:1601-1615. [PMID: 28543100 PMCID: PMC6516470 DOI: 10.1002/hep.29265] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 05/02/2017] [Indexed: 12/18/2022]
Abstract
UNLABELLED Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. Although mechanisms that trigger APAP-induced liver injury (AILI) are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injury in vivo remains unknown. Here, we examined the role of syndecan-1, the major cell-surface HSPG of hepatocytes, in AILI. Ablation of syndecan-1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times post-APAP overdose were unaffected by syndecan-1, suggesting that syndecan-1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan-1 null (Sdc1-/- ) mice were traced to a deficiency in protein kinase B (Akt) activation in hepatocytes, which led to a delayed increase in glycogen synthase kinase-3β (GSK-3β)-mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK-3β and caspases protected mice from AILI. Moreover, administration of purified syndecan-1, HS, or engineered heparan compounds containing 2-O-sulfate groups rescued Sdc1-/- mice from AILI by potentiating Akt signaling and inhibiting GSK-3β-mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared to N-acetylcysteine. CONCLUSION These results demonstrate that 2-O-sulfated domains in syndecan-1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in AILI. We propose that syndecan-1 is a critical endogenous factor that controls the balance between prosurvival signaling and apoptosis in hepatocytes in APAP liver disease. (Hepatology 2017;66:1601-1615).
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Affiliation(s)
- Eon Jeong Nam
- Division of Respiratory Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Kazutaka Hayashida
- Division of Respiratory Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Rafael S. Aquino
- Division of Respiratory Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - John R. Couchman
- Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark
| | | | - Jian Liu
- Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, NC
| | - Pyong Woo Park
- Division of Respiratory Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA
- Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA
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Zunke F, Rose-John S. The shedding protease ADAM17: Physiology and pathophysiology. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:2059-2070. [DOI: 10.1016/j.bbamcr.2017.07.001] [Citation(s) in RCA: 237] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 07/08/2017] [Accepted: 07/09/2017] [Indexed: 02/07/2023]
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Sommer A, Düppe M, Baumecker L, Kordowski F, Büch J, Chico JF, Fritsch J, Schütze S, Adam D, Sperrhacke M, Bhakdi S, Reiss K. Extracellular sphingomyelinase activity impairs TNF-α-induced endothelial cell death via ADAM17 activation and TNF receptor 1 shedding. Oncotarget 2017; 8:72584-72596. [PMID: 29069811 PMCID: PMC5641154 DOI: 10.18632/oncotarget.19983] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 07/11/2017] [Indexed: 12/21/2022] Open
Abstract
ADAM17, a prominent member of the “Disintegrin and Metalloproteinase” (ADAM) family, is an important regulator of endothelial cell proliferation and cell survival. The protease controls vital cellular functions through cleavage of growth factors, cytokines and their receptors including transforming growth factor-alpha (TGF-α), tumor necrosis factor-alpha (TNF-α) and TNF-α receptor 1 (TNFR1). TNF-α is the major inducer of endothelial cell death in cardiovascular diseases. The latter are also characterized by elevated plasma and tissue levels of extracellular sphingomyelinase (SMase). Whether the SMase affects ADAM activity and thus endothelial cell function has not been addressed to date. Here, we analyzed the effect of SMase on ADAM17-mediated shedding in COS7 cells and in human umbilical vein endothelial cells (HUVECs). Exposure to SMase significantly increased ADAM17-mediated release of alkaline-phosphatase (AP)-tagged TGF-α in COS7 cells and shedding of endogenously expressed TNFR1 in HUVECs. We previously presented evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase function. We found that SMase treatment led to PS externalization in both cell types. Transient non-apoptotic PS exposure is often mediated by Ca2+-dependent phospholipid scramblases. Accordingly, the Ca2+-chelator EGTA markedly reduced the breakdown of phospholipid asymmetry and shedding of TGF-α and TNFR1. Moreover, sheddase activity was significantly diminished in the presence of the competing PS-headgroup OPLS. SMase-stimulated TNFR1 shedding strikingly diminished TNF-α-induced signalling cascades and endothelial cell death. Taken together, our data suggest that SMase activity might act as protective factor for endothelial cells in cardiovascular diseases.
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Affiliation(s)
- Anselm Sommer
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Marie Düppe
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Lena Baumecker
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Felix Kordowski
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Joscha Büch
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | | | - Jürgen Fritsch
- Institute of Immunology, University of Kiel, 24105 Kiel, Germany
| | - Stefan Schütze
- Institute of Immunology, University of Kiel, 24105 Kiel, Germany
| | - Dieter Adam
- Institute of Immunology, University of Kiel, 24105 Kiel, Germany
| | - Maria Sperrhacke
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Sucharit Bhakdi
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
| | - Karina Reiss
- Department of Dermatology, University of Kiel, 24105 Kiel, Germany
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Iwona BS. Growth Factors in the Pathogenesis of Retinal Neurodegeneration in Diabetes Mellitus. Curr Neuropharmacol 2017; 14:792-804. [PMID: 27528260 PMCID: PMC5333593 DOI: 10.2174/1570159x14666160813182009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 11/12/2015] [Accepted: 01/06/2015] [Indexed: 12/13/2022] Open
Abstract
Neurodegeneration is an initial process in the development of diabetic retinopathy (DR). High quantities of glutamate, oxidative stress, induction of the renin-angiotensin system (RAS) and elevated levels of RAGE are crucial elements in the retinal neurodegeneration caused by diabetes mellitus. At least, there is emerging proof to indicate that the equilibrium between the neurotoxic and neuroprotective components will affect the state of the retinal neurons. Somatostatin (SST), pigment epithelium-derived factor (PEDF), and erythropoietin (Epo) are endogenous neuroprotective peptides that are decreased in the eye of diabetic persons and play an essential role in retinal homeostasis. On the other hand, insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) are pivotal proteins which participate in the development of new capillaries and finally cause damage to the retinal neurons. During recent years, our knowledge about the function of growth factors in the pathogenesis of retinal neurodegeneration has increased. However, intensive investigations are needed to clarify the basic processes that contribute to retinal neurodegeneration and its association with damage to the capillary blood vessels. The objective of this review article is to show new insights on the role of neurotransmitters and growth factors in the pathogenesis of diabetic retinopathy. The information contained in this manuscript may provide the basis for novel strategies based on the factors of neurodegeneration to diagnose, prevent and treat DR in its earliest phases.
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Affiliation(s)
- Ben-Skowronek Iwona
- Department Pediatric Endocrinology and Diabetology, Medical University of Lublin, ul. Prof. A. Gebali 6, 20-093 Lublin, Poland
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Abstract
A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis.
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Affiliation(s)
- Hartland W Jackson
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
- Bodenmiller Laboratory, University of Zürich, Institute for Molecular Life Sciences, Winterthurstrasse 190, 8057 Zürich, Switzerland
| | - Virginie Defamie
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
| | - Paul Waterhouse
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
| | - Rama Khokha
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Centre, TMDT 301-13, 101 College Street, Toronto, Ontario, M5G IL7 Canada
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Miller MA, Sullivan RJ, Lauffenburger DA. Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer. Clin Cancer Res 2016; 23:623-629. [PMID: 27895032 DOI: 10.1158/1078-0432.ccr-16-0869] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 11/01/2016] [Accepted: 11/01/2016] [Indexed: 12/21/2022]
Abstract
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL6R; the Notch receptors; type-I and -III TGFβ receptors; receptor tyrosine kinases (RTK) such as HER2, HER4, and VEGFR2; and, in particular, MET and TAM-family RTKs AXL and Mer (MerTK). Activation of receptor shedding by mechanical cues, hypoxia, radiation, and phosphosignaling offers insight into mechanisms of drug resistance. This particularly holds for kinase inhibitors targeting BRAF (such as vemurafenib and dabrafenib) and MEK (such as trametinib and cobimetinib), along with direct sheddase inhibitors. Receptor proteolysis can be detected in patient fluids and is especially relevant in melanoma, glioblastoma, lung cancer, and triple-negative breast cancer where RTK substrates, MAPK signaling, and ADAMs are frequently dysregulated. Translatable strategies to exploit receptor shedding include combination kinase inhibitor regimens, recombinant decoy receptors based on endogenous counterparts, and, potentially, immunotherapy. Clin Cancer Res; 23(3); 623-9. ©2016 AACR.
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Affiliation(s)
- Miles A Miller
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ryan J Sullivan
- Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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Altara R, Booz GW. Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy. Hypertension 2016; 68:849-50. [DOI: 10.1161/hypertensionaha.116.07715] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Raffaele Altara
- From the Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson
| | - George W. Booz
- From the Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson
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Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells. Oncotarget 2016; 6:32138-53. [PMID: 26451607 PMCID: PMC4741664 DOI: 10.18632/oncotarget.5171] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 09/24/2015] [Indexed: 01/16/2023] Open
Abstract
CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells.
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Komposch K, Sibilia M. EGFR Signaling in Liver Diseases. Int J Mol Sci 2015; 17:E30. [PMID: 26729094 PMCID: PMC4730276 DOI: 10.3390/ijms17010030] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 12/17/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
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Affiliation(s)
- Karin Komposch
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
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Wang CY, Liou JP, Tsai AC, Lai MJ, Liu YM, Lee HY, Wang JC, Pan SL, Teng CM. A novel action mechanism for MPT0G013, a derivative of arylsulfonamide, inhibits tumor angiogenesis through up-regulation of TIMP3 expression. Oncotarget 2015; 5:9838-50. [PMID: 25226613 PMCID: PMC4259441 DOI: 10.18632/oncotarget.2451] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Tissue inhibitors of metalloproteinases 3 (TIMP3) were originally characterized as inhibitors of matrix metalloproteinases (MMPs), acting as potent antiangiogenic proteins. In this study, we demonstrated that the arylsulfonamide derivative MPT0G013 has potent antiangiogenic activities in vitro and in vivo via inducing TIMP3 expression. Treatments with MPT0G013 significantly inhibited endothelial cell functions, such as cell proliferation, migration, and tube formation, as well as induced p21 and cell cycle arrest at the G0/G1 phase. Subsequent microarray analysis showed significant induction of TIMP3 gene expression by MPT0G013, and siRNA-mediated blockage of TIMP3 up-regulation abrogated the antiangiogenic activities of MPT0G013 and prevented inhibition of p-AKT and p-ERK proteins. Importantly, MPT0G013 exhibited antiangiogenic activities in in vivo Matrigel plug assays, inhibited tumor growth and up-regulated TIMP3 and p21 proteins in HCT116 mouse xenograft models. These data suggest potential therapeutic application of MPT0G013 for angiogenesis-related diseases such as cancer.
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Affiliation(s)
- Chih-Ya Wang
- Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jing-Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - An-Chi Tsai
- The Ph.D. program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Mei-Jung Lai
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Yi-Min Liu
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Hsueh-Yun Lee
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Jing-Chi Wang
- The Ph.D. program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Shiow-Lin Pan
- The Ph.D. program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Che-Ming Teng
- Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan
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Fan D, Takawale A, Shen M, Wang W, Wang X, Basu R, Oudit GY, Kassiri Z. Cardiomyocyte A Disintegrin And Metalloproteinase 17 (ADAM17) Is Essential in Post-Myocardial Infarction Repair by Regulating Angiogenesis. Circ Heart Fail 2015; 8:970-9. [PMID: 26136458 DOI: 10.1161/circheartfailure.114.002029] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 06/17/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme that mediates shedding of many membrane-bound molecules, thereby regulating multiple cellular responses. We investigated the role of cardiomyocyte ADAM17 in myocardial infarction (MI). METHODS AND RESULTS Cardiomyocyte-specific ADAM17 knockdown mice (ADAM17(flox/flox)/α-MHC-Cre; f/f/Cre) and parallel controls (ADAM17(flox/flox); f/f) were subjected to MI by ligation of the left anterior descending artery. Post MI, f/f/Cre mice showed compromised survival, higher rates of cardiac rupture, more severe left ventricular dilation, and suppressed ejection fraction compared with parallel f/f-MI mice. Ex vivo ischemic injury (isolated hearts) resulted in comparable recovery in both genotypes. Myocardial vascular density (fluorescent-labeled lectin perfusion and CD31 immunofluorescence staining) was significantly lower in the infarct areas of f/f/Cre-MI compared with f/f-MI mice. Activation of vascular endothelial growth factor receptor 2 (VEGFR2), its mRNA, and total protein levels were reduced in infarcted myocardium in ADAM17 knockdown mice. Transcriptional regulation of VEGFR2 by ADAM17 was confirmed in cocultured cardiomyocyte-fibroblast as ischemia-induced VEGFR2 expression was blocked by ADAM17-siRNA. Meanwhile, ADAM17-siRNA did not alter VEGFA bioavailability in the conditioned media. ADAM17 knockdown mice (f/f/Cre-MI) exhibited reduced nuclear factor-κB activation (DNA binding) in the infarcted myocardium, which could underlie the suppressed VEGFR2 expression in these hearts. Post MI, inflammatory response was not altered by ADAM17 downregulation. CONCLUSIONS This study highlights the key role of cardiomyocyte ADAM17 in post-MI recovery by regulating VEGFR2 transcription and angiogenesis, thereby limiting left ventricular dilation and dysfunction. Therefore, ADAM17 upregulation, within the physiological range, could provide protective effects in ischemic cardiomyopathy.
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Affiliation(s)
- Dong Fan
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Abhijit Takawale
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Mengcheng Shen
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Wang Wang
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Xiuhua Wang
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Ratnadeep Basu
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Gavin Y Oudit
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Zamaneh Kassiri
- From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
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WEI ZIJIAN, YU DESHUI, BI YUNLONG, CAO YANG. A disintegrin and metalloprotease 17 promotes microglial cell survival via epidermal growth factor receptor signalling following spinal cord injury. Mol Med Rep 2015; 12:63-70. [PMID: 25738567 PMCID: PMC4438914 DOI: 10.3892/mmr.2015.3395] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 12/12/2014] [Indexed: 12/16/2022] Open
Abstract
Tumour necrosis factor-α (TNF-α) converting enzyme (TACE), also termed a disintegrin and metalloprotease 17 (ADAM17), is involved in multiple cell signalling pathways. Through the secretion of epidermal growth factor receptor (EGFR) ligands, ADAM17 can activate the EGFR and is involved in various downstream signalling pathways. The present study aimed to investigate whether ADAM17‑induced EGFR transactivation is involved in microglial cell survival following spinal cord injury (SCI). Reverse transcription quantitative polymerase chain reaction and western blot analysis revealed that ADAM17 was overexpressed in a mouse model following SCI. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that the viability of human microglia and oligodendrocytes were significantly reduced in a time- and dose-dependent manner following treatment with the ADAM17 antagonist, TNF protease inhibitor 2. Hoechst 33258 staining and flow cytometric analysis revealed that inhibiting ADAM17 increased the rate of cellular apoptosis in neuronal and glial cell cultures, which was accompanied by increased cleavage of caspase-3. Western blot analysis demonstrated that inhibiting ADAM17 resulted in a reduction in the phosphorylation of the EGFR signalling pathway components and thereby impaired functional recovery, inhibited cell viability and prompted microglial apoptosis following SCI. Pre-treatment with the EGFR inhibitor, AG1478, rescued the ADAM17‑mediated proliferation of microglial cells. These data demonstrated that ADAM17 contributed to microglial cell survival, predominantly by EGFR signalling, following SCI.
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Affiliation(s)
- ZIJIAN WEI
- Graduate School of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - DESHUI YU
- Department of Orthopedics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - YUNLONG BI
- Department of Orthopedics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - YANG CAO
- Department of Orthopedics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
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Jackson HW, Hojilla CV, Weiss A, Sanchez OH, Wood GA, Khokha R. Timp3 deficient mice show resistance to developing breast cancer. PLoS One 2015; 10:e0120107. [PMID: 25807548 PMCID: PMC4373869 DOI: 10.1371/journal.pone.0120107] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3−⁄− mice have delayed tumor onset and 36% of MMTV-Neu Timp3−⁄− mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1.
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Affiliation(s)
| | - Carlo V. Hojilla
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Ashley Weiss
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Otto H. Sanchez
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Geoffrey A. Wood
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
| | - Rama Khokha
- Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
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Bandsma RHJ, van Goor H, Yourshaw M, Horlings RK, Jonkman MF, Schölvinck EH, Karrenbeld A, Scheenstra R, Kömhoff M, Rump P, Koopman-Keemink Y, Nelson SF, Escher JC, Cutz E, Martín MG. Loss of ADAM17 is associated with severe multiorgan dysfunction. Hum Pathol 2015; 46:923-8. [PMID: 25804906 DOI: 10.1016/j.humpath.2015.02.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 02/02/2015] [Accepted: 02/13/2015] [Indexed: 11/25/2022]
Abstract
ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T-cell stimulation assays showed severely diminished tumor necrosis factor-α and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement.
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Affiliation(s)
- Robert H J Bandsma
- The Division of Pediatric Gastroenterology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands.
| | - Harry van Goor
- Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Michael Yourshaw
- Departments of Human Genetics, Pathology and Laboratory Medicine David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Rudolf K Horlings
- Department of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Marcel F Jonkman
- Department of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Elisabeth H Schölvinck
- Division of Pediatric Infectious Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Arend Karrenbeld
- Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Rene Scheenstra
- The Division of Pediatric Gastroenterology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Martin Kömhoff
- Division of Nephrology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Patrick Rump
- Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Yvonne Koopman-Keemink
- The Department of Pediatrics, Hagaziekenhuis Juliana Kinderziekenhuis, Sportlaan 600, 2566 MJ The Hague, the Netherlands
| | - Stanley F Nelson
- Departments of Human Genetics, Pathology and Laboratory Medicine David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Johanna C Escher
- The Department of Pediatric Gastroenterology, Sophia Children's Hospital-Erasmus Medical Center, Dr. Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands
| | - Ernest Cutz
- The Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto M5G 1X8, Canada
| | - Martín G Martín
- Departments of Human Genetics, Pathology and Laboratory Medicine David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
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TIMP3 controls cell fate to confer hepatocellular carcinoma resistance. Oncogene 2014; 34:4098-108. [PMID: 25347747 DOI: 10.1038/onc.2014.339] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 08/29/2014] [Accepted: 09/04/2014] [Indexed: 02/07/2023]
Abstract
Inflammation enables human cancers and is a critical promoter of hepatocellular carcinoma (HCC). TIMP3 (Tissue inhibitor of metalloproteinase 3), a natural metalloproteinase inhibitor, controls cytokine and growth factor bioavailability to keep inflammation in check and regulate cell survival in the liver. TIMP3 is also found silenced in human cancers. We therefore tested whether Timp3 affects HCC predisposition. Remarkably, genetic loss of Timp3 protected from carcinogen-induced HCC through the immediate engagement of several tumor suppressor pathways, while tumor necrosis factor (TNF) signaling was dispensable for this protection. All wild-type mice developed HCC by 12 months, whereas HCC incidence was reduced to 33% at 12 months and 57% at 15 months in Timp3 null mice. Upon acute carcinogen treatment the deficient livers exhibited greater cytokine expression, but lower cell death and higher hepatocyte senescence. We found that precocious activation of p53, p38 and Notch preceded senescence and hepatic cell differentiation, and these events were conserved throughout tumorigenesis. Timp3-deficient mouse embryo fibroblasts also responded to carcinogen by favoring senescence over apoptosis. We conclude that Timp3 status determines p53, p38 and Notch coactivation to instruct hepatic cell fate and transformation and uncover mechanisms that are protective even within a pro-inflammatory microenvironment.
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40
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Lisi S, D'Amore M, Sisto M. ADAM17 at the interface between inflammation and autoimmunity. Immunol Lett 2014; 162:159-69. [PMID: 25171914 DOI: 10.1016/j.imlet.2014.08.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 07/23/2014] [Accepted: 08/11/2014] [Indexed: 02/04/2023]
Abstract
The discovery of the disintegrin and metalloproteinase 17 (ADAM17), originally identified as tumor necrosis factor-a converting enzyme (TACE) for its ability as sheddase of TNF-α inspired scientists to attempt to elucidate the molecular mechanisms underlying ADAM17 implication in diseased conditions. In recent years, it has become evident that this protease can modify many non matrix substrates, such as cytokines (e.g. TNF-α), cytokine receptors (e.g. IL-6R and TNF-R), ligands of ErbB (e.g. TGF-α and amphiregulin) and adhesion proteins (e.g. Lselectin and ICAM-1). Several recent studies have described experimental model system to better understand the role of specific signaling molecules, the interplay of different signals and tissue interactions in regulating ADAM17-dependent cleavage of most relevant substrates in inflammatory diseases. The central question is whether ADAM17 can influence the outcome of inflammation and if so, how it performs this regulation in autoimmunity, since inflammatory autoimmune diseases are often characterized by deregulated metalloproteinase activities. This review will explore the latest research on the influence of ADAM17 on the progression of inflammatory processes linked to autoimmunity and its role as modulator of inflammation.
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Affiliation(s)
- Sabrina Lisi
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, Laboratory of Cell Biology, University of Bari Medical School, Bari, Italy.
| | - Massimo D'Amore
- Department of Interdisciplinary Medicine, Section of Rheumatology, University of Bari Medical School, Bari, Italy
| | - Margherita Sisto
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, Laboratory of Cell Biology, University of Bari Medical School, Bari, Italy.
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Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, Hess FM, Ohtsuka T, Okada Y, Ailles L, Ludwig A, Wrana JL, Kislinger T, Khokha R. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol 2014; 16:889-901. [DOI: 10.1038/ncb3021] [Citation(s) in RCA: 163] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Accepted: 07/10/2014] [Indexed: 12/12/2022]
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Miyata K, Yotsumoto F, Nam SO, Odawara T, Manabe S, Ishikawa T, Itamochi H, Kigawa J, Takada S, Asahara H, Kuroki M, Miyamoto S. Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma. Cancer Med 2014; 3:1159-69. [PMID: 25060396 PMCID: PMC4302667 DOI: 10.1002/cam4.301] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 06/19/2014] [Accepted: 06/24/2014] [Indexed: 01/28/2023] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is a worst histological subtype than other ovarian malignant tumor. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. The aims of this study were to validate the efficacy of HB-EGF-targeted therapy for OCCC and to identify the transcription factor that contributed to the induction of HB-EGF by SN38 treatment in OCCC cells. HB-EGF was highly expressed in OCCC cells, and an increase of HB-EGF was induced by SN38 which had only antitumor effect among conventional anticancer agents on OCCC. A specific inhibitor of HB-EGF, a cross-reacting material 197 (CRM197), led to a synergistic increase in the number of apoptotic OCCC cells with the treatment of SN38. The luciferase assay with 5'-deletion promoter constructs identified a GC-rich element between -125 and -178 (the distal transcription start site was denoted +1) as a cis-regulatory region, and the treatment of SN38 induced luciferase activity in this region. An in silico and chromatin immunoprecipitation analysis estimated that SP1 bound to the cis-regulatory region of HB-EGF in OCCC cells. Real-time PCR and cell viability assays showed that the transfection of a small interfering RNA targeting SP1 suppressed the expression of HB-EGF induced by SN38, resulting in the enhanced sensitivity of SN38. Taken together, these results indicate that induction of HB-EGF expression contributed to defense mechanism against treatment of SN38 through the transcriptional activity of SP1 in OCCC cells.
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Affiliation(s)
- Kohei Miyata
- Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan; Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan
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43
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Scheving LA, Zhang X, Garcia OA, Wang RF, Stevenson MC, Threadgill DW, Russell WE. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice. Am J Physiol Gastrointest Liver Physiol 2014; 306:G370-81. [PMID: 24407590 PMCID: PMC3949019 DOI: 10.1152/ajpgi.00116.2013] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.
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Affiliation(s)
| | | | | | | | | | - David W. Threadgill
- 6Department of Genetics, North Carolina State University, Raleigh, North Carolina
| | - William E. Russell
- 1Departments of Pediatrics, ,2Cell and Developmental Biology, ,3Digestive Disease Research Center, ,4Vanderbilt Diabetes Center, ,5Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee;
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Mikami Y, Mizuno S, Nakamoto N, Hayashi A, Sujino T, Sato T, Kamada N, Matsuoka K, Hisamatsu T, Ebinuma H, Hibi T, Yoshimura A, Kanai T. Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation. PLoS One 2014; 9:e84619. [PMID: 24392145 PMCID: PMC3879334 DOI: 10.1371/journal.pone.0084619] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 11/25/2013] [Indexed: 12/15/2022] Open
Abstract
The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2−/− mice adoptively transferred with CD4+CD45RBhigh T cells; and IL-10−/− mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b−CD11clowPDCA-1+ plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4+CD45RBhigh T cell-transferred RAG-2−/− mice and IL-10−/− mice in parallel with the emergence of macrophages (Mφs) and conventional DCs (cDCs). Furthermore, liver Mφ/cDCs emerging during intestinal inflammation not only promote the proliferation of naïve CD4+ T cells, but also instruct them to differentiate into IFN-γ-producing Th1 cells in vitro. The emergence of pathological Mφ/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mφ/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.
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Affiliation(s)
- Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Shinta Mizuno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Atsushi Hayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Research Laboratory, Miyarisan Pharmaceutical, Tokyo, Japan
| | - Tomohisa Sujino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshiro Sato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Nobuhiko Kamada
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tadakazu Hisamatsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshifumi Hibi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- * E-mail: (TK); (AY)
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- * E-mail: (TK); (AY)
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45
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Berasain C, Avila MA. The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis. J Gastroenterol 2014; 49:9-23. [PMID: 24318021 DOI: 10.1007/s00535-013-0907-x] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 10/28/2013] [Indexed: 02/04/2023]
Abstract
The liver displays an outstanding wound healing and regenerative capacity unmatched by any other organ. This reparative response is governed by a complex network of inflammatory mediators, growth factors and metabolites that are set in motion in response to hepatocellular injury. However, when liver injury is chronic, these regenerative mechanisms become dysregulated, facilitating the accumulation of genetic alterations leading to unrestrained cell proliferation and the development of hepatocellular carcinoma (HCC). The epidermal growth factor receptor (EGFR or ErbB1) signaling system has been identified as a key player in all stages of the liver response to injury, from early inflammation and hepatocellular proliferation to fibrogenesis and neoplastic transformation. The EGFR system engages in extensive crosstalk with other signaling pathways, acting as a true signaling hub for other growth factors, cytokines and inflammatory mediators. Here, we briefly review essential aspects of the biology of the EGFR, the other ErbB receptors, and their ligands in liver injury, regeneration and HCC development. Some aspects of the preclinical and clinical experience with EGFR therapeutic targeting in HCC are also discussed.
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Affiliation(s)
- Carmen Berasain
- Division of Hepatology and Gene Therapy and CIBEREhd, CIMA-University of Navarra, Avda. Pio XII, n55, 31008, Pamplona, Spain,
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46
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Adrain C, Freeman M. Regulation of receptor tyrosine kinase ligand processing. Cold Spring Harb Perspect Biol 2014; 6:6/1/a008995. [PMID: 24384567 DOI: 10.1101/cshperspect.a008995] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A primary mode of regulating receptor tyrosine kinase (RTK) signaling is to control access of ligand to its receptor. Many RTK ligands are synthesized as transmembrane proteins. Frequently, the active ligand must be released from the membrane by proteolysis before signaling can occur. Here, we discuss RTK ligand shedding and describe the proteases that catalyze it in flies and mammals. We focus principally on the control of EGF receptor ligand shedding, but also refer to ligands of other RTKs. Two prominent themes emerge. First, control by regulated trafficking and cellular compartmentalization of the proteases and their ligand substrates plays a key role in shedding. Second, many external signals converge on the shedding proteases and their control machinery. Proteases therefore act as regulatory hubs that integrate information that the cell receives and translate it into precise outgoing signals. The activation of signaling by proteases is therefore an essential element of the cellular communication machinery.
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Affiliation(s)
- Colin Adrain
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom
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47
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Gill SE, Gharib SA, Bench EM, Sussman SW, Wang RT, Rims C, Birkland TP, Wang Y, Manicone AM, McGuire JK, Parks WC. Tissue inhibitor of metalloproteinases-3 moderates the proinflammatory status of macrophages. Am J Respir Cell Mol Biol 2013; 49:768-77. [PMID: 23742180 DOI: 10.1165/rcmb.2012-0377oc] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Tissue inhibitor of metalloproteinases-3 (TIMP-3) has emerged as a key mediator of inflammation. Recently, we reported that the resolution of inflammation is impaired in Timp3(-/-) mice after bleomycin-induced lung injury. Here, we demonstrate that after LPS instillation (another model of acute lung injury), Timp3(-/-) mice demonstrate enhanced and persistent neutrophilia, increased numbers of infiltrated macrophages, and delayed weight gain, compared with wild-type (WT) mice. Because macrophages possess broad immune functions and can differentiate into cells that either stimulate inflammation (M1 macrophages) or are immunosuppressive (M2 macrophages), we examined whether TIMP-3 influences macrophage polarization. Comparisons of the global gene expression of unstimulated or LPS-stimulated bone marrow-derived macrophages (BMDMs) from WT and Timp3(-/-) mice revealed that Timp3(-/-) BMDMs exhibited an increased expression of genes associated with proinflammatory (M1) macrophages, including Il6, Il12, Nos2, and Ccl2. Microarray analyses also revealed a baseline difference in gene expression between WT and Timp3(-/-) BMDMs, suggesting altered macrophage differentiation. Furthermore, the treatment of Timp3(-/-) BMDMs with recombinant TIMP-3 rescued this altered gene expression. We also examined macrophage function, and found that Timp3(-/-) M1 cells exhibit significantly more neutrophil chemotactic activity and significantly less soluble Fas ligand-induced caspase-3/7 activity, a marker of apoptosis, compared with WT M1 cells. Macrophage differentiation into immunosuppressive M2 cells is mediated by exposure to IL-4/IL-13, and we found that Timp3(-/-) M2 macrophages demonstrated a lower expression of genes associated with an anti-inflammatory phenotype, compared with WT M2 cells. Collectively, these findings indicate that TIMP-3 functions to moderate the differentiation of macrophages into proinflammatory (M1) cells.
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Affiliation(s)
- Sean E Gill
- 1 Center for Lung Biology, University of Washington, Seattle, Washington
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48
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Vidal PM, Lemmens E, Avila A, Vangansewinkel T, Chalaris A, Rose-John S, Hendrix S. ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice. Cell Death Dis 2013; 4:e954. [PMID: 24336074 PMCID: PMC3877539 DOI: 10.1038/cddis.2013.466] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 10/16/2013] [Accepted: 10/23/2013] [Indexed: 02/05/2023]
Abstract
A disintegrin and metalloprotease 17 (ADAM17) is a sheddase with important substrates including tumor necrosis factor-α (TNF-α) and its receptors, the p75 neurotrophin receptor (p75NTR), and members of the epidermal growth factor family. The rationale of this study was to inhibit ADAM17-induced shedding of soluble TNF-α in order to reduce detrimental inflammation after spinal cord injury (SCI). However, using the specific ADAM17 blocker BMS-561392 in neuronal and glial cell cultures, we show that proper functioning of ADAM17 is vital for oligodendrocyte and microglia survival in a p44 MAPK-dependent manner. In contrast, genetic ablation of ADAM17 specifically increases microglial death. Surprisingly, although blocking ADAM17 in vivo does not substantially change the ratio between membrane-bound and soluble TNF-α, it increases expression of the pro-apoptotic marker Bax and microglial apoptosis while impairing functional recovery after SCI. These data suggest that ADAM17 is a key survival factor for microglial cells after SCI.
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Affiliation(s)
- P M Vidal
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - E Lemmens
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - A Avila
- 1] Department of Physiology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium [2] Developmental Neurology Unit, GIGA-Neurosciences, University of Liège, Liège, Belgium [3] Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, Liège, Belgium
| | - T Vangansewinkel
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - A Chalaris
- Institute of Biochemistry, Christian Albrechts University, Kiel, Germany
| | - S Rose-John
- Institute of Biochemistry, Christian Albrechts University, Kiel, Germany
| | - S Hendrix
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
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49
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Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 2013; 13:649-65. [PMID: 23969736 DOI: 10.1038/nri3499] [Citation(s) in RCA: 395] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Over the past 50 years, steady growth in the field of metalloproteinase biology has shown that the degradation of extracellular matrix components represents only a fraction of the functions performed by these enzymes and has highlighted their fundamental roles in immunity. Metalloproteinases regulate aspects of immune cell development, effector function, migration and ligand-receptor interactions. They carry out ectodomain shedding of cytokines and their cognate receptors. Together with their endogenous inhibitors TIMPs (tissue inhibitor of metalloproteinases), these enzymes regulate signalling downstream of the tumour necrosis factor receptor and the interleukin-6 receptor, as well as that downstream of the epidermal growth factor receptor and Notch, which are all pertinent for inflammatory responses. This Review discusses the metalloproteinase family as a crucial component in immune cell development and function.
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50
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Xu H, Li H, Cao D, Wu Y, Chen Y. Tumor necrosis factor α (TNF-α) receptor-I is required for TNF-α-mediated fulminant virus hepatitis caused by murine hepatitis virus strain-3 infection. Immunol Lett 2013; 158:25-32. [PMID: 24286726 PMCID: PMC7126990 DOI: 10.1016/j.imlet.2013.11.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 11/05/2013] [Accepted: 11/05/2013] [Indexed: 11/25/2022]
Abstract
TNFR1−/− mice displayed a dramatic decrease in tissue necrosis and cell apoptosis in the MHV-3 infected spleens and livers. TNFR1 deficiency directly impeded FGL2 secretion as well as reduced Fas and FasL expression in MHV-3 infected livers. TNFR1 deficiency impeded neutrophils, which produce proinflammatory factors and FGL2 directly, infiltration into liver and spleen. TNF-α plays an essential role in the pathogenesis of fulminant virus hepatitis (FH) caused by infection with murine hepatitis virus strain-3 (MHV-3). However, the specific TNF-α receptors (TNFR) involved in this disease and how they mediate this effect are uncertain. Here, we showed that the expression of TNFR1 and TNFR2 in the liver and spleen was triggered by MHV-3. However, only TNFR1−/− mice were resistant to MHV-3 mediated FH, as displayed by a dramatic decrease in tissue necrosis and cell apoptosis in the infected spleens and livers from TNFR1−/− mice, as well as prolonged survival in these mice compared to wild type littermate controls. Mechanistically, TNFR1 deficiency directly impeded the serum and tissue levels of fibrinogen-like protein 2 (FGL2), a virus-induced procoagulant molecule that promotes cell apoptosis. Additionally, the expression of apoptosis-associated molecules, Fas and Fas ligand (FasL) in the infected organs from TNFR1−/− mice were also decreased. Moreover, the infiltration of neutrophils rather than Foxp3+ regulatory T cells, which produce proinflammatory factors and FGL2 directly, into the infected liver and spleen tissues was also decreased in TNFR1−/− mice. These combined results indicate that signaling through TNFR1 plays an essential role in the pathogenesis of FH caused by MHV-3 infection, and interruption of this signaling pathway could be useful for clinical therapy.
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Affiliation(s)
- Huan Xu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China; Undergraduate Administration Office, Third Military Medical University, Chongqing 400037, People's Republic of China
| | - Hong Li
- Department of Otorhinolaryngology and Head-Neck Surgery, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, People's Republic of China
| | - Dayan Cao
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Yongwen Chen
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China.
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