[76] IL-6 also promotes increased production of MMPs.[77] Neovascularization is dependent on EC activation, migration and proliferation. Pickens et al. introduced a novel function for IL-17 as an angiogenic mediator in RA.[78] IL-17 synergizes with TNF-α in stimulating VEGF, EGF, HGF and KGF production by synovial fibroblasts. IL-17 also acts through CXCR2-dependent pathways. BYL719 concentration IL-18 is a pro-inflammatory cytokine that is elevated in synovial fluids and synovial tissues in patients with RA. In the RA joint, IL-18 can contribute to the inflammatory process by inducing leukocyte extravasation through

up-regulation of EC adhesion molecules, the release of chemokines from RA synovial fibroblasts, and directly as monocytes, lymphocytes and neutrophil chemoattractants. IL-18 up-regulates the production of key regulators of osteoclastogenesis (RANKL [receptor activator of nuclear factor kappa-B ligand], M-CSF, GM-CSF and osteoprotegerin) from FLS

and also induces find more the serum amyloid A protein synthesis from rheumatoid synovial cells in a dose-dependent manner.[79, 80] IL-18 can also help maintain and develop the inflammatory pannus by inducing EC migration and angiogenesis. IL-18 does this function directly by binding and activating ECs and indirectly by inducing RA synovial fibroblasts to produce angiogenic chemokines and VEGF.[81] These data support the notion that IL-18 has a unique role in inducing the secretion of angiogenic elements by synovial fibroblasts in RA.[82] IL-18 is present in RA synovial fluid in high levels, where it functions as a leukocyte chemoattractant and angiogenic mediator to effect angiogenesis by inducing the secretion DNA Damage inhibitor of angiogenic factors

such as SDF-1α/CXCL12, MCP-1/CCL2, and VEGF.[82, 83] In conclusion, synovial fluid IL-18 levels in RA patients are good indicators of disease activity. IL-10 potentially inhibits angiogenesis through preventing the production of angiogenic mediators such as IL-8. It can also inhibit the proliferation of ECs, which is mediated by VEGF and FGF2. Also the release of angiogenic cytokies IL-1, IL-6 and TNF-α can be inhibited by IL-10. However, IL-4 activities in angiogenesis are controversial.[41] IL-4 can modulate neovascularization through pro-angiogenic and angiostatic mediators. It can also down-regulate IL-12R expression.[84] Angiostatin can inhibit angiogenesis in collagen-induced arthritis (CIA). Albini et al. presented evidence that IL-12 with potent anti-angiogenic activity is the mediator of angiostatin activity. Also it is demonstrated that angiostatin induces IL-12 mRNA synthesis by macrophages, suggesting that these cells produce IL-12 upon angiostatin stimulation.[85] IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-γ and angiostatic CXCR3 chemokine ligands.