The Role of IL-17 in the Angiogenesis of Rheumatoid Arthritis
Annual rept. 1 Jul 2011-30 Jun 2012
ILLINOIS UNIV AT CHICAGO
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We show that IL-17 mediated endothelial migration and tube formation is mediate through ligation of IL-17 to IL-17RC and activation of PI3K AKT pathway. To demonstrate the indirect role of IL-17 in rheumatoid arthritis RA angiogenesis, potent proangiogenic factor such as VEGF was examined. Interestingly we found that that RA synovial fluid induced endothelial chemotaxis mediated by IL-17 did not synergize with VEGF suggesting that VEGF may not play a crucial role in IL-17 induced joint neovascularization . Therefore role of other potential proangiogenic factors was examined in IL-17 induced arthritis model. We show that expression of CXCLI and CXCL5 is highly elevated in RA synovial tissues treated with IL-17 and in IL-17 induced experimental arthritis while VEGF was not markedly increased in any of the mentioned models. Next we document that immunodepletion of CXCL5 but not CXCL 1 relieves IL-17 induced arthritis. Results from our study further demonstrate that anti-CXCL5 antibody treatment reduces joint TNF-a levels and vascularization in IL-17 induced arthritis model. We show that while CXCL1 can induce endothelial migration through activation of PI3K pathway, this process was mediated by CXCL5 through NF -KB signaling. Since both CXCLI and IL-17 can mediate angiogenesis through the same pathway, blocking of CXCLI is ineffective in this process whereas suppression of CXCL5 can effectively reduce NF -KB mediated angiogenesis through an IL-17 non-overlapping mechanism. In conclusion, these observations suggest that IL-17-mediated joint vascularization may be in part due to CXCL5 induction.
- Medicine and Medical Research