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Husain I, Shah H, Jordan CZ, Natesh NR, Fay OK, Chen Y, Privratsky JR, Kitai H, Souma T, Varghese S, Howell DN, Thorp EB, Luo X. Targeting allograft inflammatory factor 1 reprograms kidney macrophages to enhance repair. J Clin Invest 2025; 135:e185146. [PMID: 39836477 PMCID: PMC11870741 DOI: 10.1172/jci185146] [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: 07/23/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025] Open
Abstract
The role of macrophages (MΦs) remains incompletely understood in kidney injury and repair. The plasticity of MΦs offers an opportunity to polarize them toward mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney MΦs augmented their own allograft inflammatory factor 1 (AIF-1) expression after injury. Aif1 genetic deletion led to MΦ polarization toward a reparative phenotype while halting the development of kidney fibrosis. The enhanced repair was mediated by higher levels of antiinflammatory and proregenerative markers, leading to a reduction in cell death and an increase in proliferation of kidney tubular epithelial cells after ischemia followed by reperfusion injury (I/RI). Adoptive transfer of Aif1-/- MΦs into Aif1+/+ mice conferred protection against I/RI. Conversely, depletion of MΦs reversed the tissue-reparative effects in Aif1-/- mice. We further demonstrated increased expression of AIF-1 in human kidney biopsies from native kidneys with acute kidney injury or chronic kidney disease, as well as in biopsies from kidney allografts undergoing acute or chronic rejection. We conclude that AIF-1 is a MΦ marker of renal inflammation, and its targeting uncouples MΦ reparative functions from profibrotic functions. Thus, therapies inhibiting AIF-1 when ischemic injury is inevitable have the potential to reduce the global burden of kidney disease.
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Affiliation(s)
- Irma Husain
- Division of Nephrology, Department of Medicine, and
- Duke Transplant Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Holly Shah
- Division of Nephrology, Department of Medicine, and
| | | | - Naveen R. Natesh
- Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, North Carolina, USA
| | | | | | | | - Hiroki Kitai
- Division of Nephrology, Department of Medicine, and
| | | | - Shyni Varghese
- Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, North Carolina, USA
- Department of Mechanical Engineering and Materials Science, and
- Department of Orthopaedic Surgery, Duke University, Durham, North Carolina, USA
| | | | - Edward B. Thorp
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Xunrong Luo
- Division of Nephrology, Department of Medicine, and
- Duke Transplant Center, Duke University School of Medicine, Durham, North Carolina, USA
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Kalyuzhnaya YN, Logvinov AK, Pashkevich SG, Golubova NV, Seryogina ES, Potapova EV, Dremin VV, Dunaev AV, Demyanenko SV. An Alternative Photothrombotic Model of Transient Ischemic Attack. Transl Stroke Res 2024:10.1007/s12975-024-01285-2. [PMID: 39069596 DOI: 10.1007/s12975-024-01285-2] [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: 06/05/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Animal models mimicking human transient ischemic attack (TIA) and cerebral microinfarcts are essential tools for studying their pathogenetic mechanisms and finding methods of their treatment. Despite its advantages, the model of single arteriole photothrombosis requires complex experimental equipment and highly invasive surgery, which may affect the results of further studies. Hence, to achieve high translational potential, we focused on developing a TIA model based on photothrombosis of arterioles to combine good reproducibility and low invasiveness. For the first time, noninvasive laser speckle contrast imaging (LSCI) was used to monitor blood flow in cerebral arterioles and reperfusion was achieved. We demonstrate that irradiation of mouse cerebral cortical arterioles using a 532-nm laser with a 1-mm-wide beam at 2.4 or 3.7 mW for 55 or 40 s, respectively, after 15 mg/kg intravenous Rose Bengal administration, induces similar ischemia-reperfusion lesions resulting in microinfarct formation. The model can be used to study the pathogenesis of spontaneously developing cerebral microinfarcts in neurodegeneration. Reducing the exposure times by 10 s while maintaining the same other parameters caused photothrombosis of the arteriole with reperfusion in less than 1 h. This mode of photodynamic exposure caused cellular and subcellular level ischemic changes in neurons and promoted the activation of astrocytes and microglia in the first day after irradiation, but not later, without the formation of microinfarcts. This mode of photodynamic exposure most accurately reproduced human TIA, characterized by the absence of microinfarcts.
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Affiliation(s)
- Y N Kalyuzhnaya
- Laboratory of Molecular Neuroscience, Academy of Biology and Biotechnology, Southern Federal University, 194/1 Stachki Ave, Rostov-On-Don, 344090, Russia
| | - A K Logvinov
- Laboratory of Molecular Neuroscience, Academy of Biology and Biotechnology, Southern Federal University, 194/1 Stachki Ave, Rostov-On-Don, 344090, Russia
| | - S G Pashkevich
- State Scientific Institution "Institute of Physiology, of the National Academy of Sciences of Belarus", Akademicheskaya Str., 28, 220072, Minsk, Belarus
| | - N V Golubova
- Research and Development Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya St, Orel, 302026, Russia
| | - E S Seryogina
- Research and Development Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya St, Orel, 302026, Russia
| | - E V Potapova
- Research and Development Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya St, Orel, 302026, Russia
| | - V V Dremin
- Research and Development Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya St, Orel, 302026, Russia
| | - A V Dunaev
- Research and Development Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya St, Orel, 302026, Russia
| | - S V Demyanenko
- Laboratory of Molecular Neuroscience, Academy of Biology and Biotechnology, Southern Federal University, 194/1 Stachki Ave, Rostov-On-Don, 344090, Russia.
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Soltani A, Chugaeva UY, Ramadan MF, Saleh EAM, Al-Hasnawi SS, Romero-Parra RM, Alsaalamy A, Mustafa YF, Zamanian MY, Golmohammadi M. A narrative review of the effects of dexamethasone on traumatic brain injury in clinical and animal studies: focusing on inflammation. Inflammopharmacology 2023; 31:2955-2971. [PMID: 37843641 DOI: 10.1007/s10787-023-01361-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/26/2023] [Indexed: 10/17/2023]
Abstract
Traumatic brain injury (TBI) is a type of brain injury resulting from a sudden physical force to the head. TBI can range from mild, such as a concussion, to severe, which might result in long-term complications or even death. The initial impact or primary injury to the brain is followed by neuroinflammation, excitotoxicity, and oxidative stress, which are the hallmarks of the secondary injury phase, that can further damage the brain tissue. Dexamethasone (DXM) has neuroprotective effects. It reduces neuroinflammation, a critical factor in secondary injury-associated neuronal damage. DXM can also suppress the microglia activation and infiltrated macrophages, which are responsible for producing pro-inflammatory cytokines that contribute to neuroinflammation. Considering the outcomes of this research, some of the effects of DXM on TBI include: (1) DXM-loaded hydrogels reduce apoptosis, neuroinflammation, and lesion volume and improves neuronal cell survival and motor performance, (2) DXM treatment elevates the levels of Ndufs2, Gria3, MAOB, and Ndufv2 in the hippocampus following TBI, (3) DXM decreases the quantity of circulating endothelial progenitor cells, (4) DXM reduces the expression of IL1, (5) DXM suppresses the infiltration of RhoA + cells into primary lesions of TBI and (6) DXM treatment led to an increase in fractional anisotropy values and a decrease in apparent diffusion coefficient values, indicating improved white matter integrity. According to the study, the findings show that DXM treatment has neuroprotective effects in TBI. This indicates that DXM is a promising therapeutic approach to treating TBI.
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Affiliation(s)
- Afsaneh Soltani
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Uliana Y Chugaeva
- Department of Pediatric, Preventive Dentistry and Orthodontics, Institute of Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | - Ebraheem Abdu Musad Saleh
- Department of Chemistry, Prince Sattam Bin Abdulaziz University, College of Arts and Science, 11991, Wadi Al-Dawasir, Saudi Arabia
| | | | | | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran.
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran.
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran.
| | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Chan-Ling T, Hu P, Li Calzi S, Warner J, Uddin N, DuPont M, Neuringer M, Kievit P, Renner L, Stoddard J, Ryals R, Boulton ME, McGill T, Grant MB. Glial, Neuronal, Vascular, Retinal Pigment Epithelium, and Inflammatory Cell Damage in a New Western Diet-Induced Primate Model of Diabetic Retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1789-1808. [PMID: 36965774 PMCID: PMC10616715 DOI: 10.1016/j.ajpath.2023.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/31/2023] [Accepted: 02/16/2023] [Indexed: 03/27/2023]
Abstract
This study investigated retinal changes in a Western diet (WD)-induced nonhuman primate model of type 2 diabetes. Rhesus nonhuman primates, aged 15 to 17 years, were fed a high-fat diet (n = 7) for >5 years reflective of the traditional WD. Age-matched controls (n = 6) were fed a standard laboratory primate diet. Retinal fundus photography, optical coherence tomography, autofluorescence imaging, and fluorescein angiography were performed before euthanasia. To assess diabetic retinopathy (DR), eyes were examined using trypsin digests, lipofuscin autofluorescence, and multimarker immunofluorescence on cross-sections and whole mounts. Retinal imaging showed venous engorgement and tortuosity, aneurysms, macular exudates, dot and blot hemorrhages, and a marked increase in fundus autofluorescence. Post-mortem changes included the following: decreased CD31 blood vessel density (P < 0.05); increased acellular capillaries (P < 0.05); increased density of ionized calcium-binding adaptor molecule expressing amoeboid microglia/macrophage; loss of regular distribution in stratum and spacing typical of ramified microglia; and increased immunoreactivity of aquaporin 4 and glial fibrillary acidic protein (P < 0.05). However, rhodopsin immunoreactivity (P < 0.05) in rods and neuronal nuclei antibody-positive neuronal density of 50% (P < 0.05) were decreased. This is the first report of a primate model of DR solely induced by a WD that replicates key features of human DR.
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Affiliation(s)
- Tailoi Chan-Ling
- Department of Anatomy, Faculty of Medicine and Health, Bosch Institute, University of Sydney, Camperdown, New South Wales, Australia.
| | - Ping Hu
- Department of Anatomy, Faculty of Medicine and Health, Bosch Institute, University of Sydney, Camperdown, New South Wales, Australia; Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, Alabama
| | - Sergio Li Calzi
- Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, Alabama
| | - Jeff Warner
- Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, Alabama
| | - Nasir Uddin
- Department of Anatomy, Faculty of Medicine and Health, Bosch Institute, University of Sydney, Camperdown, New South Wales, Australia; Faculty of Science and Technology, Centre for Research in Therapeutic Solutions, University of Canberra, Bruce, Australian Capital Territory, Australia
| | - Mariana DuPont
- Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, Alabama
| | - Martha Neuringer
- Department of Neuroscience, Oregon Health and Science University, Beaverton, Oregon
| | - Paul Kievit
- Division of Cardiometabolic Health, Oregon Health and Science University, Beaverton, Oregon
| | - Lauren Renner
- Department of Neuroscience, Oregon Health and Science University, Beaverton, Oregon
| | - Jonathan Stoddard
- Integrated Pathology Core, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon
| | - Renee Ryals
- Department of Ophthalmology, Oregon Health and Science University, Beaverton, Oregon
| | - Michael E Boulton
- Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, Alabama
| | - Trevor McGill
- Department of Neuroscience, Oregon Health and Science University, Beaverton, Oregon
| | - Maria B Grant
- Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, Alabama.
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Zhang X, Wang LP, Ziober A, Zhang PJ, Bagg A. Ionized Calcium Binding Adaptor Molecule 1 (IBA1). Am J Clin Pathol 2021; 156:86-99. [PMID: 33582751 DOI: 10.1093/ajcp/aqaa209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Ionized calcium binding adaptor molecule 1 (IBA1), a marker of microglia/macrophages, has not been investigated in human hematopathologic contexts. We evaluated its expression in mature and immature neoplasms of monocytic/histiocytic and dendritic cell (DC) origin. METHODS Immunohistochemistry for IBA1, CD14, CD68, and CD163 was performed on a total of 114 cases, including a spectrum of monocytic/histiocytic and DC neoplasms (20 tissue based and 59 bone marrow based) and several nonhistiocytic/monocytic/DC neoplasms as control groups (15 tissue based and 20 bone marrow based). RESULTS IBA1 expression was observed in all types of mature tissue-based histiocytic/DC neoplasms (20/20) but not in the corresponding control group (0/15). In bone marrow-based cases, IBA1 was expressed in most acute myeloid leukemias (AMLs) with monocytic differentiation (48/53), both blastic plasmacytoid dendritic cell neoplasms (2/2), and all chronic myelomonocytic leukemias (4/4), while it was positive in only one nonmonocytic AML (1/15) and none of the acute lymphoblastic leukemias (0/5). Collectively, IBA1 showed much higher sensitivity and specificity (93.7%, 97.1%) compared with CD14 (65.4%, 88.2%), CD68 (74.4%, 74.2%), and CD163 (52.6%, 90.6%). CONCLUSIONS IBA1 is a novel, highly sensitive, and specific marker for diagnosing neoplasms of monocytic/histiocytic and DC origin.
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Affiliation(s)
- Xiaoming Zhang
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Li-Ping Wang
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Amy Ziober
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Paul J Zhang
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Adam Bagg
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
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The Crosstalk between Calcium Ions and Aldosterone Contributes to Inflammation, Apoptosis, and Calcification of VSMC via the AIF-1/NF- κB Pathway in Uremia. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3431597. [PMID: 33343805 PMCID: PMC7732390 DOI: 10.1155/2020/3431597] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 10/21/2020] [Accepted: 10/28/2020] [Indexed: 12/14/2022]
Abstract
Vascular calcification is a major complication of maintenance hemodialysis patients. Studies have confirmed that calcification mainly occurs in the vascular smooth muscle cells (VSMC) of the vascular media. However, the exact pathogenesis of VSMC calcification is still unknown. This study shows that the crosstalk between calcium and aldosterone via the allograft inflammatory factor 1 (AIF-1) pathway contributes to calcium homeostasis and VSMC calcification, which is a novel mechanism of vascular calcification in uremia. In vivo results showed that the level of aldosterone and inflammatory factors increased in calcified arteries, whereas no significant changes were observed in peripheral blood. However, the expression of inflammatory factors markedly increased in the peripheral blood of uremic rats without aortic calcification and gradually returned to normal levels with aggravation of aortic calcification. In vitro results showed that there was an interaction between calcium ions and aldosterone in macrophages or VSMC. Calcium induced aldosterone synthesis, and in turn, aldosterone also triggered intracellular calcium content upregulation in macrophages or VSMC. Furthermore, activated macrophages induced inflammation, apoptosis, and calcification of VSMC. Activated VSMC also imparted a similar effect on untreated VSMC. Finally, AIF-1 enhanced aldosterone- or calcium-induced VSMC calcification, and NF-κB inhibitors inhibited the effect of AIF-1 on VSMC. These in vivo and in vitro results suggest that the crosstalk between calcium ions and aldosterone plays an important role in VSMC calcification in uremia via the AIF-1/NF-κB pathway. Local calcified VSMC induced the same pathological process in surrounding VSMC, thereby contributing to calcium homeostasis and accelerating vascular calcification.
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Allograft Inflammatory Factor-1 in Metazoans: Focus on Invertebrates. BIOLOGY 2020; 9:biology9110355. [PMID: 33114451 PMCID: PMC7692721 DOI: 10.3390/biology9110355] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/26/2020] [Accepted: 10/21/2020] [Indexed: 11/17/2022]
Abstract
Simple Summary During their life, all living organisms defend themselves from pathogens using complex strategies. Vertebrates and invertebrates share mechanisms and molecules that guarantee their overall bodily integrity. Allograft inflammatory factor-1 (AIF-1) is a protein extensively studied in vertebrates, and especially in mammals. This factor, generally involved in inflammation events occurring upon pathogenic infection or tissue injury, is linked to several important human diseases. This review collects data on the presence and role of AIF-1 in invertebrates, which are still poorly investigated organisms. Multiple alignment and phylogenetic analysis reveal that AIF-1 is conserved in vertebrates and invertebrates, suggesting similarity of functions. In some invertebrate species, the expression of AIF-1 increases considerably after a bacterial challenge, indicating that it plays a key role during the immune responses. This review highlights the importance of studying this protein in invertebrates as a way to improve our knowledge of innate immunity mechanisms and to better understand inflammatory regulation events in mammals. Abstract Allograft inflammatory factor-1 (AIF-1) is a calcium-binding scaffold/adaptor protein often associated with inflammatory diseases. Originally cloned from active macrophages in humans and rats, this gene has also been identified in other vertebrates and in several invertebrate species. Among metazoans, AIF-1 protein sequences remain relatively highly conserved. Generally, the highest expression levels of AIF-1 are observed in immunocytes, suggesting that it plays a key role in immunity. In mammals, the expression of AIF-1 has been reported in different cell types such as activated macrophages, microglial cells, and dendritic cells. Its main immunomodulatory role during the inflammatory response has been highlighted. Among invertebrates, AIF-1 is involved in innate immunity, being in many cases upregulated in response to biotic and physical challenges. AIF-1 transcripts result ubiquitously expressed in all examined tissues from invertebrates, suggesting its participation in a variety of biological processes, but its role remains largely unknown. This review aims to present current knowledge on the role and modulation of AIF-1 and to highlight its function along the evolutionary scale.
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Sun J, Xu H, Qi M, Zhang C, Shi J. Identification of key genes in osteosarcoma by meta‑analysis of gene expression microarray. Mol Med Rep 2019; 20:3075-3084. [PMID: 31432118 PMCID: PMC6755242 DOI: 10.3892/mmr.2019.10543] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 06/17/2019] [Indexed: 12/17/2022] Open
Abstract
Osteosarcoma (OS) is one of the most malignant tumors in children and young adults. To better understand the underlying mechanism, five related datasets deposited in the Gene Expression Omnibus were included in the present study. The Bioconductor ‘limma’ package was used to identify differentially expressed genes (DEGs) and the ‘Weighted Gene Co-expression Network Analysis’ package was used to construct a weighted gene co-expression network to identify key modules and hub genes, associated with OS. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes overrepresentation analyses were used for functional annotation. The results indicated that 1,405 genes were dysregulated in OS, including 927 upregulated and 478 downregulated genes, when the cut off value was set at a ≥2 fold-change and an adjusted P-value of P<0.01 was used. Functional annotation of DEGs indicated that these genes were involved in the extracellular matrix (ECM) and that they function in several processes, including biological adhesion, ECM organization, cell migration and leukocyte migration. These findings suggested that dysregulation of the ECM shaped the tumor microenvironment and modulated the OS hallmark. Genes assigned to the yellow module were positively associated with OS and could contribute to the development of OS. In conclusion, the present study has identified several key genes that are potentially druggable genes or therapeutics targets in OS. Functional annotations revealed that the dysregulation of the ECM may contribute to OS development and, therefore, provided new insights to improve our understanding of the mechanisms underlying OS.
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Affiliation(s)
- Junkui Sun
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongen Xu
- Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Muge Qi
- Henan Center for Disease Control and Prevention, Zhengzhou, Henan 450016, P.R. China
| | - Chi Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jianxiang Shi
- Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Egaña-Gorroño L, Chinnasamy P, Casimiro I, Almonte VM, Parikh D, Oliveira-Paula GH, Jayakumar S, Law C, Riascos-Bernal DF, Sibinga NES. Allograft inflammatory factor-1 supports macrophage survival and efferocytosis and limits necrosis in atherosclerotic plaques. Atherosclerosis 2019; 289:184-194. [PMID: 31439353 DOI: 10.1016/j.atherosclerosis.2019.07.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 07/12/2019] [Accepted: 07/24/2019] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIMS Allograft inflammatory factor-1 (AIF1) has been characterized as a pro-inflammatory molecule expressed primarily in the monocyte/macrophage (MP) lineage and positively associated with various forms of vascular disease, including atherosclerosis. Studies of AIF1 in atherosclerosis have relied on mouse models in which AIF1 was overexpressed in either myeloid or smooth muscle cells, resulting in increased atherosclerotic plaque burden. How physiologic expression of AIF1 contributes to MP biology in atherogenesis is not known. METHODS Effects of global AIF1 deficiency on atherosclerosis were assessed by crossing Aif1-/- and ApoE-/- mice, and provoking hyperlipidemia with high fat diet feeding. Atherosclerotic plaques were studied en face and in cross section. Bone marrow-derived MPs (BMDMs) were isolated from Aif1-/- mice for study in culture. RESULTS Atherosclerotic plaques in Aif1-/-;ApoE-/- mice showed larger necrotic cores compared to those in ApoE-/- animals, without change in overall lesion burden. In vitro, lack of AIF1 reduced BMDM survival, phagocytosis, and efferocytosis. Mechanistically, AIF1 supported activation of the NF-κB pathway and expression of related target genes involved in stress response, inflammation, and apoptosis. Consistent with this in vitro BMDM phenotype, AIF1 deficiency reduced NF-κB pathway activity in vivo and increased apoptotic cell number in atherosclerotic lesions from Aif1-/-;ApoE-/- mice. CONCLUSIONS These findings characterize AIF1 as a positive regulator of the NF-κB pathway that supports MP functions such as survival and efferocytosis. In inflammatory settings such as atherosclerosis, these AIF1-dependent activities serve to clear cellular and other debris and limit necrotic core expansion, and may oppose lesion destabilization.
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Affiliation(s)
- Lander Egaña-Gorroño
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Prameladevi Chinnasamy
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Isabel Casimiro
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Vanessa M Almonte
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Dippal Parikh
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Gustavo H Oliveira-Paula
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Smitha Jayakumar
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Calvin Law
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Dario F Riascos-Bernal
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Nicholas E S Sibinga
- Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology) and Department of Developmental and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
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10
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Sarkar A, Shukla SK, Alqatawni A, Kumar A, Addya S, Tsygankov AY, Rafiq K. The Role of Allograft Inflammatory Factor-1 in the Effects of Experimental Diabetes on B Cell Functions in the Heart. Front Cardiovasc Med 2018; 5:126. [PMID: 30258845 PMCID: PMC6145033 DOI: 10.3389/fcvm.2018.00126] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 08/21/2018] [Indexed: 01/18/2023] Open
Abstract
Diabetes mellitus (DM) often causes chronic inflammation, hypertrophy, apoptosis and fibrosis in the heart and subsequently leads to myocardial remodeling, deteriorated cardiac function and heart failure. However, the etiology of the cardiac disease is unknown. Therefore, we assessed the gene expression in the left ventricle of diabetic and non-diabetic mice using Affymetrix microarray analysis. Allograft inflammatory factor-1 (AIF-1), one of the top downregulated B cell inflammatory genes, is associated with B cell functions in inflammatory responses. Real-time reverse transcriptase-polymerase chain reaction confirmed the Affymetrix data. The expression of CD19 and AIF-1 were downregulated in diabetic hearts as compared to control hearts. Using in vitro migration assay, we showed for the first time that AIF-1 is responsible for B cell migration as B cells migrated to GFP-AIF-1-transfected H9C2 cells compared to empty vector-transfected cells. Interestingly, overexpression of AIF-1 in diabetic mice prevented streptozotocin-induced cardiac dysfunction, inflammation and promoted B cell homing into the heart. Our results suggest that AIF-1 downregulation inhibited B cell homing into diabetic hearts, thus promoting inflammation that leads to the development of diabetic cardiomyopathy, and that overexpression of AIF-1 could be a novel treatment for this condition.
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Affiliation(s)
- Amrita Sarkar
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States
| | - Sanket K Shukla
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States
| | - Aseel Alqatawni
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States
| | - Anil Kumar
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Sankar Addya
- Kimmel Cancer Centre, Thomas Jefferson University, Philadelphia, PA, United States
| | - Alexander Y Tsygankov
- Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Khadija Rafiq
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, United States
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11
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Ikeda H, Ishii A, Sano K, Chihara H, Arai D, Abekura Y, Nishi H, Ono M, Saji H, Miyamoto S. Activatable fluorescence imaging of macrophages in atherosclerotic plaques using iron oxide nanoparticles conjugated with indocyanine green. Atherosclerosis 2018; 275:1-10. [DOI: 10.1016/j.atherosclerosis.2018.05.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 05/01/2018] [Accepted: 05/16/2018] [Indexed: 10/16/2022]
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12
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Li Y, Wang X, Zhang L, Yuan X, Hao J, Ni J, Hao L. Upregulation of allograft inflammatory factor‑1 expression and secretion by macrophages stimulated with aldosterone promotes renal fibroblasts to a profibrotic phenotype. Int J Mol Med 2018; 42:861-872. [PMID: 29749461 PMCID: PMC6034929 DOI: 10.3892/ijmm.2018.3667] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 05/04/2018] [Indexed: 02/07/2023] Open
Abstract
Macrophages have been identified as a key cell type in the pathogenesis of renal interstitial fibrosis (RIF). However, the mechanism through which macrophages drive fibrosis remains unclear. The current study focuses on the effects and possible underlying mechanism of allograft inflammatory factor-1 (AIF-1), an inflammation-responsive scaffold protein expressed and secreted by macrophages, in promoting fibroblasts to a profibrotic phenotype. In vivo experiments indicated that AIF-1, CD68 and α-smooth muscle actin (α-SMA) were upregulated in kidney tissues of mice subjected to unilateral ureteric obstruction, while their expressions were inhibited by an aldosterone receptor antagonist, spironolactone. Double immunofluorescence staining revealed that AIF-1 expression co-localized with CD68-positive macrophages in the renal interstitium, indicating that AIF-1 expression in macrophages was increased in the RIF animal model. Furthermore, to identify the role of AIF-1 in promoting fibrosis, its expression and secretion by the RAW264.7 macrophage cell line were detected in vitro. The expression levels of α-SMA, phosphorylated p38 (p-p38) and fibronectin (FN) in fibroblasts were examined subsequent to co-culture with macrophages. The increase in AIF-1 expression and secretion was confirmed in RAW264.7 cells in response to aldosterone. After 72 h of co-culture between fibroblasts and macrophages stimulated with aldosterone, the α-SMA expression was induced in fibroblasts, with significantly increased expression levels of FN and p-p38 observed. In addition, AIF-1 expression was reduced by stable transfection of RAW264.7 cells with AIF-1 small interfering RNA, resulting in significantly reduced expression levels of α-SMA, p-p38 and FN in fibroblasts co-cultured with macrophages as compared with normal macrophages. These findings indicate that the expression of AIF-1 in macrophages is critical for the activation of renal fibroblasts to a profibrotic phenotype. AIF-1 expression was upregulated in macrophages, and may be a novel mechanism linking macrophages to the promotion of RIF via the p38 signaling pathway.
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Affiliation(s)
- Yushu Li
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xingzhi Wang
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Lei Zhang
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xueying Yuan
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jianbing Hao
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jie Ni
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Lirong Hao
- Department of Nephropathy, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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13
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Huang J, Li S, Liu Y, Liu C, Xie L, Zhang R. Hemocytes in the extrapallial space of Pinctada fucata are involved in immunity and biomineralization. Sci Rep 2018; 8:4657. [PMID: 29545643 PMCID: PMC5854705 DOI: 10.1038/s41598-018-22961-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 03/01/2018] [Indexed: 01/04/2023] Open
Abstract
In bivalves, the mantle tissue secretes organic matrix and inorganic ions into the extrapallial space (EPS) to form the shells. In addition, more and more evidences indicate the participation of hemocytes in shell mineralization, but no direct evidence has been reported that verifies the presence of hemocytes in the EPS, and their exact roles in biomineralization remain uncertain. Here, we identified hemocytes from the EPS of Pinctada fucata. Numerous components involved in cellular and humoral immunity were identified by proteome analysis, together with several proteins involved in calcium metabolism. The hemocytes exerted active phagocytosis and significantly upregulated the expression of immune genes after immune stimulation. A group of granulocytes were found to contain numerous calcium-rich vesicles and crystals, which serve as a calcium pool. During shell regeneration, some genes involved in calcium metabolism are upregulated. Strikingly, most of the shell matrix proteins were absent in the hemocytes, suggesting that they might not be solely responsible for directing the growth of the shell. Taken together, our results provided comprehensive information about the function of hemocytes in immunity and shell formation.
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Affiliation(s)
- Jingliang Huang
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Shiguo Li
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yangjia Liu
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Chuang Liu
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.,Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Liping Xie
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Rongqing Zhang
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. .,Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, 314000, China.
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14
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Schorn T, Drago F, Tettamanti G, Valvassori R, de Eguileor M, Vizioli J, Grimaldi A. Homolog of allograft inflammatory factor-1 induces macrophage migration during innate immune response in leech. Cell Tissue Res 2014; 359:853-64. [PMID: 25435328 DOI: 10.1007/s00441-014-2058-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 10/24/2014] [Indexed: 11/29/2022]
Abstract
Allograft inflammatory factor-1 (AIF-1) is a 17-kDa cytokine-inducible calcium-binding protein that, in vertebrates, plays an important role in the allograft immune response. Its expression is mostly limited to the monocyte/macrophage lineage. Until recently, AIF-1 was assumed to be a novel molecule involved in inflammatory responses. To clarify this aspect, we have investigated the expression of AIF-1 after bacterial challenge and its potential role in regulating the innate immune response in an invertebrate model, the medicinal leech (Hirudo medicinalis). Analysis of an expressed sequence tag library from the central nervous system of Hirudo revealed the presence of the gene Hmaif-1/alias Hmiba1, showing high homology with vertebrate aif-1. Immunohistochemistry with an anti-HmAIF-1 polyclonal antibody revealed the constitutive presence of this protein in spread CD68(+) macrophage-like cells. A few hours after pathogen (bacterial) injection into the body wall, the amount of these immunopositive cells co-expressing HmAIF-1 and the common leucocyte marker CD45 increased at the injected site. Moreover, the recombinant protein HmAIF-1 induced massive angiogenesis and was a potent chemoattractant for macrophages. Following rHmAIF-1 stimulation, macrophage-like cells co-expressed the macrophage marker CD68 and the surface glycoprotein CD45, which, in vertebrates, seems to have a role in the integrin-mediated adhesion of macrophages and in the regulation of the functional responsiveness of cells to chemoattractants. CD45 is therefore probably involved in leech macrophage-like cell activation and migration towards an inflammation site. We have also examined its potential effect on HmAIF-1-induced signalling.
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Affiliation(s)
- Tilo Schorn
- Department of Biotechnology and Life Sciences, University of Insubria, Via J.H. Dunant 3, 21100, Varese, Italy
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15
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Lorente-Cebrián S, Decaunes P, Dungner E, Bouloumié A, Arner P, Dahlman I. Allograft inflammatory factor 1 (AIF-1) is a new human adipokine involved in adipose inflammation in obese women. BMC Endocr Disord 2013; 13:54. [PMID: 24267103 PMCID: PMC4175115 DOI: 10.1186/1472-6823-13-54] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 08/20/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Allograft inflammatory factor 1 (AIF-1) is a putative obesity gene. Our aim was to examine the expression of AIF-1 in human white adipose tissue (WAT) in relation to obesity and metabolic phenotypes in women. METHODS WAT secretion of AIF-1 was determined in subcutaneous adipose tissue pieces in vitro by ELISA from 5 subjects. mRNA expression of AIF-1 was determined by RT-qPCR in the isolated cell fractions of adipose tissue (n = 5-6 per group), in subcutaneous and visceral WAT pieces from non-obese (n = 12) and obese women (n = 23), and in some subcutaneous WAT also before and after weight reduction (n = 10). Finally, adipose AIF-1 mRNA was related to metabolic phenotypes in 96 subjects with a wide range of BMI. RESULTS AIF-1 was secreted in a time dependent fashion from WAT. The major source of AIF-1 was WAT resident macrophages. Expression of AIF-1 was similar in visceral and subcutaneous WAT and was two-fold increased in obese women (P < 0.01). AIF-1 mRNA expression levels were normalized after weight reduction (P < 0.01). Expression of AIF-1 was inversely correlated with insulin sensitivity as assessed by insulin tolerance test (KITT), and circulating levels of adiponectin (P = 0.02), and positively correlated with insulin resistance as estimated by HOMA (=0.0042). CONCLUSIONS AIF-1 is a novel adipokine produced mainly by macrophages within human WAT. Its expression is increased in obese women and associates with unfavourable metabolic phenotypes. AIF-1 may play a paracrine role in the regulation of WAT function through cross-talk between macrophages and other cell types within the adipose tissue.
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Affiliation(s)
- Silvia Lorente-Cebrián
- Department of Medicine Huddinge, Lipid Laboratory, Novum, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Huddinge, Stockholm, Sweden
| | - Pauline Decaunes
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut des maladies cardiovasculaires et métaboliques, Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Elisabeth Dungner
- Department of Medicine Huddinge, Lipid Laboratory, Novum, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Huddinge, Stockholm, Sweden
| | - Anne Bouloumié
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut des maladies cardiovasculaires et métaboliques, Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Peter Arner
- Department of Medicine Huddinge, Lipid Laboratory, Novum, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Huddinge, Stockholm, Sweden
| | - Ingrid Dahlman
- Department of Medicine Huddinge, Lipid Laboratory, Novum, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Huddinge, Stockholm, Sweden
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Fukui M, Tanaka M, Toda H, Asano M, Yamazaki M, Hasegawa G, Imai S, Fujinami A, Ohta M, Nakamura N. The serum concentration of allograft inflammatory factor-1 is correlated with metabolic parameters in healthy subjects. Metabolism 2012; 61:1021-5. [PMID: 22225958 DOI: 10.1016/j.metabol.2011.12.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 12/04/2011] [Accepted: 12/05/2011] [Indexed: 02/04/2023]
Abstract
Obesity is associated with low-grade chronic inflammation characterized by inflamed adipose tissue with increased infiltration of macrophages. The aim of this study was to investigate the correlations between the serum concentration of allograft inflammatory factor-1 (AIF-1), which is a marker of activated macrophages, and metabolic parameters. The serum AIF-1 concentrations were measured in 303 healthy subjects (163 men and 140 women). We then evaluated the relationships between the serum AIF-1 concentrations and metabolic parameters, including fasting plasma glucose levels, serum lipid concentration, uric acid concentration, and waist circumference. The serum AIF-1 concentrations positively correlated with levels of fasting plasma glucose (r = 0.159, P =.0056), hemoglobin A(1c) (r = 0.169, P = .0032), triglycerides (r = 0.137, P = .0172), and uric acid (r = 0.146, P = .0108) and with waist circumference (r = 0.221, P = .0001) and body mass index (r = 0.185, P = .0012), whereas the serum AIF-1 concentrations inversely correlated with high-density lipoprotein cholesterol level (r = -0.178, P = .0019). Stepwise multiple regression analysis demonstrated that hemoglobin A(1c) level (β = .133, F = 5.490, P < .05) and waist circumference (β = .197, F = 11.954, P < .05) were independent predictors of the serum AIF-1 concentrations. The serum AIF-1 concentrations correlated with clinical and biochemical metabolic parameters. Allograft inflammatory factor-1 may be a significant predictor of activated macrophages as well as cardiovascular disease in humans.
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Affiliation(s)
- Michiaki Fukui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kamigyo-ku, Kyoto 602-8566, Japan.
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17
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Steck AJ, Kinter J, Renaud S. Differential gene expression in nerve biopsies of inflammatory neuropathies. J Peripher Nerv Syst 2011; 16 Suppl 1:30-3. [PMID: 21696494 DOI: 10.1111/j.1529-8027.2011.00302.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
DNA microarray analysis is a powerful tool for simultaneous analysis and comparison of gene products expressed in normal and diseased tissues. We used this technique to identify differentially expressed genes (DEGs) in nerve biopsy samples of chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VAS) patients. We found novel previously uncharacterized genes of relevance to CIDP or VAS pathogenesis. Of particular interest in CIDP were tachykinin precursor 1, which may be involved in pain mediation, stearoyl-co-enzyme A (CoA) desaturase, which may be a marker for remyelination, HLA-DQB1, CD69, an early T-cell activation gene, MSR1, a macrophage scavenger receptor, and PDZ and LIM domain 5 (PDLIM5), a factor regulating nuclear factor (NF)-kappa B activity. Genes upregulated in VAS included IGLJ3, IGHG3, IGKC, and IGL, which all function in B-cell selection or antigen recognition of B cells. Other upregulated genes included chemokines, such as CXCL9 and CCR2, as well as CPA3, a mast cell carboxypeptidase. Allograft inflammatory factor-1 (AIF-1), a modulator of immune response was upregulated both in CIDP and VAS. Microarray-based analysis of human sural nerve biopsies showed distinct gene expression patterns in CIDP and VAS. DEGs might provide clues to the pathogenesis of the diseases and be potential targets for therapeutics.
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Affiliation(s)
- Andreas J Steck
- Department of Biomedicine Department of Neurology, University Hospital Basel, Petersgraben 4, Basel, Switzerland.
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18
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Expression of allograft inflammatory factor-1 (AIF-1) in acute cellular rejection of cardiac allografts. Cardiovasc Pathol 2011; 20:e177-84. [DOI: 10.1016/j.carpath.2010.08.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 07/27/2010] [Accepted: 08/09/2010] [Indexed: 11/18/2022] Open
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Sommerville LJ, Kelemen SE, Ellison SP, England RN, Autieri MV. Increased atherosclerosis and vascular smooth muscle cell activation in AIF-1 transgenic mice fed a high-fat diet. Atherosclerosis 2011; 220:45-52. [PMID: 21862018 DOI: 10.1016/j.atherosclerosis.2011.07.095] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Revised: 06/22/2011] [Accepted: 07/13/2011] [Indexed: 02/02/2023]
Abstract
Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, scaffold signal transduction protein constitutively expressed in inflammatory cells, but inducible in vascular smooth muscle cells (VSMCs) in response to injury or inflammatory stimuli. Although several basic science and population studies have reported increased AIF-1 expression in human and experimental atherosclerosis, a direct causal effect of AIF-1 expression on development of atherosclerosis has not been reported. The purpose of this study is to establish a direct relationship between AIF-1 expression and development of atherosclerosis. AIF-1 expression is detected VSMC in atherosclerotic lesions from ApoE(-/-) mice, but not normal arteries from wild-type mice. AIF-1 expression can be induced in cultured VSMC by stimulation with oxidized LDL (ox-LDL). Transgenic mice in which AIF-1 expression is driven by the G/C modified SM22 alpha promoter to restrict AIF-1 expression to VSMC develop significantly increased atherosclerosis compared with wild-type control mice when fed a high-fat diet (P=0.022). Cultured VSMC isolated from Tg mice demonstrated significantly increased migration in response to ox-LDL compared with matched controls (P<0.001). VSMC isolated from Tg mice and cultured human VSMC which over express AIF-1 demonstrated increased expression of MMP-2 and MMP-9 mRNA and protein and increased NF-κB activation in response to ox-LDL as compared with wild-type control mice. VSMC which over express AIF-1 have significantly increased uptake of ox-LDL, and increased CD36 expression. Together, these data suggest a strong association between AIF-1 expression, NF-κB activation, and development of experimental atherosclerosis.
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Affiliation(s)
- Laura J Sommerville
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, United States
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McDaniel DO, Zhou X, Moore CK, Aru G. Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1. Transplant Proc 2011; 42:4235-7. [PMID: 21168672 DOI: 10.1016/j.transproceed.2010.09.091] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Accepted: 09/22/2010] [Indexed: 10/18/2022]
Abstract
BACKGROUND Evidence suggests that injury-induced activation of the recipient's innate immune response determines the outcome of allograft transplantation. The mechanism responsible for the induction of such innate immune response is not clear yet. We hypothesized that in cardiac transplantation settings, the initial myocardial ischemia and postischemia graft reperfusion may release allograft inflammatory factor (AIF) 1, causing Toll-like receptor (TLR)-mediated activation of macrophages and dendritic cells, leading to the production of cytokines and the activation of adaptive alloimmunity. Therefore, our goal was to validate the presence of these biomarkers in the peripheral blood and biopsy specimens of patients presenting allograft rejection. METHODS We studied 90 peripheral blood and 30 endomyocardial biopsy specimens from patients who had undergone cardiac transplantation. Specimens were tested by quantitative reverse-transcription polymerase chain reaction to determine TLR-2 and -4 and AIF-1 expression levels, correlating with clinical rejection grades. The group differences for mRNA transcript levels between the rejection grades were determined by 1-way analysis of variance. The level of significance was set at P < .05 for comparison between the groups. RESULTS The mean ± SEM level of TLR-2 mRNA expression was increased 1.7-fold in monocytes (P < .05) and 4.2-fold in biopsy samples from groups with grade 3A compared with grade 1A or grade 0 rejection (P < .0001). AIF-1 expression was increased 2.4-fold in monocytes (P < .05) and 4.2-fold in biopsy samples comparing grade 3A versus 1A rejections. The TLR-4 mRNA expression was also increased in the group with 3A rejections; however, the difference was only significant in biopsy specimens (P < .0001). CONCLUSIONS Our data demonstrated that expression profiles of AIF-1 and TLR-2 correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting their potential as diagnostic biomarkers for early detection of allograft rejection.
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Affiliation(s)
- D O McDaniel
- Department of Surgery, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
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21
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Daintain/AIF-1 promotes breast cancer cell migration by up-regulated TNF-α via activate p38 MAPK signaling pathway. Breast Cancer Res Treat 2011; 131:891-8. [PMID: 21509525 DOI: 10.1007/s10549-011-1519-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2011] [Accepted: 04/11/2011] [Indexed: 12/15/2022]
Abstract
Tumor-associated macrophages can release a vast diversity of growth factors, proteolytic enzymes, cytokines, and inflammatory mediators. Many of these factors are key agents in cancer metastasis. Daintain/AIF-1 is a macrophage-derived inflammatory cytokine which defined a distinct subset of tumor-associated activated macrophages/microglial cells. Previous study demonstrated that daintain/AIF-1 could promote breast cancer proliferation through activating NF-κB/cyclin D1 pathway and facilitate tumor growth. However, the effect of Daintain/AIF-1 on cell migration and cancer metastasis has never been reported. Herein, we used a mimic tumor microenvironment by incubating breast cancer cell lines, MDA-MB-231 and MCF-7 cells, with macrophage-conditioned medium with or without purified daintain/AIF-1 polypeptide to evaluate cell migration. Results indicated that daintain/AIF-1 enhanced the migration of MDA-MB-231 and MCF-7 cells in the manner of TNF-α up-regulation. Further study found that daintain/AIF-1 activates p38 MAPK signaling pathway contributing to up-regulation of TNF-α in MDA-MB-231 and MCF-7 cells. Therefore, this novel daintain/AIF-1-p38-TNF-α pathway and insight into daintain/AIF-1 might have potential benefits in the control of tumor metastasis during cancer therapy.
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Allograft Inflammatory Factor-1 is Up-regulated in Warm and Cold Ischemia-Reperfusion Injury in Rat Liver and May be Inhibited by FK506. J Surg Res 2011; 165:158-64. [DOI: 10.1016/j.jss.2009.05.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2009] [Revised: 05/05/2009] [Accepted: 05/19/2009] [Indexed: 11/23/2022]
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Lee AW, Chen TL, Shih CM, Huang CY, Tsao NW, Chang NC, Chen YH, Fong TH, Lin FY. Ursolic acid induces allograft inflammatory factor-1 expression via a nitric oxide-related mechanism and increases neovascularization. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:12941-9. [PMID: 21070071 DOI: 10.1021/jf103265x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Ursolic acid (UA), a triterpenoid compound found in plants, is used in the human diet and in medicinal herbs and possesses a wide range of biological benefits including antioxidative, anti-inflammatory, and anticarcinogenic effects. Endothelial expression of allograft inflammatory factor-1 (AIF-1) mediates vasculogenesis, and nitric oxide (NO) produced by endothelial NO (eNOS) represents a mechanism of vascular protection. It is unclear whether UA affects the neovascularization mediated by AIF-1 and eNOS expression. This study investigated the effects and mechanisms of UA on angiogenesis in vivo in hind limb ischemic animal models and in vitro in human coronary artery endothelial cells (HCECs). This study explored the impact of UA on endothelial cell (EC) activities in vitro in HCECs, vascular neovasculogenesis in vivo in a mouse hind limb ischemia model, and the possible role of AIF-1 in vasculogenesis. The results demonstrate that UA enhances collateral blood flow recovery through induction of neovascularization in a hind limb ischemia mouse model. In vitro data showed that UA increases tube formation and migration capacities in human endothelial cells, and exposing HCECs to UA increased AIF-1 expression through a NO-related mechanism. Moreover, UA administration increased capillary density and eNOS and AIF-1 expression in ischemic muscle. These findings suggest that UA may be a potential therapeutic agent in the induction of neovascularization and provide a novel mechanistic insight into the potential effects of UA on ischemic vascular diseases.
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Affiliation(s)
- Ai-Wei Lee
- Graduate Institute of Medical Sciences and Department of Anatomy, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Yamamoto A, Ashihara E, Nakagawa Y, Obayashi H, Ohta M, Hara H, Adachi T, Seno T, Kadoya M, Hamaguchi M, Ishino H, Kohno M, Maekawa T, Kawahito Y. Allograft inflammatory factor-1 is overexpressed and induces fibroblast chemotaxis in the skin of sclerodermatous GVHD in a murine model. Immunol Lett 2010; 135:144-50. [PMID: 21040744 DOI: 10.1016/j.imlet.2010.10.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Revised: 10/23/2010] [Accepted: 10/24/2010] [Indexed: 11/29/2022]
Abstract
Allograft inflammatory factor (AIF)-1 has been identified in chronic rejection of rat cardiac allografts and is thought to be involved in the immune response. We previously showed that AIF-1 was strongly expressed in synovial tissues in rheumatoid arthritis and that rAIF-1 increased the IL-6 production of synoviocytes and peripheral blood mononuclear cells. Recently, the expression of AIF-1 has been reported in systemic sclerosis (SSc) tissues, whose clinical features and histopathology are similar to those of chronic graft-vs-host disease (GVHD). To clarify the pathogenic mechanism of fibrosis, we examined the expression and function of AIF in sclerodermatous (Scl) GVHD mice. We demonstrated that immunoreactive AIF-1 and IL-6 were significantly expressed in infiltrating mononuclear cells and fibroblasts in thickened skin of Scl GVHD mice compared with control. The immunohistochemical findings were confirmed by Western blot analysis. Wound healing assay also revealed that rAIF-1 increased the migration of normal human dermal fibroblasts (NHDF) directly, but cell growth assay did not show that rAIF-1 increased the proliferation of them. These findings suggest that AIF-1, which can induce the migration of fibroblasts and the production of IL-6 in affected skin tissues, is an important molecule promoting fibrosis in GVHD. Although the biological function of AIF-1 has not been completely elucidated, AIF-1 can induce IL-6 secretion on mononuclear cells and fibroblast chemotaxis. AIF-1 may accordingly provide an attractive new target for antifibrotic therapy in SSc as well as Scl GVHD.
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Affiliation(s)
- Aihiro Yamamoto
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
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25
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Kinter J, Broglio L, Steck AJ, Tolnay M, Fuhr P, Latov N, Kalbermatten D, Sinnreich M, Schaeren-Wiemers N, Renaud S. Gene expression profiling in nerve biopsy of vasculitic neuropathy. J Neuroimmunol 2010; 225:184-9. [DOI: 10.1016/j.jneuroim.2010.05.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Revised: 05/04/2010] [Accepted: 05/05/2010] [Indexed: 10/19/2022]
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Barker AK, McDaniel DO, Zhou X, He Z, Aru G, Thomas T, Moore CK. Combined Analysis of Allograft Inflammatory Factor-1, Interleukin-18, and Toll-Like Receptor Expression and Association with Allograft Rejection and Coronary Vasculopathy. Am Surg 2010. [DOI: 10.1177/000313481007600834] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In cardiac transplantation settings, the initial myocardial ischemia and reperfusion may cause myocyte tissue injury and the release of allograft inflammatory factor-1 (AIF-1). This in part may trigger the innate immune response through the modulation of Toll-like receptor-2 (TLR-2) and AIF-1 expression and function, causing the release of proinflammatory cytokines. The goal was to demonstrate these markers in the peripheral blood and biopsy specimen from recipients with cardiac allograft rejection and coronary vasculopathy (CV). Peripheral blood and endomyocardial specimens were tested by reverse transcriptase-polymerase chain reaction and immunohistochemistry stains for identification of TLR-2, -4, interleukin-18, and AIF-1 markers and analyzed against clinical rejection grades for rejection. The differences for mRNA transcript levels were determined by one-way analysis of variance. The mRNA expression levels were significantly varied for TLR-2 in monocytes with different rejection grades ( P < 0.0001). The mean ± SEM level of mRNA expression for 3A grade rejection was 64.21 ± 3.8; grade 1A, 38.4 ± 3.5; and for Grade 0 was 38.46 ± 2.8. The TLR-4 mRNA expression was increased but the specificity was not statistically significant. The TLR-2 immunoreactivity was strongly detected in infiltrating mononuclear cells and cardiac myocytes in Grade 3A rejection. AIF-1 expression was increased significantly in the group with 3A rejection and Grade III CV as compared with Grade 0 or 1A. Interleukin-18 receptors were strongly detected in Grade 3A rejection and CV. The expression profiles of AIF-1, TLR-2, and interleukin-18 were correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting a potential for diagnostic biomarkers for early detection of allograft rejection.
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Affiliation(s)
- Andrea K. Barker
- Departments of Surgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - D. Olga McDaniel
- Departments of Surgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Xinchun Zhou
- Pathology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Zelda He
- Pathology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Giorgio Aru
- Departments of Surgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Tammy Thomas
- Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Charles K. Moore
- Medicine, University of Mississippi Medical Center, Jackson, Mississippi
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Jia J, Cai Y, Wang R, Fu K, Zhao YF. Overexpression of allograft inflammatory factor-1 promotes the proliferation and migration of human endothelial cells (HUV-EC-C) probably by up-regulation of basic fibroblast growth factor. Pediatr Res 2010; 67:29-34. [PMID: 19745784 DOI: 10.1203/pdr.0b013e3181bf572b] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Our previous study demonstrated that allograft inflammatory factor-1 (AIF-1) is present in the vessels of infantile hemangiomas but neither in the vessels of vascular malformations, pyogenic granulomas, normal skin, placental tissues nor in the neovessels of squamous cell carcinomas of the tongue. The purpose of this study was to explore the impact of AIF-1 alterations on endothelial cells (EC). Stable introduction of AIF-1 to the human umbilical vein EC line (HUV-EC-C) in vitro revealed that AIF-1 enhances the proliferation and migration of the EC and promotes G0/G1-to-S-phase transition, accompanied by up-regulation of basic fibroblast growth factor (p < 0.05). In contrast, AIF-1 did not affect the expression of granulocyte colony-stimulating factor, VEGF-a, monocyte chemoattractant protein-1, or tissue inhibitor of metalloproteinase-1. AIF-1 expression was not induced by hypoxia, VEGF-a, basic fibroblast growth factor, or insulin-like growth factor-2 in EC. Taken together, these findings suggest that the impact of AIF-1 on EC would stimulate angiogenesis and consequently affect the progression of infantile hemangiomas.
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Affiliation(s)
- Jun Jia
- Key Laboratory of Oral Biomedical Engineering, Wuhan University, Wuhan 430079, China
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28
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Hinoki A, Kimura K, Higuchi S, Eguchi K, Takaguri A, Ishimaru K, Frank GD, Gerthoffer WT, Sommerville LJ, Autieri MV, Eguchi S. p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo. Hypertension 2009; 55:161-5. [PMID: 19901155 DOI: 10.1161/hypertensionaha.109.143057] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Vascular smooth muscle cell hypertrophy, proliferation, or migration occurs in hypertension, atherosclerosis, and restenosis after angioplasty, leading to pathophysiological vascular remodeling. Angiotensin II and platelet-derived growth factor are well-known participants of vascular remodeling and activate a myriad of downstream protein kinases, including p21-activated protein kinase (PAK1). PAK1, an effector kinase of small GTPases, phosphorylates several substrates to regulate cytoskeletal reorganization. However, the exact role of PAK1 activation in vascular remodeling remains to be elucidated. Here, we have hypothesized that PAK1 is a critical target of intervention for the prevention of vascular remodeling. Adenoviral expression of dominant-negative PAK1 inhibited angiotensin II-stimulated vascular smooth muscle cell migration. It also inhibited vascular smooth muscle cell proliferation induced by platelet-derived growth factor. PAK1 was activated in neointima of the carotid artery after balloon injury in the rat. Moreover, marked inhibition of the neointima hyperplasia was observed in a dominant-negative PAK1 adenovirus-treated carotid artery after the balloon injury. Taken together, these results suggest that PAK1 is involved in both angiotensin II and platelet-derived growth factor-mediated vascular smooth muscle cell remodeling, and inactivation of PAK1 in vivo could be effective in preventing pathophysiological vascular remodeling.
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Affiliation(s)
- Akinari Hinoki
- Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3500 N Broad St, Philadelphia, PA 19140, USA
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Broglio L, Erne B, Tolnay M, Schaeren-Wiemers N, Fuhr P, Steck AJ, Renaud S. Allograft inflammatory factor-1: A pathogenetic factor for vasculitic neuropathy. Muscle Nerve 2008; 38:1272-9. [DOI: 10.1002/mus.21033] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Tian Y, Jain S, Kelemen SE, Autieri MV. AIF-1 expression regulates endothelial cell activation, signal transduction, and vasculogenesis. Am J Physiol Cell Physiol 2008; 296:C256-66. [PMID: 18787073 DOI: 10.1152/ajpcell.00325.2008] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Endothelial cell (EC) activation plays a key role in vascular inflammation, thrombosis, and angiogenesis. Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein that has been implicated in the regulation of inflammation. The expression and function of AIF-1 in EC is uncharacterized, and the purpose of this study was to characterize AIF-1 expression and function in ECs. AIF-1 expression colocalized with CD31-positive ECs in neointima of inflamed human arteries but not normal arteries. AIF-1 is detected at low levels in unstimulated EC, but expression can be increased in response to serum and soluble factors. Stable transfection of AIF-1 small interfering RNA (siRNA) in ECs reduced AIF-1 protein expression by 73% and significantly reduced EC proliferation and migration (P < 0.05 and 0.001). Rescue of AIF-1 expression restored both proliferation and migration of siRNA-expressing ECs, and AIF-1 overexpression enhanced both of these activities, suggesting a strong association between AIF-1 expression and EC activation. Activation of mitogen-activated protein kinase p44/42 and PAK1 was significantly reduced in siRNA ECs challenged with inflammatory stimuli. Reduction of AIF-1 expression did not decrease EC tube-like structure or microvessel formation from aortic rings, but overexpression of AIF-1 did significantly increase the number and complexity of these structures. These data indicate that AIF-1 expression plays an important role in signal transduction and activation of ECs and may also participate in new vessel formation.
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Affiliation(s)
- Ying Tian
- Temple Univ. School of Medicine, Rm. 810, MRB, 3420 N. Broad St., Philadelphia, PA 19140, USA
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31
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Sommerville LJ, Xing C, Kelemen SE, Eguchi S, Autieri MV. Inhibition of allograft inflammatory factor-1 expression reduces development of neointimal hyperplasia and p38 kinase activity. Cardiovasc Res 2008; 81:206-15. [PMID: 18779232 DOI: 10.1093/cvr/cvn242] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
AIMS Allograft inflammatory factor-1 (AIF-1) is a calcium-binding, scaffold-signalling protein expressed in vascular smooth muscle cells (VSMCs) in response to injury. The effects of AIF-1 attenuation on development of intimal hyperplasia are unknown, and the molecular mechanisms of these effects remain uncharacterized. The goals of the present study were to determine whether AIF-1 knockdown reduced VSMC proliferation, migration, and intimal hyperplasia, and determine AIF-1 effects on signal transduction in VSMCs. METHODS AND RESULTS Balloon angioplasty-injured rat carotid arteries transduced with adenovirus to overexpress AIF-1 (AdAIF-1) significantly increased, and adenovirus to knock down AIF-1 (AdsiRNA) expression significantly decreased neointimal formation compared with green fluorescent protein (AdGFP) and Adscrambled controls (P < 0.05 and P < 0.01, n = 6). Primary rat VSMCs transduced with AdAIF-1 displayed a significant increase in proliferation, and AdsiRNA-transduced VSMCs proliferated significantly more slowly than controls (P < 0.05). VSMCs transduced with AdAIF-1 show increased migration when compared with control VSMCs (P < 0.01). Rat VSMCs transduced with AdAIF-1 showed constitutive and prolonged activation of the mitogen-activated protein kinase p38, whereas AdsiRNA-treated VSMCs showed decreased p38 activation compared with AdGFP (P < 0.05). Immunohistochemical analysis of AdAIF-1-transduced carotid arteries showed increased staining with a phospho-specific p38 antibody compared with AdGFP-transduced arteries. A specific p38 inhibitor abrogated AIF-1-induced VSMC proliferation, but not AIF-1-induced migration. CONCLUSION Taken together, AIF-1 expression plays a key role in the development of neointimal hyperplasia. AIF-1 expression enhances the activation of p38 MAP kinase. AIF-1-enhanced proliferation is p38 kinase dependent, but AIF-1-enhanced VSMC migration is p38 independent.
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Affiliation(s)
- Laura J Sommerville
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, 810, MRB, 3420 North Broad Street, Philadelphia, PA 19140, USA
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Schulze JO, Quedenau C, Roske Y, Adam T, Schüler H, Behlke J, Turnbull AP, Sievert V, Scheich C, Mueller U, Heinemann U, Büssow K. Structural and functional characterization of human Iba proteins. FEBS J 2008; 275:4627-40. [DOI: 10.1111/j.1742-4658.2008.06605.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Autieri MV. Kruppel-like factor 4: transcriptional regulator of proliferation, or inflammation, or differentiation, or all three? Circ Res 2008; 102:1455-7. [PMID: 18566311 DOI: 10.1161/circresaha.108.178954] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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34
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Su CH, Yeh HI, Hou CJY, Tsai CH. Nonviral Technologies for Gene Therapy in Cardiovascular Research. INT J GERONTOL 2008. [DOI: 10.1016/s1873-9598(08)70009-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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35
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Alexis JD, Pyo RT, Chereshnev I, Katz J, Rollins BJ, Charo IF, Taubman MB. Inhibition of MCP-1/CCR2 signaling does not inhibit intimal proliferation in a mouse aortic transplant model. J Vasc Res 2008; 45:538-46. [PMID: 18463419 DOI: 10.1159/000129688] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Accepted: 01/21/2008] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Transplant arteriopathy is the leading cause of long term morbidity and mortality following heart transplantation. Animal models have demonstrated that monocyte chemoattractant protein (MCP)-1 is induced early after transplant in cardiac and aortic allografts. We have previously reported that deficiency of MCP-1 or its receptor, CC chemokine receptor 2 (CCR2), is associated with a reduction in intimal proliferation in a mouse femoral artery injury model. Using knockout mice, we have now examined the role of MCP-1 and CCR2 in the development of the intimal proliferation of transplant arteriopathy. METHODS C57Bl/6 CCR2 and MCP-1 wild-type and knockout mice were used in the studies and aortic transplants were performed between Balb/c mice and C57Bl/6 mice. Aortas from recipient animals were harvested 8 weeks after transplant. RESULTS Unlike arterial injury, in an aortic transplant model inhibition of MCP-1/CCR2 signaling did not result in reduced intimal proliferation. CONCLUSIONS Despite a pathology that appears similar, the inflammatory mediators that regulate transplant arteriopathy differ from those regulating intimal proliferation secondary to wire injury. Our results suggest that targeting MCP-1/CCR2 signaling is not sufficient to block transplant arteriopathy across a complete MHC-mismatch barrier.
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Affiliation(s)
- Jeffrey D Alexis
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14586, USA.
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36
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Liu S, Tan WY, Chen QR, Chen XP, Fu K, Zhao YY, Chen ZW. Daintain/AIF-1 promotes breast cancer proliferation via activation of the NF-kappaB/cyclin D1 pathway and facilitates tumor growth. Cancer Sci 2008; 99:952-7. [PMID: 18341653 PMCID: PMC11159275 DOI: 10.1111/j.1349-7006.2008.00787.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2007] [Revised: 01/28/2008] [Accepted: 01/30/2008] [Indexed: 12/13/2022] Open
Abstract
Recent research indicates that inflammatory factors play important roles in the initiation and progression of cancers, including breast cancer. Daintain/allograft inflammatory factor-1 (AIF-1) is a crucial mediator in the inflammatory response, but it has not yet been reported whether daintain/AIF-1 is involved in the development of breast cancers. In this study, immunohistochemical analysis found strong positive expression of daintain/AIF-1 in breast ductal tumor epithelia, but only weakly positive or negative expression in the adjacent histologically normal ductal epithelia. Then, the effect of daintian/AIF-1 on the proliferation of the breast cancer cell line MDA-MB-231 was explored via transduction of the daintian/AIF-1 gene into the cells, and via inhibition of the expression of daintain/AIF-1 through short interference RNA. The results demonstrated that up-regulation and down-regulation of daintain/AIF-1 expressions promoted and inhibited the proliferation of MDA-MB-231, respectively. More interestingly, daintain/AIF-1 overexpression facilitated tumor growth in female nude mice. Furthermore, we found that daintain/AIF-1 overexpression up-regulated the expression of cyclin D1 and enhanced the transcriptional activity of nuclear factor-kappa B (NF-kappaB), a regulator of cyclin D1 expression. In contrast, the down-regulation of daintain/AIF-1 expression decreased cyclin D1 expression and inhibited the transcriptional activity of NF-kappaB. These results strongly suggest that daintain/AIF-1 can promote the growth of breast tumors via activating NF-kappaB signaling, which consequently up-regulates the expression of cyclin D1, implying that daintain/AIF-1 may be a novel target molecule for the prognosis and therapy of breast cancer.
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Affiliation(s)
- Shou Liu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology 1037 Ruoyu Road, Wuhan 430074, PR China
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37
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Sommerville LJ, Kelemen SE, Autieri MV. Increased smooth muscle cell activation and neointima formation in response to injury in AIF-1 transgenic mice. Arterioscler Thromb Vasc Biol 2007; 28:47-53. [PMID: 17991871 DOI: 10.1161/atvbaha.107.156794] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Allograft Inflammatory Factor-1 (AIF-1) is a calcium binding scaffold protein which is rapidly induced in vascular smooth muscle cells (VSMCs) in response to injury and inflammation. A transgenic mouse in which AIF-1 expression was driven by a VSMC-specific SM22alpha promoter was generated to establish a direct relationship between AIF-1 expression and intimal hyperplasia. METHODS AND RESULTS Morphological analysis of partially ligated carotid artery demonstrate a significant increase in neointimal area of AIF-1 Tg versus wild-type mice (569+/-64 um versus 256+/-49 um, P=0.004). Immunohistochemistry using antibody to the proliferation marker Ki-67 show a significantly greater number of proliferating cells in the AIF-1 Tg lesion compared with wild-type arteries (10.6%+/-1.0 versus 3.6%+/-.9, P=0.0007). AIF-1 Tg arteries also had a greater number of cells with activated signal transduction kinase p38 (55.4%+/-7.0 versus 22.6%+/-5.4, P=0.002) and PAK1 (67.5%+/-6.7 versus 35.3%+/-10.2, P=0.02) compared with wild-type. Cultured VSMCs explanted from AIF-1 Tg proliferate (55.5+/-3.6x10(3) versus 37.2+/-2.0x10(3) cells/mL, P=0.0001) and migrate more rapidly (39.2+/-3.2 versus 17.1+/-1.5 VSMCs per HPF, P=0.0003) than wild-type, and have significantly greater levels of activated p38 and PAK1 than did VSMCs from wild-type littermates (P<0.05). CONCLUSIONS These data indicate that AIF-1 expression results in increased signal transduction, neointimal formation, and VSMC proliferation in injured mouse carotid arteries.
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Affiliation(s)
- Laura J Sommerville
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
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38
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Köhler C. Allograft inflammatory factor-1/Ionized calcium-binding adapter molecule 1 is specifically expressed by most subpopulations of macrophages and spermatids in testis. Cell Tissue Res 2007; 330:291-302. [PMID: 17874251 DOI: 10.1007/s00441-007-0474-7] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2007] [Accepted: 07/13/2007] [Indexed: 11/25/2022]
Abstract
Ionized calcium-binding adapter molecule 1 (Iba1) is a 147-amino-acid calcium-binding protein widely in use as a marker for microglia. It has actin-crosslinking activity and is involved in aspects of motility-associated rearrangement of the actin cytoskeleton. The Iba1 gene and protein are identical to allograft inflammatory factor-1 (AIF-1), a protein involved in various aspects of inflammation, which was investigated independently from Iba1. Although regarded to be monocyte/macrophage-specific, expression by germ cells in testis showed that AIF-1/Iba1 is not exclusively expressed by cells of the monocyte/macrophage lineage. Furthermore, AIF-1 was found in cells not belonging to the monocyte/macrophage lineage under pathological conditions. Here, the distribution of AIF-1/Iba1 in the normal mouse has been examined, by immunohistochemistry, to determine whether AIF-1/Iba1 expression is confined to macrophages and spermatids. Spermatids are the only cells not belonging to the monocyte/macrophage lineage found to express AIF-1/Iba1 in the normal mouse, by this method. This study has not demonstrated AIF-1/Iba1 expression in dendritic cells, although this protein might be expressed by subsets of dendritic cells. AIF-1/Iba1 can be regarded a "pan-macrophage marker" because, except for alveolar macrophages, all subpopulations of macrophages examined express AIF-1/Iba1.
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Affiliation(s)
- Christoph Köhler
- Institute II of Anatomy, University of Cologne, Joseph Stelzmann Strasse 9, 50931, Cologne, Germany.
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39
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Otieno FG, Lopez AM, Jimenez SA, Gentiletti J, Artlett CM. Allograft inflammatory factor-1 and tumor necrosis factor single nucleotide polymorphisms in systemic sclerosis. ACTA ACUST UNITED AC 2007; 69:583-91. [PMID: 17498268 DOI: 10.1111/j.1399-0039.2007.00830.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Tumor necrosis factor (TNF) alleles have been associated with systemic sclerosis (SSc); however, these alleles may be in linkage with other genes. Allograft inflammatory factor-1 (AIF-1) is a newly identified gene on the short arm of chromosome 6 in the class III region of the human leukocyte antigen. It appears to be involved in inflammation and was originally identified in rat cardiac allografts undergoing rejection. AIF-1 has several sequence variations (single nucleotide polymorphisms, SNPs), three of which result in nonsynonymous changes in amino acid coding. We analyzed the linkage of five TNFA and five AIF-1 SNPs by polymerase chain reaction in 239 Caucasian individuals. The TNFA-1031T/T genotype was found to be associated with SSc (P < 0.0001) and both the DcSSc (diffuse subset of SSc) and the LcSSc (limited subset of SSc) subsets (P= 0.0004 and P= 0.0009, respectively) and the TNFA-237G/G genotype was found to be associated with all SSc (P= 0.0003) and with the DcSSc and LcSSc subsets (P= 0.01 and P= 0.005, respectively). Furthermore, the TNFA-857C/T genotype was associated with LcSSc (P= 0.0003) and TNFA-307A/A genotype associated with DcSSc (P= 0.028). In AIF-1, RS2269475 exon 4A allele, which generates a nonsynonymous change (tryptophan to arginine), was significantly associated in patients with SSc (P= 0.0009) and was associated with those patients who had DcSSc (P= 0.002). A strong linkage disequilibrium was observed between the AIF-1 alleles, A allele of RS2269475 and the A allele of RS4711274 (P < 0.0001), and linkage was observed between AIF-1 and TNFA alleles. Here, we report a novel and significant association of a nonsynonymous change within the AIF-1 with SSc and identified the linkage with TNFA alleles within 50 kb of this gene. Our study lends support that TNFA may be an important inflammatory modulator in SSc and may play a significant role with AIF-1 in disease pathogenesis.
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Affiliation(s)
- F G Otieno
- Division of Rheumatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
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40
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Kimura M, Kawahito Y, Obayashi H, Ohta M, Hara H, Adachi T, Tokunaga D, Hojo T, Hamaguchi M, Omoto A, Ishino H, Wada M, Kohno M, Tsubouchi Y, Yoshikawa T. A Critical Role for Allograft Inflammatory Factor-1 in the Pathogenesis of Rheumatoid Arthritis. THE JOURNAL OF IMMUNOLOGY 2007; 178:3316-22. [PMID: 17312183 DOI: 10.4049/jimmunol.178.5.3316] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Rheumatoid arthritis (RA) is characterized by massive synovial proliferation, angiogenesis, subintimal infiltration of inflammatory cells and the production of cytokines such as TNF-alpha and IL-6. Allograft inflammatory factor-1 (AIF-1) has been identified in chronic rejection of rat cardiac allografts as well as tissue inflammation in various autoimmune diseases. AIF-1 is thought to play an important role in chronic immune inflammatory processes, especially those involving macrophages. In the current work, we examined the expression of AIF-1 in synovial tissues and measured AIF-1 in synovial fluid (SF) derived from patients with either RA or osteoarthritis (OA). We also examined the proliferation of synovial cells and induction of IL-6 following AIF-1 stimulation. Immunohistochemical staining showed that AIF-1 was strongly expressed in infiltrating mononuclear cells and synovial fibroblasts in RA compared with OA. Western blot analysis and semiquantitative RT-PCR analysis demonstrated that synovial expression of AIF-1 in RA was significantly greater than the expression in OA. AIF-1 induced the proliferation of cultured synovial cells in a dose-dependent manner and increased the IL-6 production of synovial fibroblasts and PBMC. The levels of AIF-1 protein were higher in synovial fluid from patients with RA compared with patients with OA (p < 0.05). Furthermore, the concentration of AIF-1 significantly correlated with the IL-6 concentration (r = 0.618, p < 0.01). These findings suggest that AIF-1 is closely associated with the pathogenesis of RA and is a novel member of the cytokine network involved in the immunological processes underlying RA.
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Affiliation(s)
- Mizuho Kimura
- Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Japan
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Tian Y, Autieri MV. Cytokine expression and AIF-1-mediated activation of Rac2 in vascular smooth muscle cells: a role for Rac2 in VSMC activation. Am J Physiol Cell Physiol 2007; 292:C841-9. [PMID: 16987989 DOI: 10.1152/ajpcell.00334.2006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein involved in vascular smooth muscle cell (VSMC) migration and proliferation. The objective of this study is to characterize AIF-1 functional protein interactions that may regulate VSMC activation. Through use of a bacterial two-hybrid screen, we identified a molecular interaction between AIF-1 and the small GTPase, Rac2, which was verified by pull-down and colocalization experiments. This was unexpected in that Rac2 expression had been considered to be restricted to hematopoietic cells. The Rac2/AIF-1 interaction is functional, in that a loss-of-function, point-mutated AIF-1 does not interact with Rac2; Rac2 colocalizes with AIF-1 in the cytoplasm of VSMC and cotranslocates to lamellopodia upon platelet-derived growth factor stimulation; and AIF-1 expression in VSMC leads to Rac2 activation. Because Rac2 function in VSMC had not been described, we focused on characterization of its function in these cells. Rac2 protein expression in VSMC is inducible by inflammatory cytokines, and Rac2 activation in VSMC is also responsive to inflammatory cytokines. Rac2 expression and activation patterns differ from the ubiquitously expressed Rac1. We hypothesized that Rac2 participates in VSMC activation. Retroviral overexpression of Rac2 in primary VSMC leads to increased migration, activation of the NADPH oxidation cascade, and increased activation of the Rac2 effector protein Pak1 and its proximal effectors, ERK1/2, and p38 (P < 0.05 for all). The major points of this study indicate a functional interaction between AIF-1 and Rac2 in VSMC leading to Rac2 activation and a potential function for Rac2 in inflammation-driven VSMC response to injury.
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Affiliation(s)
- Ying Tian
- Dept. of Physiology, Cardiovascular Research Center, Temple Univ. School of Medicine, Philadelphia, PA 10140, USA
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Jia J, Zhao YF, Zhao JH. Potential roles of allograft inflammatory factor-1 in the pathogenesis of hemangiomas. Med Hypotheses 2007; 68:288-90. [PMID: 17010532 DOI: 10.1016/j.mehy.2006.07.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2006] [Accepted: 07/19/2006] [Indexed: 01/13/2023]
Abstract
Hemangiomas are benign tumors of the vascular endothelium and are the most common tumors of infancy. These tumors are characterized by an initial phase of rapid proliferation in the first months of life, which is followed, in most cases, by spontaneous slow involution. Despite their high prevalence, their detailed pathogenesis remains unknown. Recent studies suggest that immunity responses, inflammatory cells and their precursors, myeloid cells, play important roles in the growth and involution of hemangiomas. The allograft inflammatory factor-1 is a powerful gene that is involved in several kinds of inflammatory response-related diseases. Studies also show that it is implicated in angiogenesis, proliferation and differentiation of stem cells, and development of tumors. Taken all these evidences into consideration, we hypothesize that allograft inflammatory factor-1 plays potential roles in pathogenesis, proliferation and involution of hemangioma. Investigating the role of allograft inflammatory factor-1 in the proliferation and involution of hemangioma will lead to a better understanding of pathogenesis of this lesion. Furthermore, the subtle regulation of allograft inflammatory factor-1 in the involution of hemangiomas will help design a new anti-angiogenic therapy for some tumors.
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Affiliation(s)
- Jun Jia
- Key Laboratory of Oral Biomedical Engineering, Ministry of Education (KLOBM), Wuhan University, Wuhan, China
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Litvin J, Chen X, Keleman S, Zhu S, Autieri M. Expression and function of periostin-like factor in vascular smooth muscle cells. Am J Physiol Cell Physiol 2006; 292:C1672-80. [PMID: 17092992 DOI: 10.1152/ajpcell.00153.2006] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In injured blood vessels activated vascular smooth muscle cells (VSMCs) migrate from the media to the intima, proliferate and synthesize matrix proteins. This results in occlusion of the lumen and detrimental clinical manifestations. We have identified a novel isoform of the periostin family of proteins referred to as periostin-like factor (PLF). PLF expression in VSMCs was increased following treatment with mitogenic compounds, suggesting that PLF plays a role in VSMC activation. Correspondingly, proliferation of the cells was significantly reduced with anti-PLF antibody treatment. PLF expression increased VSMC migration, an essential cellular process leading to vascular restenosis after injury. PLF protein was localized to neointimal VSMC of rat and swine balloon angioplasty injured arteries, as well as in human arteries with transplant restenosis, supporting the hypothesis that PLF is involved in VSMC activation and vascular proliferative diseases. Taken together, these data suggest a role for PLF in the regulation of vascular proliferative disease.
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Affiliation(s)
- Judith Litvin
- Temple University, School of Medicine, Department of Anatomy and Cell Biology, 3420 N. Broad St., MRB 615, Philadelphia, PA 19140, USA.
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Deakin JE, Papenfuss AT, Belov K, Cross JGR, Coggill P, Palmer S, Sims S, Speed TP, Beck S, Graves JAM. Evolution and comparative analysis of the MHC Class III inflammatory region. BMC Genomics 2006; 7:281. [PMID: 17081307 PMCID: PMC1654159 DOI: 10.1186/1471-2164-7-281] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2006] [Accepted: 11/02/2006] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The Major Histocompatibility Complex (MHC) is essential for immune function. Historically, it has been subdivided into three regions (Class I, II, and III), but a cluster of functionally related genes within the Class III region has also been referred to as the Class IV region or "inflammatory region". This group of genes is involved in the inflammatory response, and includes members of the tumour necrosis family. Here we report the sequencing, annotation and comparative analysis of a tammar wallaby BAC containing the inflammatory region. We also discuss the extent of sequence conservation across the entire region and identify elements conserved in evolution. RESULTS Fourteen Class III genes from the tammar wallaby inflammatory region were characterised and compared to their orthologues in other vertebrates. The organisation and sequence of genes in the inflammatory region of both the wallaby and South American opossum are highly conserved compared to known genes from eutherian ("placental") mammals. Some minor differences separate the two marsupial species. Eight genes within the inflammatory region have remained tightly clustered for at least 360 million years, predating the divergence of the amphibian lineage. Analysis of sequence conservation identified 354 elements that are conserved. These range in size from 7 to 431 bases and cover 15.6% of the inflammatory region, representing approximately a 4-fold increase compared to the average for vertebrate genomes. About 5.5% of this conserved sequence is marsupial-specific, including three cases of marsupial-specific repeats. Highly Conserved Elements were also characterised. CONCLUSION Using comparative analysis, we show that a cluster of MHC genes involved in inflammation, including TNF, LTA (or its putative teleost homolog TNF-N), APOM, and BAT3 have remained together for over 450 million years, predating the divergence of mammals from fish. The observed enrichment in conserved sequences within the inflammatory region suggests conservation at the transcriptional regulatory level, in addition to the functional level.
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Affiliation(s)
- Janine E Deakin
- ARC Centre for Kangaroo Genomics, Research School of Biological Sciences, The Australian National University, Canberra, ACT 0200, Australia
| | - Anthony T Papenfuss
- Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
| | - Katherine Belov
- Centre for Advanced Technologies in Animal Genetics and Reproduction, Faculty of Veterinary Science, The University of Sydney, NSW 2006, Australia
| | - Joseph GR Cross
- ARC Centre for Kangaroo Genomics, Research School of Biological Sciences, The Australian National University, Canberra, ACT 0200, Australia
| | - Penny Coggill
- Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Sophie Palmer
- Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Sarah Sims
- Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Terence P Speed
- Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
| | - Stephan Beck
- Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Jennifer A Marshall Graves
- ARC Centre for Kangaroo Genomics, Research School of Biological Sciences, The Australian National University, Canberra, ACT 0200, Australia
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Tsubata Y, Sakatsume M, Ogawa A, Alchi B, Kaneko Y, Kuroda T, Kawachi H, Narita I, Yamamoto T, Gejyo F. Expression of allograft inflammatory factor-1 in kidneys: A novel molecular component of podocyte. Kidney Int 2006; 70:1948-54. [PMID: 17035944 DOI: 10.1038/sj.ki.5001941] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Our comprehensive gene expression profiles of the kidneys in an anti-glomerular basement membrane (GBM) nephritis model using DNA arrays revealed that allograft inflammatory factor-1 (AIF-1) was one of the highly expressed genes. Here, we explored the pathological significance of AIF-1 expression in the kidneys. The expression pattern of AIF-1 mRNA and protein in the kidneys of normal and diseased rats, such as anti-GBM nephritis and puromycin aminonucleoside nephrosis, was investigated by in situ hybridization, immunohistochemistry, and immunoelectron microscopy. Furthermore, the expression of AIF-1 in human kidneys and urinary sediments was examined. AIF-1 was expressed at both mRNA and protein levels in podocytes of normal and diseased rats, and in infiltrating cells in anti-GBM nephritis kidneys. The expression of AIF-1 in podocytes was constitutive; positive in podocytes of both normal and diseased rats. In humans, AIF-1 was expressed in podocytes and infiltrating inflammatory cells, similarly. Moreover, it was detected in urinary podocytes from patients with immunoglobulin A nephropathy. These data document for the first time that AIF-1, a constitutively expressed protein in rat and human podocytes, is a novel molecular component of podocytes, and that the upregulation of AIF-1 in an anti-GBM nephritis model may mainly be a consequence of its expression in infiltrating cells.
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Affiliation(s)
- Y Tsubata
- Department of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Del Galdo F, Maul GG, Jiménez SA, Artlett CM. Expression of allograft inflammatory factor 1 in tissues from patients with systemic sclerosis and in vitro differential expression of its isoforms in response to transforming growth factor beta. ACTA ACUST UNITED AC 2006; 54:2616-25. [PMID: 16868985 DOI: 10.1002/art.22010] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE Allograft inflammatory factor 1 (AIF-1), a protein initially identified in chronically rejected rat cardiac allografts, is involved in the immune response and proliferative vasculopathy that occurs during allograft rejection. Three well-characterized isoforms of AIF-1 result from alternative messenger RNA (mRNA) splicing. We previously identified a strong association of systemic sclerosis (SSc) with a polymorphism in AIF-1 isoform 2. The purpose of this study was to investigate AIF-1 expression in affected tissues from patients with SSc and to examine the regulation of its isoforms by transforming growth factor beta (TGFbeta). METHODS AIF-1 in the skin and lung tissues of patients with SSc was analyzed by immunochemistry. AIF-1 isoform expression in response to TGFbeta and interferon-gamma stimulation was examined by quantitative polymerase chain reaction (PCR). RESULTS AIF-1 protein was present in affected vessels of the lung and skin lesions of patients with SSc. Quantitative PCR showed an average of 14-fold higher mRNA levels in affected SSc skin than in normal skin. Double-label immunofluorescence staining demonstrated that T cells, macrophages, and endothelial cells in affected tissues expressed AIF-1. Stimulation of peripheral blood mononuclear cells with TGFbeta caused a specific and significant increase in the expression of AIF-1 isoform 2 transcripts (P < 0.005), which was due to stabilization of AIF-1 isoform 2 mRNA. CONCLUSION These data suggest that AIF-1 plays an important role in the pathogenesis of SSc owing to its increased expression in affected tissues and to the specific stimulation of AIF-1 isoform 2 by TGFbeta.
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MESH Headings
- Calcium-Binding Proteins
- Cells, Cultured
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Drug Combinations
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Fluorescent Antibody Technique, Indirect
- Gene Expression
- Humans
- Interferon-gamma/pharmacology
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/metabolism
- Lung/metabolism
- Lung/pathology
- Macrophages/metabolism
- Macrophages/pathology
- Microfilament Proteins
- Nuclear Proteins
- Protein Isoforms
- RNA Processing, Post-Transcriptional
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Scleroderma, Systemic/metabolism
- Scleroderma, Systemic/pathology
- Skin/metabolism
- Skin/pathology
- T-Lymphocytes/metabolism
- T-Lymphocytes/pathology
- Transforming Growth Factor beta/pharmacology
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Tian Y, Kelemen SE, Autieri MV. Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli. Am J Physiol Cell Physiol 2006; 290:C1083-91. [PMID: 16291819 DOI: 10.1152/ajpcell.00381.2005] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein. Several studies have reported increased AIF-1 expression in activated macrophages and have implicated AIF-1 as a marker of activated macrophages. However, the function of AIF-1 in macrophages and the mechanism whereby it participates in macrophage activation are unknown at this time. Immunohistochemical analysis colocalized AIF-1 expression with CD68-positive macrophages in atherosclerotic human coronary arteries. Subsequent experiments were designed to determine a role for AIF-1 in macrophage activation in response to atherogenic stimuli. Stimulation of human and murine macrophages with oxidized LDL significantly increased AIF-1 expression above basal levels. Stable transfection of AIF-1 small interfering RNA (siRNA) in macrophages reduced AIF-1 protein expression by 79% and reduced macrophage proliferation by 52% ( P < 0.01). Inhibition of proliferation was not due to induction of apoptosis. Sequences that did not knock down AIF-1 expression had no effect on proliferation. AIF-1 siRNA expression reduced macrophage migration by 60% ( P < 0.01). Both proliferation and migration of siRNA-expressing macrophages could be restored by adenoviral expression of AIF-1 ( P < 0.001 and 0.005, respectively), suggesting a tight association between AIF-1 expression and macrophage activation. Phosphorylation of Akt, p44/42 MAPK, and p38 kinase were significantly reduced in siRNA macrophages challenged with oxidized LDL ( P < 0.05). Phosphorylation of p38 kinase was significantly inhibited in siRNA macrophages stimulated with T lymphocyte conditioned medium ( P < 0.05). These data indicate that AIF-1 mediates atherogenesis-initiated signaling and activation of macrophages.
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Affiliation(s)
- Ying Tian
- Department of Physiology, Cardiovascular Research Center, Temple University School of Medicine, Rm. 810, MRB, 3420 N. Broad St., Philadelphia, PA 19140, USA
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Kelemen SE, Autieri MV. Expression of allograft inflammatory factor-1 in T lymphocytes: a role in T-lymphocyte activation and proliferative arteriopathies. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 167:619-26. [PMID: 16049345 PMCID: PMC1603575 DOI: 10.1016/s0002-9440(10)63003-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Allograft inflammatory factor (AIF)-1 is a cytoplasmic, calcium-binding protein whose expression in transplanted human hearts correlates with rejection and development of coronary artery vasculopathy (CAV). AIF-1 is constitutively expressed in monocytes/macrophages, but its expression in human lymphocytes has not been described. After immunohistochemical analysis of human coronary arteries with CAV, we identified AIF-1 expression in CD3-positive lymphocytes. AIF-1 was differentially expressed in peripheral blood mononuclear cells and in the T-lymphoblastoid MOLT-4 cell line exposed to various cytokines, suggesting a role for AIF-1 in T-lymphocyte activation. To determine AIF-1 function, MOLT-4 cells were stably transduced by AIF-1 retrovirus. Overexpression of AIF-1 in these cells led to a 238% increase in cell number compared to empty vector controls. AIF-1 polymerized nonmuscle actin and MOLT-4 cells overexpressing AIF-1 migrated 95% more rapidly than empty vector controls. Primary human vascular smooth muscle cells cultured in conditioned media from AIF-1-transduced MOLT-4 cells proliferated 99% more rapidly than vascular smooth muscle cells cultured in conditioned media from empty vector-transduced MOLT-4 cells. These data indicate that AIF-1 is expressed in activated T lymphocytes, that its expression enhances activation of lymphocytes, and that AIF-1 expression in activated lymphocytes may have important ramifications for activation of adjacent arterial vascular smooth muscle cells and development of CAV.
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Affiliation(s)
- Sheri E Kelemen
- Department of Cardiology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, USA
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Kelemen SF, Eisen HJ, Autieri MV. Expression of the FAST-1 transcription factor in coronary artery transplant vasculopathy and activated vascular smooth muscle cells. J Heart Lung Transplant 2005; 24:246-50. [PMID: 15737749 DOI: 10.1016/j.healun.2004.01.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2003] [Revised: 12/23/2003] [Accepted: 01/05/2004] [Indexed: 10/25/2022] Open
Abstract
BACKGROUND The activation of vascular smooth muscle cells (VSMCs) causes most of the obliterative vasculopathy responsible for solid-organ allograft failure. Identification of genes expressed in activated VSMCs may provide clues to the pathogenesis and progression of cardiac allograft vasculopathy (CAV). METHODS We performed cDNA micro-array analysis of mRNA isolated from a healthy human coronary artery, from a coronary artery from a patient with CAV, and from quiescent and stimulated cultured human coronary artery VSMCs. Western blot analysis and immunohistochemistry verified fork-head activin signal transducer 1 (FAST-1) expression. RESULTS Fold-change analysis determined that increased expression of a transcription factor involved in transforming growth factor beta (TGF-beta) signaling, FAST-1, was induced in arteries with CAV and in activated VSMCs, compared with normal and unstimulated cells. Western blotting confirmed increased FAST-1 expression in arteries with CAV vs normal arteries and arteries from failing hearts and confirmed increased expression in cultured VSMCs stimulated with a variety of cytokines. Immunohistochemical analysis determined that FAST-1 expression localized to neo-intimal VSMCs in rejecting arteries. In cultured VSMCs, FAST-1 immunolocalizes to the nucleus after TGF-beta stimulation. CONCLUSIONS These results demonstrate differential expression of the FAST-1 gene in the VSMC response to inflammatory stimuli. Considering the significant role of TGF-beta in vascular fibroproliferative diseases, this work suggests that FAST-1 may participate in the VSMC response to injury and may represent a potential molecular target for modulating the progression of CAV.
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Affiliation(s)
- Sheri F Kelemen
- Department of Cardiology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
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Autieri MV, Chen X. The ability of AIF-1 to activate human vascular smooth muscle cells is lost by mutations in the EF-hand calcium-binding region. Exp Cell Res 2005; 307:204-11. [PMID: 15922740 DOI: 10.1016/j.yexcr.2005.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2004] [Revised: 02/28/2005] [Accepted: 03/01/2005] [Indexed: 12/01/2022]
Abstract
Allograft Inflammatory Factor-1 (AIF-1) is a cytoplasmic calcium-binding protein expressed in vascular smooth muscle cells (VSMC) in response to injury or cytokine stimulation. AIF-1 contains a partially conserved EF-hand calcium-binding domain, and participates in VSMC activation by activation of Rac1 and induction of Granulocyte-Colony Stimulating Factor (G-CSF) expression; however, the mechanism whereby AIF-1 mediates these effects is presently uncharacterized. To determine if calcium binding plays a functional role in AIF-1 activity, a single site-specific mutation was made in the EF-hand calcium-binding domain to abrogate binding of calcium (AIF-1DeltaA), which was confirmed by calcium overlay. Functionally, similar to wild-type AIF-1, AIF-1DeltaA was able to polymerize F-actin in vitro. However, in contrast to wild-type AIF-1, over-expression of AIF-1DeltaA was unable to increase migration or proliferation of primary human VSMC. Further, it was unable to activate Rac1, or induce G-CSF expression to the degree as wild-type AIF-1. Taken together, modification of the wild-type EF-hand domain and native calcium-binding activity results in a loss of AIF-1 function. We conclude that appropriate calcium-binding potential is critical in AIF-1-mediated effects on VSMC pathophysiology, and that AIF-1 activity is mediated by Rac1 activation and G-CSF expression.
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Affiliation(s)
- Michael V Autieri
- Department of Physiology, Cardiovascular Research Center, Temple University School of Medicine, Room 810, MRB 3420 N. Broad Street, Philadelphia PA 19140, USA.
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