Abstract
To examine the ability of interleukin-17A (IL-17A) to stimulate angiogenesis, cell migration, and cytoskeletal rearrangement. 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 α (GROα) 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-GROα and anti-MCP-1 antibodies. Binding of β1 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-GROα, anti-MCP-1, or IgG control was assessed by Rac GTPase pull-down assays and Western blotting. IL-17A significantly up-regulated angiogenesis and endothelial cell invasion. It significantly induced GROα and MCP-1 expression in RASFs. Migration of PBMCs, RASFs, and HDECs was induced by IL-17A; these effects were blocked by anti-GROα or anti-MCP-1 antibodies. IL-17A significantly up-regulated β1 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-GROα or anti-MCP-1 antibodies had no effect on IL-17A-induced Rac1 activation. 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.
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