The Role of IL-17 in the Angiogenesis of Rheumatoid Arthritis
Revised annual rept. 1 Jul 2010-30 Jun 2011
ILLINOIS UNIV AT CHICAGO
Pagination or Media Count:
TH-17 cells are a newly discovered CD4 helper T-cells that produce interleukin-17A also known as IL-17. IL-17 is found in Rheumatoid Arthritis RA synovial tissue and fluid, and the percentage of TH-17 cells is significantly higher in RA synovial fluid compared to RA or normal peripheral blood 1, 2. IL-17 has been shown to have a profound effect in experimental models of arthritis however its role in Rheumatoid Arthritis is undefined. Angiogenesis is an early and a critical event in the pathogenesis of RA. Since our preliminary data suggests that IL-17 plays an important role in RA angiogenesis, this grant was proposed to determine the mechanism by which IL-17 induces neovascularization. Our overriding hypothesis is that IL-17 mediates angiogenesis in RA through activation of the PI3K pathway, and this effect may be dependent or independent of other proangiogenic factors. To test this hypothesis we will investigate the contribution of IL-17 and its receptors to RA synovial fluid-mediated endothelial migration and blood vessel growth. We will also identify signaling pathways that are involved in IL-17-mediated neovascularization and examine whether mice deficient in a particular signaling pathway are unable to mediate neovascularization through IL-17. To further examine the role of IL-17 and its synergistic effect with TNF- in inducing HMVEC migration in vivo, we will employ a RA synovial tissue ST severe combined immunodeficient SCID chimera mouse model. Additionally, the indirect role of IL-17 in induction of angiogenesis and arthritis will be examined by blocking the effect of VEGF in in vitro and in vivo models of angiogenesis and experimental arthritis. The unmet need is to elucidate the mechanisms by which IL-17 mediates angiogenesis in RA and to determine whether targeting IL-17 andor its intermediary molecules will provide a therapeutic intervention for RA patients.
- Medicine and Medical Research