Interleukin-17A Induction of Angiogenesis, Cell Migration, and Cytoskeletal Rearrangement

被引：47

作者：

Moran, Ellen M. ^{[2
]}

Connolly, Mary ^{[2
]}

Gao, Wei ^{[2
]}

McCormick, Jennifer ^{[2
]}

Fearon, Ursula ^{[2
]}

Veale, Douglas J. ^{[1
,2
]}

机构：

[1] Univ Coll Dublin, Dept Rheumatol, Dublin Acad Med Ctr, Dublin 4, Ireland

[2] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland

来源：

ARTHRITIS AND RHEUMATISM | 2011年 / 63卷 / 11期

关键词：

FIBROBLAST-LIKE SYNOVIOCYTES; RHEUMATOID-ARTHRITIS PATIENTS; TUMOR-NECROSIS-FACTOR; CARTILAGE DEGRADATION; NEUTROPHIL RECRUITMENT; INTEGRIN ACTIVATION; ONCOSTATIN-M; FACTOR-ALPHA; GTPASE RAC; IL-17;

D O I：

10.1002/art.30582

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective. To examine the ability of interleukin-17A (IL-17A) to stimulate angiogenesis, cell migration, and cytoskeletal rearrangement. Methods. The effect of IL-17A on microvascular tube formation and extracellular matrix invasion by human dermal endothelial cells (HDECs) was assessed using Matrigel matrix and Transwell Matrigel invasion chambers. IL-17A-induced growth-related oncogene alpha (GRO alpha) and monocyte chemotactic protein 1 (MCP-1) production in rheumatoid arthritis synovial fibroblasts (RASFs) and HDECs was measured by enzyme-linked immunosorbent assay. IL-17A-induced migration was assessed using peripheral blood mononuclear cell (PBMC) migration assays and wound-repair scratch assays, with or without anti-GRO alpha and anti-MCP-1 antibodies. Binding of beta 1 integrin receptors was assessed using integrin binding assays. Cytoskeletal assembly/disassembly in RASFs and HDECs were assessed by immunofluorescence staining for F-actin. IL-17A-induced cell migration and cytoskeletal disassembly were assessed in the presence of a Rac1 inhibitor (NSC23766). Rac1 activation following IL-17 stimulation in the presence or absence of anti-GRO alpha, anti-MCP-1, or IgG control was assessed by Rac GTPase pull-down assays and Western blotting. Results. IL-17A significantly up-regulated angiogenesis and endothelial cell invasion. It significantly induced GRO alpha and MCP-1 expression in RASFs. Migration of PBMCs, RASFs, and HDECs was induced by IL-17A; these effects were blocked by anti-GRO alpha or anti-MCP-1 antibodies. IL-17A significantly up-regulated beta 1 integrin receptor binding and induced cytoskeletal disassembly in RASFs and HDECs. Rac1 activation was directly induced by IL-17A. IL-17A-induced wound repair and actin rearrangement were inhibited by a pharmacologic inhibitor of Rac1 (NSC23766). Anti-GRO alpha or anti-MCP-1 antibodies had no effect on IL-17A-induced Rac1 activation. Conclusion. IL-17A induces angiogenesis, cell migration, and cell invasion, all of which are key processes in the pathogenesis of rheumatoid arthritis and ones that are mediated in part through chemokine-and cytoskeleton-dependent pathways.

引用

页码：3263 / 3273

页数：11

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