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Tao SS, Fang X, Xu LZ, Zhang RD, Luo QQ, Tang J, Dai XF, Xu SZ, Yang XK, Pana HF. Association of gene polymorphisms and the decreased expression of long non-coding RNA LOC553103 with rheumatoid arthritis. Postgrad Med J 2024:qgae055. [PMID: 38656404 DOI: 10.1093/postmj/qgae055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/14/2024] [Accepted: 04/06/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are involved in many key bioprocesses, including the occurrence and development of rheumatoid arthritis (RA). We aimed to analyze the association of genetic variants of long non-coding RNA LOC553103 and its peripheral blood mononuclear cells (PBMC) expression with RA. METHODS We enrolled 457 RA patients and 551 healthy controls and conducted a case-control study to analyze the relationship between LOC553103 gene rs272879 and the susceptibility of RA by TaqMan single nucleotide polymorphism genotyping. Among them, we sampled 92 cases and 92 controls, respectively, to detect the PBMC level of LOC553103 using quantitative real-time polymerase chain reaction technology. We explored the association between LOC553103 rs272879 and its PBMC expression levels in 71 RA patients. Mann-Whitney, Chi-square, and Spearman correlation analysis were used for statistical analysis and P-value <.05 was considered statistically significant. RESULTS The genotype frequency of LOC553103 rs272879 CC was increased, and CG was decreased in RA patients compared to the control group (χ2 = 6.772, P = .034). The LOC553103 expression level in PBMC of RA patients was downregulated compared to healthy control (Z = -4.497, P < .001). Moreover, negative correlations were observed between the PBMC level of LOC553103 and erythrocyte sedimentation rate (rs = -0.262, P = .018), white blood cell count (rs = -0.382, P = .004), platelet (rs = -0.293, P = .030), and disease activity score in 28 joints (rs = -0.271, P = .016) in RA patients. CONCLUSIONS This study provides the first evidence supporting an association between LOC553103 gene polymorphisms and susceptibility of RA and a relationship of PBMC level of LOC553103 with clinical manifestations and laboratory indicators of RA patients.
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Affiliation(s)
- Sha-Sha Tao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Preventive Medicine Experimental Teaching Center, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xi Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Liang-Zi Xu
- Department of Clinical Medicine, First Clinical Medical College, Anhui Medical University, Hefei, Anhui 230032, China
| | - Ruo-Di Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Qing-Qing Luo
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jian Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xiao-Fan Dai
- Department of Public Affairs Administration, School of Health Service Management, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Shu-Zhen Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xiao-Ke Yang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
| | - Hai-Feng Pana
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
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Chiu YH, Liang YH, Hwang JJ, Wang HS. IL-1β stimulated human umbilical cord mesenchymal stem cells ameliorate rheumatoid arthritis via inducing apoptosis of fibroblast-like synoviocytes. Sci Rep 2023; 13:15344. [PMID: 37714911 PMCID: PMC10504325 DOI: 10.1038/s41598-023-42585-1] [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: 03/07/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023] Open
Abstract
Rheumatoid arthritis (RA) is characterized by synovial proliferation and lymphocyte accumulation leading to progressive damage of the periarticular bone and the articular cartilage. The hyperplasia of the synovial intima lining mainly consists of fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) which exhibit apoptosis-resistance, hyper-proliferation, and high invasiveness. The therapeutic efficacy of mesenchymal stem cells (MSCs) treatment in RA has been shown to be due to its immuno-regulatory ability. However, the exact factors and mechanisms involved in MSCs treatment in RA remain unclear. In this study, TRAIL receptor-Death receptor 4 (DR4), DR5, and LFA-1 ligand-intercellular adhesion molecule-1 (ICAM-1) were upregulated in IL-1β-stimulated HFLS-RA. We demonstrated that the total cell number of IL-1β-stimulated hUCMSCs adhering to IL-1β-stimulated HFLA-RA increased via LFA-1/ICAM-1 interaction. Direct co-culture of IL-1β-stimulated hUCMSCs with IL-1β-stimulated HFLS-RA increased the apoptosis of HFLS-RA. RA symptoms in the CIA mouse model improved after administration of IL-1β-stimulated hUCMSCs. In conclusion, IL-1β-stimulated hUCMSCs adhering to HFLS-RA occurred via LFA-1/ICAM-1 interaction, apoptosis of HFLS-RA was induced via TRAIL/DR4, DR5 contact, and RA symptoms and inflammation were significantly improved in a CIA mouse model. The results of this study suggest that IL-1β-stimulated hUCMSCs have therapeutic potential in RA treatment.
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Affiliation(s)
- Yun-Hsuan Chiu
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC
| | - Ya-Han Liang
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC
| | - Jeng-Jong Hwang
- Department of Medical Imaging, Chung Shan Medical University Hospital affiliated with Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, 402, Taiwan, ROC
| | - Hwai-Shi Wang
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC.
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3
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Wu D, Li Y, Xu R. Can pyroptosis be a new target in rheumatoid arthritis treatment? Front Immunol 2023; 14:1155606. [PMID: 37426634 PMCID: PMC10324035 DOI: 10.3389/fimmu.2023.1155606] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/07/2023] [Indexed: 07/11/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of undefined etiology, with persistent synovial inflammation and destruction of articular cartilage and bone. Current clinical drugs for RA mainly include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and so on, which can relieve patients' joint symptoms. If we want to have a complete cure for RA, there are still some limitations of these drugs. Therefore, we need to explore new mechanisms of RA to prevent and treat RA radically. Pyroptosis is a newly discovered programmed cell death (PCD) in recent years, which is characterized by the appearance of holes in cell membranes, cell swelling and rupture, and the release of intracellular pro-inflammatory factors into the extracellular space, resulting in a strong inflammatory response. The nature of pyroptosis is pro-inflammatory, and whether it is participating in the development of RA has attracted a wide interest among scholars. This review describes the discovery and mechanism of pyroptosis, the main therapeutic strategies for RA, and the role of pyroptosis in the mechanism of RA development. From the perspective of pyroptosis, the study of new mechanisms of RA may provide a potential target for the treatment of RA and the development of new drugs in the clinics.
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Affiliation(s)
- Dengqiang Wu
- Department of Clinical Laboratory, Ningbo No.6 Hospital, Ningbo, China
| | - Yujie Li
- Department of Clinical Laboratory, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Ranxing Xu
- Department of Clinical Laboratory, Ningbo No.6 Hospital, Ningbo, China
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Chakraborty D, Gupta K, Biswas S. A mechanistic insight of phytoestrogens used for Rheumatoid arthritis: An evidence-based review. Biomed Pharmacother 2020; 133:111039. [PMID: 33254019 DOI: 10.1016/j.biopha.2020.111039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/06/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Assessment of the potential therapeutic benefits offered by naturally occurring phytoestrogens necessitate inspection of their potency and sites of action in impeding the chronic, systemic, autoimmune, joint destructing disorder Rheumatoid arthritis (RA). Possessing structural and functional similarity with human estrogen, phytoestrogen promisingly replaces the use of hormone therapy in eradicating RA symptoms with their anti-inflammatory, anti-oxidative, anti-proliferative, anti-angiogenesis, immunomodulatory, joint protection properties abolishing the harmful side effects of synthetic drugs. Scientific evidences revealed that use of phytoestrogens from different chemical categories including flavonoids, alkaloids, stilbenoids derived from different plant species manifest beneficial effects on RA through various cellular mechanisms including suppression of pro-inflammatory cytokines in particular tumor necrosis factor (TNF-α), interleukin(IL-6) and nuclear factor kappa B (NF-κB) and destructive metalloproteinases, inhibition of oxidative stress, suppressing inflammatory signalling pathways, attenuating osteoclastogenesis ameliorating cartilage degradation and bone erosion. This review summarizes the evidences of different phytoestrogen treatment and their pharmacological mechanisms in both in vitro and in vivo studies along with discussing clinical evaluations in RA patients showing phytoestrogen as a promising agent for RA therapy. Further investigations and more clinical trials are mandatory to clarify the utility of these plant derived compounds in RA prevention and in managing oestrogen deficient diseases in patients.
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Affiliation(s)
- Debolina Chakraborty
- Department of Integrative and Functional Biology, CSIR - Institute of Genomics & Integrative Biology, Mall Road, Delhi, 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
| | - Kriti Gupta
- Department of Integrative and Functional Biology, CSIR - Institute of Genomics & Integrative Biology, Mall Road, Delhi, 110007, India.
| | - Sagarika Biswas
- Department of Integrative and Functional Biology, CSIR - Institute of Genomics & Integrative Biology, Mall Road, Delhi, 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Zhang Q, Liu J, Zhang M, Wei S, Li R, Gao Y, Peng W, Wu C. Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis. Biomolecules 2019; 9:biom9120795. [PMID: 31795133 PMCID: PMC6995542 DOI: 10.3390/biom9120795] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/23/2019] [Accepted: 11/24/2019] [Indexed: 01/15/2023] Open
Abstract
Rheumatoid arthritis (RA) is a known chronic autoimmune disease can cause joint deformity and even loss of joint function. Fibroblast-like synoviocytes (FLS), one of the main cell types in synovial tissues of RA patients, are key effector cells in the development of RA and are considered as promising therapeutic targets for treating RA. Herbal medicines are precious resources for finding novel agents for treating various diseases including RA. It is reported that induction of apoptosis in FLS is an important mechanism for the herbal medicines to treat RA. Consequently, this paper reviewed the current available references on pro-apoptotic effects of herbal medicines on FLS and summarized the related possible signal pathways. Taken together, the main related signal pathways are concluded as death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other reported pathways such as janus kinase/signal transducers and activators of transcription (JAK-STAT) signal pathway. Understanding the apoptosis induction pathways in FLS of these herbal medicines will not only help clear molecular mechanisms of herbal medicines for treating RA but also be beneficial for finding novel candidate therapeutic drugs from natural herbal medicines. Thus, we expect the present review will highlight the importance of herbal medicines and its components for treating RA via induction of apoptosis in FLS, and provide some directions for the future development of these mentioned herbal medicines as anti-RA drugs in clinical.
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Affiliation(s)
- Qing Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Q.Z.); (J.L.); (M.Z.); (R.L.)
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Q.Z.); (J.L.); (M.Z.); (R.L.)
| | - Mengmeng Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Q.Z.); (J.L.); (M.Z.); (R.L.)
| | - Shujun Wei
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (S.W.); (Y.G.)
| | - Ruolan Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Q.Z.); (J.L.); (M.Z.); (R.L.)
| | - Yongxiang Gao
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (S.W.); (Y.G.)
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Q.Z.); (J.L.); (M.Z.); (R.L.)
- Correspondence: (W.P.); (C.W.); Tel.: +86-028-61801001 (W.P. & C.W.)
| | - Chunjie Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Q.Z.); (J.L.); (M.Z.); (R.L.)
- Correspondence: (W.P.); (C.W.); Tel.: +86-028-61801001 (W.P. & C.W.)
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Anel A, Gallego-Lleyda A, de Miguel D, Naval J, Martínez-Lostao L. Role of Exosomes in the Regulation of T-cell Mediated Immune Responses and in Autoimmune Disease. Cells 2019; 8:cells8020154. [PMID: 30759880 PMCID: PMC6406439 DOI: 10.3390/cells8020154] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 01/24/2019] [Accepted: 02/11/2019] [Indexed: 01/01/2023] Open
Abstract
: T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.
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Affiliation(s)
- Alberto Anel
- Immunity, Cancer & Stem Cells Group, Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
| | - Ana Gallego-Lleyda
- Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
| | - Diego de Miguel
- Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, Gower St, Bloomsbury, WC1E 6BT London, UK.
| | - Javier Naval
- Immunity, Cancer & Stem Cells Group, Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
| | - Luis Martínez-Lostao
- Immunology Department, Lozano Blesa Clinical Hospital, and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain.
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7
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Dong H, Liu F, Ma F, Xu L, Pang L, Li X, Liu B, Wang L. Montelukast inhibits inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Int Immunopharmacol 2018; 61:215-221. [PMID: 29890415 DOI: 10.1016/j.intimp.2018.04.042] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 04/22/2018] [Accepted: 04/24/2018] [Indexed: 02/08/2023]
Abstract
Montelukast, a potent selective antagonist of cysteinyl leukotriene (cysLT) receptors, has displayed its important anti-oxidative and anti-inflammatory effects in various tissues and organs. Rheumatoid arthritis (RA) is an immune disease defined by hyperplastic synovitis and joint destruction. Fibroblast-like synoviocytes in RA (RA-FLSs) are the main cell component of the hyperplastic synovium. Whether montelukast can protect against the inflammatory milieu of RA remains unclear. Here, it is shown that cysLT1R is present in FLSs and unregulated in RA-FLSs. Montelukast has an inhibitory effect on the inflammatory microenvironment of RA by decreasing the secretion of IL-6, IL-8, MMP-3 and MMP-13 in FLSs induced by IL-1β. Notably, treatment with montelukast attenuated IL-1β-induced phosphorylation of IκBα, IκBα degradation, nuclear translocation of p65 and NF-κB activity to express a luciferase reporter gene in FLSs. The findings of the current study provide evidence for a novel therapeutic strategy for RA using montelukast.
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Affiliation(s)
- Hongyu Dong
- Department of Rheumatology and Immunology, Shijingshan teaching hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Feng Liu
- Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
| | - Fengyun Ma
- Department of Rheumatology and Immunology, Shijingshan teaching hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Lianna Xu
- Department of Rheumatology and Immunology, Shijingshan teaching hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Linna Pang
- Department of Rheumatology and Immunology, Shijingshan teaching hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Xuyan Li
- Department of Rheumatology and Immunology, Shijingshan teaching hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Bo Liu
- Department of Rheumatology and Immunology, Shijingshan teaching hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Liang Wang
- Center of Orthopedics, The 309th Hospital of PLA, Beijing 100091, China
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8
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Liu XZ, Fan J, Qi K, Liu SP, Xu WD, Gao Y, Gu XD, Li J, Bai CG, Shi YQ, Zhang LL, Zhao DB. Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway. Oncotarget 2017; 8:12649-12663. [PMID: 28187436 PMCID: PMC5355042 DOI: 10.18632/oncotarget.15172] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 01/24/2017] [Indexed: 12/13/2022] Open
Abstract
Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.
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Affiliation(s)
- Xing Zhen Liu
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China.,Army Convalescence Area, Hangzhou Sanatorium of People's Liberation Army, Hangzhou, China
| | - Jie Fan
- Army Convalescence Area, Hangzhou Sanatorium of People's Liberation Army, Hangzhou, China
| | - Ke Qi
- Department of Joint Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Shu Peng Liu
- Experimental Center, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Wei Dong Xu
- Department of Joint Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Ying Gao
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Xiao Dan Gu
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Jia Li
- Department of Joint Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Chen Guang Bai
- Department of Pathology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Ye Qing Shi
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Lan Ling Zhang
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Dong Bao Zhao
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
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An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis. Cell Mol Immunol 2017; 15:846-857. [PMID: 28392572 DOI: 10.1038/cmi.2017.2] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 12/11/2016] [Accepted: 12/11/2016] [Indexed: 02/04/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.
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Siegmund D, Lang I, Wajant H. Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2. FEBS J 2016; 284:1131-1159. [PMID: 27865080 DOI: 10.1111/febs.13968] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/10/2016] [Accepted: 11/17/2016] [Indexed: 12/25/2022]
Abstract
Since their identification more than 20 years ago, the death receptors CD95, TRAILR1, and TRAILR2 have been intensively studied with respect to their cell death-inducing activities. These receptors, however, can also trigger a variety of cell death-independent cellular responses reaching from the activation of proinflammatory gene transcription programs over the stimulation of proliferation and differentiation to induction of cell migration. The cell death-inducing signaling mechanisms of CD95 and the TRAIL death receptors are well understood. In contrast, despite the increasing recognition of the biological and pathophysiological relevance of the cell death-independent activities of CD95, TRAILR1, and TRAILR2, the corresponding signaling mechanisms are less understood and give no fully coherent picture. This review is focused on the cell death-independent activities of CD95 and the TRAIL death receptors and addresses mainly three questions: (a) how are these receptors linked to noncell death pathways at the molecular level, (b) which factors determine the balance of cell death and cell death-independent activities of CD95 and the TRAIL death receptors at the cellular level, and (c) what are the consequences of the cell death-independent functions of these receptors for their role in cancer and inflammatory diseases.
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Affiliation(s)
- Daniela Siegmund
- Division of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University Hospital Würzburg, Germany
| | - Isabell Lang
- Division of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University Hospital Würzburg, Germany
| | - Harald Wajant
- Division of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University Hospital Würzburg, Germany
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Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Inflammation 2016; 39:39-46. [PMID: 26228975 DOI: 10.1007/s10753-015-0220-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Here, we explored the effects of suberoylanilide hydroxamic acid (SAHA) on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS)). FLS obtained from RA patients were treated with SAHA. SAHA significantly inhibited the viability of RA FLS in a concentration-dependent manner up to 5 μM. SAHA-treated FLS showed a significant increase in the percentage of apoptosis and the expression and activity of caspase-3 and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated SAHA-induced apoptosis, decreasing the percentage of apoptosis by about 60 %. A significant decline in phosphorylated IκBα and nuclear factor kappa B (NF-κB) p65 and concomitant increase in total IκBα were shown in SAHA-treated FLS. Additionally, the levels of anti-apoptotic Bcl-2 proteins (Bcl-xL and Mcl-1) were significantly reduced by SAHA. Collectively, SAHA induces apoptosis of RA FLS, at least partially, through generation of ROS and suppression of NF-κB activation and Bcl-xL and Mcl-1 expression.
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Audo R, Hegglin A, Severac D, Dantec C, Combe B, Hahne M, Morel J. Identification of genes regulating TRAIL-induced apoptosis in rheumatoid arthritis fibroblasts-like synoviocytes. Genes Immun 2015; 16:462-9. [DOI: 10.1038/gene.2015.31] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 05/21/2015] [Accepted: 06/23/2015] [Indexed: 01/05/2023]
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Funcke JB, Zoller V, El Hay MA, Debatin KM, Wabitsch M, Fischer-Posovszky P. TNF-related apoptosis-inducing ligand promotes human preadipocyte proliferation via ERK1/2 activation. FASEB J 2015; 29:3065-75. [PMID: 25857555 DOI: 10.1096/fj.14-267278] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 03/16/2015] [Indexed: 12/31/2022]
Abstract
Upon obesity, adipose tissue is excessively expanded and characterized by pathologic processes like hypoxia, fibrosis, and inflammation. Death ligands belonging to the TNF superfamily such as TNF-α are important contributors to these derangements and exert a pronounced influence on the metabolic and cellular homeostasis of adipose tissue. Here, we sought to identify the effect of the death ligand TNF-related apoptosis-inducing ligand (TRAIL) on the adipose tissue precursor cell pool and therefore investigated its influence on preadipocyte proliferation. Treatment of human preadipocytes with TRAIL resulted in a time- and dose-dependent increase in proliferation (EC50 3.4 ng/ml) comparable to IGF-1. Although no apoptosis was observed, TRAIL triggered a rapid cleavage of caspase-8 and -3. Neither inhibition of caspase activity by zVAD.fmk (20 µM) nor ablation of caspase-8 expression by lentivirus-delivered small hairpin RNA (shRNA) abolished the proliferative response. TRAIL triggered a delayed and sustained activation of ERK1/2, leaving Akt, p38, JNK, and NF-κB unaffected. Importantly, inhibition of ERK1/2 activation by PD0325901 (300 nM) or AZD6244 (5 or 10 µM) completely abolished the proliferative response. We thus reveal a hitherto unknown function of TRAIL in regulating adipose tissue homeostasis by promoting the proliferation of tissue-resident precursor cells.
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Affiliation(s)
- Jan-Bernd Funcke
- *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany
| | - Verena Zoller
- *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany
| | - Muad Abd El Hay
- *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany
| | - Klaus-Michael Debatin
- *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany
| | - Martin Wabitsch
- *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany
| | - Pamela Fischer-Posovszky
- *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany
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Audo R, Calmon-Hamaty F, Papon L, Combe B, Morel J, Hahne M. Distinct effects of soluble and membrane-bound fas ligand on fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheumatol 2015; 66:3289-99. [PMID: 25078097 DOI: 10.1002/art.38806] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 07/24/2014] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Injection of agonistic anti-Fas antibody has been shown to decrease disease symptoms in mouse models of arthritis. Additionally, membrane-bound FasL (mFasL) has been shown to induce cell death in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, levels of soluble FasL (sFasL) are increased in the joints of RA patients and have been associated with disease severity, indicating that mFasL and sFasL play opposing roles in RA. The purpose of this study was to analyze the effects of FasL on RA FLS responses. METHODS The responses of FLS from RA and osteoarthritis (OA) patients to soluble and oligomeric FasL, the latter mimicking mFasL, were analyzed by fluorescence-activated cell sorting and proliferation assays, using 3 different FasL variants. The signaling pathways that trigger FasL responses were characterized by Western blotting. RESULTS We found that mFasL and sFasL have distinct roles in RA FLS. Crosslinked FasL preferentially induced apoptosis, whereas sFasL stimulated proliferation. Moreover, sFasL activated several signaling pathways in RA FLS, such as ERK-1/2, phosphatidylinositol 3-kinase, caspase 8, and JNK, with a prominent role of JNK, since only the blockade of this pathway rendered FLS more susceptible to FasL-induced apoptosis. Crosslinked FasL induced apoptosis in FLS from OA patients, but sFasL failed to stimulate their proliferation. CONCLUSION Our findings suggest that sFasL is a disease promoter in RA, a finding consistent with previous reports describing a tumor-promoting role of FasL. Therefore, blocking of sFasL could be a therapeutic strategy for RA.
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Affiliation(s)
- Rachel Audo
- Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, Université Montpellier Sud de France, Montpellier 1 University, and Lapeyronie Teaching Hospital, Montpellier, France
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15
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Audo R, Combe B, Hahne M, Morel J. The two directions of TNF-related apoptosis-inducing ligand in rheumatoid arthritis. Cytokine 2013; 63:81-90. [DOI: 10.1016/j.cyto.2013.04.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 04/08/2013] [Accepted: 04/10/2013] [Indexed: 01/01/2023]
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Neve A, Corrado A, Cantatore FP. TNF-related apoptosis-inducing ligand (TRAIL) in rheumatoid arthritis: what's new? Clin Exp Med 2012; 14:115-20. [PMID: 23275079 DOI: 10.1007/s10238-012-0226-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 12/20/2012] [Indexed: 01/19/2023]
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein of the TNF superfamily that serves as an extracellular signal that triggers programmed cell death in tumor cells, without affecting normal cells. Recently, scientists have turned their attention to the emerging role of TRAIL in immune and autoimmune responses. TRAIL has been shown to down-regulate the self-antigens in autoimmune diseases, such as rheumatoid arthritis (RA) by exerting its apoptotic effect on activated T cells and synoviocytes and by its local anti-inflammatory effect. The impact of TRAIL molecular variants and agonistic monoclonal antibodies in the regulation of TRAIL activity in arthritis animal models strongly supports the idea of testing the role of TRAIL in humans, with the aim of developing new effective therapies that promote apoptosis of synoviocytes and/or infiltrating lymphocytes, by targeting TRAIL. The aim of this review is to summarize recent progress and current knowledge of TRAIL functions in RA.
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Affiliation(s)
- Anna Neve
- Department of Medical and Surgical Sciences, Rheumatology Clinic, University of Foggia, Ospedale "Col. D'Avanzo", V.le degli Aviatori 1, 71100, Foggia, Italy
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Abstract
Rheumatoid arthritis (RA) is the most common inflammatory disease of the musculoskeletal system primarily affecting the joints. It is characterized by massive synovial hyperplasia and subsequent destruction of articular cartilage and bone. Although various aspects in the pathogenesis of RA remain unclear, genetic, environmental and of course immunological factors have been involved. Defects in apoptosis seem to play a role in both initiation and perpetuation of RA. Apo2 ligand/ tumor necrosis factor (TNF) related apoptosis-inducing ligand (Apo2L/TRAIL) is a cytokine that belongs to the TNF superfamily capable of inducing apoptosis on tumor cells through activation of the extrinsic pathway. Besides this function, like other members of the TNF superfamily, Apo2L/TRAIL has been shown to exert important functions in the regulation of the immune system. Concerning pathological conditions, the Apo2L/TRAIL signaling pathway plays an important role in the response to infections, in immune surveillance against tumors and in autoimmune diseases such as RA. Furthermore, its implication in suppression of autoimmunity suggests that Apo2L/TRAIL has potential as therapeutic agent not only in cancer but also in autoimmune diseases. In fact, Apo2L/TRAIL-based therapies have been shown effective in various animal models of RA. This review summarizes the current knowledge on the biology of Apo2L/TRAIL and its role in RA.
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Shi J, Diao Z, Zhou J, Zhu J, Yuan H, You X, Liu Y, Zheng D. Epirubicin potentiates recombinant adeno-associated virus type 2/5-mediated TRAIL expression in fibroblast-like synoviocytes and augments the antiarthritic effects of rAAV2/5-TRAIL. ACTA ACUST UNITED AC 2012; 64:1345-54. [PMID: 22131069 DOI: 10.1002/art.33492] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Synovial cells in rheumatoid synovium display abnormal proliferation, which leads to joint destruction. TRAIL has been described as a proapoptotic factor in fibroblast-like synoviocytes (FLS). This study was undertaken to investigate the functions of rAAV2/5-TRAIL in human FLS and in arthritic mice. METHODS Primary human FLS were infected with rAAV2/5-TRAIL in the presence or absence of epirubicin. Transgene expression was monitored by both enzyme-linked immunosorbent assay and flow cytometry. The disease-modulating activity of epirubicin plus rAAV2/5-TRAIL was investigated in mice with collagen-induced arthritis (CIA). RESULTS Subtoxic doses of epirubicin potentiated rAAV2/5-mediated TRAIL expression in FLS and simultaneously enhanced the sensitivity of FLS to TRAIL. Epirubicin treatment up-regulated death receptor 4 (DR-4) and DR-5 expression and down-regulated FLIP expression, thereby enhancing the activation of procaspase 3, procaspase 8, and procaspase 9. An in vivo study showed that the combination of rAAV2/5-TRAIL gene therapy and epirubicin chemotherapy provided augmented antiarthritic effects in a mouse model of CIA. The intraarticular injection of rAAV2/5-TRAIL combined with epirubicin treatment significantly reduced the severity and incidence of CIA and joint swelling in the animals. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in the joints of the mice receiving the synthetic treatment. Results of a viral genome copy number assay indicated that epirubicin dramatically augmented the expression of rAAV2/5-TRAIL without altering its tissue distribution. CONCLUSION These results suggest that epirubicin enhances the antiarthritic effect of rAAV2/5-TRAIL and that combination treatment might be an important therapeutic alternative, with practical significance for rheumatoid arthritis.
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Affiliation(s)
- Juan Shi
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer. Biochem Pharmacol 2012; 83:1475-83. [DOI: 10.1016/j.bcp.2011.12.036] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Revised: 12/22/2011] [Accepted: 12/22/2011] [Indexed: 01/07/2023]
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Bartok B, Boyle DL, Liu Y, Ren P, Ball ST, Bugbee WD, Rommel C, Firestein GS. PI3 Kinase δ Is a Key Regulator of Synoviocyte Function in Rheumatoid Arthritis. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:1906-16. [DOI: 10.1016/j.ajpath.2012.01.030] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 01/13/2012] [Accepted: 01/19/2012] [Indexed: 11/16/2022]
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Sun QW, Jiang SM, Yang K, Zheng JM, Zhang L, Xu WD. Apigenin enhances the cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand in human rheumatoid arthritis fibroblast-like synoviocytes. Mol Biol Rep 2011; 39:5529-35. [PMID: 22189539 DOI: 10.1007/s11033-011-1356-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2011] [Accepted: 12/12/2011] [Indexed: 12/29/2022]
Abstract
Activated rheumatoid arthritis (RA) fibroblast-like synoviocytes (RAFLSs) play a central role in both initiating and driving RA. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been documented to induce apoptosis only in a small proportion of RAFLSs, which is followed by an induction of proliferation in surviving cells. Apigenin, a chemopreventive bioflavonoid, exhibits proapoptotic activity in many types of cells. In the present study, we sought to determine whether apigenin could enhance the cytotoxic effect of TRAIL on activated RAFLSs. Human RAFLSs isolated from patients with RA were treated with TRAIL (1 nM), apigenin (20 μM), or their combination, and subjected to apoptosis analysis after a 24-h incubation and proliferation analysis after a 72-h incubation. Apoptosis assay revealed that TRAIL or apigenin alone induced a marked apoptosis in RAFLS and their combination yielded a synergistic increase in RAFLS apoptosis. Immunoblotting analysis of apoptosis regulators demonstrated that combined treatment with apigenin increased caspase-3 expression and activity and decreased the Bcl-2/Bax ratio relative to treatment with TRAIL alone. The presence of apigenin significantly restrained TRAIL-induced RAFLS proliferation, coupled with restoration of the expression of two cell-cycle inhibitors p21 and p27. Moreover, the combination with apigenin blunted TRAIL-induced activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. Our data collectively demonstrate that apigenin sensitizes RAFLS to TRAIL-induced apoptosis and counteracts TRAIL-dependent RAFLS proliferation, which is likely mediated through inactivation of PI3-K/Akt signaling pathway.
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Affiliation(s)
- Qing-Wen Sun
- Central Laboratory of Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University Medical College, Shanghai, China.
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Corallini F, Celeghini C, Rimondi E, di Iasio MG, Gonelli A, Secchiero P, Zauli G. Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells. J Cell Physiol 2011; 226:2279-86. [PMID: 21660951 DOI: 10.1002/jcp.22564] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The soluble member of the TNF-R superfamily osteoprotegerin (OPG) is abundantly released under basal conditions by both mesenchymal stem cells (MSC) and fibroblasts and by endothelial cells upon stimulation with inflammatory cytokines. Since MSC, fibroblasts and endothelial cells represent key elements of the normal and tumor microenvironment and express detectable levels of surface TRAIL receptors, we investigated the effect of TRAIL on OPG release. Unexpectedly, recombinant TRAIL decreased the spontaneous OPG release in all cell types examined. Moreover, TRAIL decreased OPG release also in stromal cells co-cultured with lymphoma cells and counteracted the OPG induction by TN-alpha in HUVEC and MSC. Such down-regulation was not due to a masking effect in the ELISA quantification of the OPG released in the culture supernatants due to binding of OPG to its ligands (TRAIL and RANKL), as demonstrated by competition experiments with recombinant TRAIL and by the lack of RANKL release/induction. In addition, OPG down-regulation was not due to induction of cytotoxic effects by TRAIL, since the degree of apoptosis in response to TRAIL was negligible in all primary cell types. With regards to the possible molecular mechanism accounting for the down-regulation of OPG release by TRAIL, we found that treatment of MSC with TRAIL significantly decreased the phosphorylation levels of p38/MAPK. There is a suggestion that this pathway is involved in the stabilization of OPG mRNA. In this respect, the ability of TRAIL to decrease the release of OPG, in the absence of cell cytotoxicity, was mimicked by the p38/MAPK inhibitor SB203580.
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Affiliation(s)
- Federica Corallini
- Department of Morphology and Embryology and LTTA Centre, University of Ferrara, Ferrara, Italy
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Audo R, Calmon-Hamaty F, Baeten D, Bruyer A, Combe B, Hahne M, Morel J. Mechanisms and clinical relevance of TRAIL-triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis. ACTA ACUST UNITED AC 2011; 63:904-13. [PMID: 21305500 DOI: 10.1002/art.30181] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Results of studies in mice suggest a protective role for TRAIL in arthritis. The aim of this study was to investigate the role of TRAIL in patients with rheumatoid arthritis (RA). METHODS In the present study, we compared RA fibroblast-like synoviocytes (FLS) that were resistant or sensitive to TRAIL-induced apoptosis and the expression of TRAIL receptors in these cells, and also investigated the clinical features of the patients from whom the FLS were derived. Furthermore, we evaluated the levels of TRAIL and its soluble decoy receptor osteoprotegerin (OPG) in patients with RA, patients with osteoarthritis (OA), and patients with spondylarthritis (SpA). RESULTS Sensitivity to TRAIL-induced apoptosis varied in FLS from different patients, and the severity of disease in patients with RA was inversely correlated with the susceptibility of their FLS to TRAIL-induced apoptosis. TRAIL-sensitive cells expressed significantly lower levels of TRAILR-1, and silencing of TRAILR-1 increased TRAIL-induced apoptosis in RA FLS. TRAIL levels were elevated in the arthritic joints of patients with established RA, and TRAIL levels in the synovial fluid of these patients were elevated compared with levels in the synovial fluid of patients with OA or SpA. At baseline, a low OPG-to-TRAIL ratio in the sera of patients with early RA was associated with a better evolution of disease activity, but high serum levels of TRAIL at followup were associated with joint damage. CONCLUSION These findings suggest that TRAIL has a dual role in RA, and that the resistance of RA FLS to TRAIL-induced apoptosis is associated with a disease-promoting activity of TRAIL in RA.
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Affiliation(s)
- Rachel Audo
- Institut de Génétique Moléculaire de Montpellier, Université Montpellier I, Montpellier, France
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TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT. PLoS One 2011; 6:e19679. [PMID: 21625476 PMCID: PMC3098831 DOI: 10.1371/journal.pone.0019679] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 04/13/2011] [Indexed: 11/20/2022] Open
Abstract
Background TRAIL/Apo2L is a pro-apoptotic ligand of the TNF family that engages the apoptotic machinery through two pro-apoptotic receptors, TRAIL-R1 and TRAIL-R2. This cell death program is tightly controlled by two antagonistic receptors, TRAIL-R3 and TRAIL-R4, both devoid of a functional death domain, an intracellular region of the receptor, required for the recruitment and the activation of initiator caspases. Upon TRAIL-binding, TRAIL-R4 forms a heteromeric complex with the agonistic receptor TRAIL-R2 leading to reduced caspase-8 activation and apoptosis. Methodology/Principal Findings We provide evidence that TRAIL-R4 can also exhibit, in a ligand independent manner, signaling properties in the cervical carcinoma cell line HeLa, through Akt. Ectopic expression of TRAIL-R4 in HeLa cells induced morphological changes, with cell rounding, loss of adherence and markedly enhanced cell proliferation in vitro and tumor growth in vivo. Disruption of the PI3K/Akt pathway using the pharmacological inhibitor LY294002, siRNA targeting the p85 regulatory subunit of phosphatidylinositol-3 kinase, or by PTEN over-expression, partially restored TRAIL-mediated apoptosis in these cells. Moreover, the Akt inhibitor, LY294002, restituted normal cell proliferation index in HeLa cells expressing TRAIL-R4. Conclusions/Significance Altogether, these results indicate that, besides its ability to directly inhibit TRAIL-induced cell death at the membrane, TRAIL-R4 can also trigger the activation of signaling pathways leading to cell survival and proliferation in HeLa cells. Our findings raise the possibility that TRAIL-R4 may contribute to cervical carcinogenesis.
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Kedinger V, Muller S, Gronemeyer H. Targeted expression of tumor necrosis factor-related apoptosis-inducing ligand TRAIL in skin protects mice against chemical carcinogenesis. Mol Cancer 2011; 10:34. [PMID: 21463519 PMCID: PMC3078898 DOI: 10.1186/1476-4598-10-34] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 04/04/2011] [Indexed: 01/01/2023] Open
Abstract
Background Gene ablation studies have revealed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L, TNFSF10) plays a crucial role in tumor surveillance, as TRAIL-deficient mice exhibit an increased sensitivity to different types of tumorigenesis. In contrast, possible tumor-protective effect of increased levels of endogenous TRAIL expression in vivo has not been assessed yet. Such models will provide important information about the efficacy of TRAIL-based therapies and potential toxicity in specific tissues. Methods To this aim, we engineered transgenic mice selectively expressing TRAIL in the skin and subjected these mice to a two-step chemical carcinogenesis protocol that generated benign and preneoplastic lesions. We were therefore able to study the effect of increased TRAIL expression at the early steps of skin tumorigenesis. Results Our results showed a delay of tumor appearance in TRAIL expressing mice compared to their wild-type littermates. More importantly, the number of tumors observed in transgenic animals was significantly lower than in the control animals, and the lesions observed were mostly benign. Interestingly, Wnt/β-catenin signaling differed between tumors of wild-type and TRAIL transgenics. Conclusion Altogether, these data reveal that, at least in this model, TRAIL is able on its own to act on pre-transformed cells, and reduce their tumorigenic potential.
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Affiliation(s)
- Valerie Kedinger
- Department of Cancer Biology, Institut Génétique de Biologie Moléculaire et Cellulaire (IGBMC), France
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Martinez-Lostao L, García-Alvarez F, Basáñez G, Alegre-Aguarón E, Desportes P, Larrad L, Naval J, Martínez-Lorenzo MJ, Anel A. Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis. ACTA ACUST UNITED AC 2010; 62:2272-82. [PMID: 20506326 DOI: 10.1002/art.27501] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen-induced arthritis (AIA). METHODS We used a novel Ni(2+)-(N-5-amino-1-carboxypentyl)-iminodiacetic acid)-containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed. RESULTS Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic. CONCLUSION Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA.
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Affiliation(s)
- Luis Martinez-Lostao
- Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, Zaragoza 50009, Spain.
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SECCHIERO PAOLA, CORALLINI FEDERICA, CASTELLINO GABRIELLA, BORTOLUZZI ALESSANDRA, CARUSO LORENZO, BUGATTI SERENA, BOSCO RAFFAELLA, MONTECUCCO MAURIZIO, TROTTA FRANCESCO. Baseline Serum Concentrations of TRAIL in Early Rheumatoid Arthritis: Relationship with Response to Disease-modifying Antirheumatic Drugs. J Rheumatol 2010; 37:1461-6. [DOI: 10.3899/jrheum.091363] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Objective.To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) and the therapeutic response to disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA).Methods.Circulating levels of TRAIL and its soluble receptor OPG were measured by ELISA in paired serum samples obtained from 66 patients with early RA at their first visit (baseline) and after 1 year of therapy. Levels of TRAIL and OPG were analyzed in relation to the clinical response, defined by the 28-joint count Disease Activity Score (DAS28).Results.Both serum TRAIL and OPG increased after DMARD therapy. Baseline levels of TRAIL, but not OPG, were significantly higher (p < 0.05) in the patients that achieved a clinical response by DAS28 after 1 year of therapy, versus patients without clinical response to DMARD. Baseline serum levels of TRAIL were higher (p < 0.01) in rheumatoid factor-negative patients.Conclusion.Our data suggest that the basal level of circulating TRAIL is an important determinant in the therapeutic response to DMARD in patients with early RA.
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The discovery of novel experimental therapies for inflammatory arthritis. Mediators Inflamm 2010; 2009:698769. [PMID: 20339519 PMCID: PMC2842969 DOI: 10.1155/2009/698769] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Accepted: 12/21/2009] [Indexed: 12/16/2022] Open
Abstract
Conventional and biologic disease-modifying antirheumatic drugs have revolutionized the medical therapy of inflammatory arthritis. However, it remains unclear as to what can be done to treat immune-mediated chronic inflammation after patients become refractory to these therapies or develop serious side-effects and/or infections forcing drug withdrawal. Because of these concerns it is imperative that novel targets be continuously identified and experimental strategies designed to test potential arthritis interventions in vitro, but more importantly, in well-validated animal models of inflammatory arthritis. Over the past few years, sphingosine-1-phosphate, interleukin-7 receptor, spleen tyrosine kinase, extracellular signal-regulated kinase, mitogen-activated protein kinase 5/p38 kinase regulated/activated protein kinase, micro-RNAs, tumor necrosis factor-related apoptosis inducing ligand and the polyubiquitin-proteasome pathway were identified as promising novel targets for potential antiarthritis drug development. Indeed several experimental compounds alter the biological activity of these targets and have shown clinical efficacy in animal models of arthritis. A few of them have even entered the first phase of human clinical trials.
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García S, Liz M, Gómez-Reino JJ, Conde C. Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage. Arthritis Res Ther 2010; 12:R33. [PMID: 20187936 PMCID: PMC2875667 DOI: 10.1186/ar2941] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Revised: 02/18/2010] [Accepted: 02/26/2010] [Indexed: 01/11/2023] Open
Abstract
Introduction Synovial hyperplasia is a main feature of rheumatoid arthritis pathology that leads to cartilage and bone damage in the inflamed joints. Impaired apoptosis of resident synoviocytes is pivotal in this process. Apoptosis resistance seems to involve defects in the extrinsic and intrinsic apoptotic pathways. The aim of this study was to investigate the association of PI3Kinase/Akt and the mitochondrial apoptotic pathway in the resistance of rheumatoid arthritis (RA) fibroblast like synovial cells (FLS) to Fas-mediated apoptosis. Methods Apoptosis was assessed by ELISA quantification of nucleosomal release, Hoechst staining and activated caspase-3/7 measure in cultured RA FLS stimulated with anti-Fas antibody. Two Phosphoinositol-3-kinase/protein Kinase B (PI3 Kinase) inhibitors, Wortmannine and LY294002, were used before anti-Fas stimulation. Proapoptotic BH3 interacting domain death agonist (Bid) was suppressed in RA FLS by small interfering RNA (siRNA) transfection. Bid was overexpressed by transfection with the pDsRed2-Bid vector. Phosphorylated Akt, caspase-9, and Bid expression were analysed by western blot. Results PI3 kinase inhibition sensitizes RA FLS to Fas-induced apoptosis by increasing cleavage of Bid protein. Bid suppression completely abrogated Fas-induced apoptosis and Bid overexpression highly increased apoptotic rate of RA FLS in association with cleavage of caspase-9. Conclusions In RA FLS, phosphorylation of Akt protects against Fas-induced apoptosis through inhibition of Bid cleavage. The connection between the extrinsic and the intrinsic apoptotic pathways are critical in this Fas- mediated apoptosis and points to PI3Kinase as potential therapeutic target for RA.
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Affiliation(s)
- Samuel García
- Research Laboratory and Rheumatology Unit, Hospital Clínico Universitario, Choupana s/n, Santiago de Compostela, 15706-Spain.
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Abstract
Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.
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Affiliation(s)
- Beatrix Bartok
- Division of Rheumatology, Allergy, and Immunology, UCSD School of Medicine, La Jolla, CA, USA
| | - Gary S. Firestein
- Division of Rheumatology, Allergy, and Immunology, UCSD School of Medicine, La Jolla, CA, USA
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