Evidence of IL-18 as a novel angiogenic mediator

Angiogenesis, or new blood vessel growth, is a key process in the developme nt of synovial inflammation in rheumatoid arthritis (RA). Integral to this pathologic proliferation are proinflammatory cytokines. We hypothesized a r ole for IL-18 as an angiogenic mediator in RA. We examined the effect of hu man IL-18 on human microvascular endothelial cell (HMVEC) migration. IL-18 induced HMVEC migration at 1 nM (p < 0.05). RA synovial fluids potently ind uced endothelial cell migration, but IL-18 immunodepletion resulted in a 68 +/- 5% decrease in HMVEC migration (p < 0.05). IL-18 appears to act on HMV ECs via alpha (v)beta (3) integrin. To test whether IL-18 induced endotheli al cell tube formation in vitro, we quantitated the degree of tube formatio n on Matrigel matrix. IL-18, 1 or 10 nM, resulted in a 77% or 87% increase in tube formation compared with control (p < 0.05). To determine whether IL -18 may be angiogenic in vivo, we implanted IL-18 in Matrigel plugs in mice , and IL-18 at 1 and 10 nM induced angiogenesis (p < 0.05). The angiogenesi s observed appears to be independent of the contribution of local TNF-alpha , as evidenced by adding neutralizing anti-TNF-alpha Ab to the Matrigel plu gs. In an alternative in vivo model, sponges embedded with IL-18 or control were implanted into mice. IL-18 (10 nM) induced a 4-fold increase in angio genesis vs the control (p < 0.05). These findings support a novel function for IL-18 as an angiogenic factor in RA and may elucidate a potential thera peutic target for angiogenesis-directed diseases.