A role for IL-18 in neutrophil activation

IL-18 expression and functional activity has been identified in several aut oimmune and infectious diseases. To clarify the potential role of IL-18 dur ing early innate immune responses, we have explored the capacity of IL-18 t o activate neutrophils. Human peripheral blood-derived neutrophils constitu tively expressed IL-18R (alpha and beta) commensurate with the capacity to rapidly respond to IL-18. IL-18 induced cytokine and chemokine release from neutrophils that was protein synthesis dependent, upregulated CD11b expres sion, induced granule release, and enhanced the respiratory burst following exposure to fMLP, but had no effect upon the rate of neutrophil apoptosis. The capacity to release cytokine and chemokine was significantly enhanced in neutrophils derived from rheumatoid arthritis synovial fluid, indicating differential responsiveness to IL-18 dependent upon prior neutrophil activ ation in vivo. Finally, IL-18 administration promoted neutrophil accumulati on in vivo, whereas IL-18 neutralization suppressed the severity of footpad inflammation following carrageenan injection. The latter was accompanied b y reduction in tissue myeloperoxidase expression and suppressed local TNF-a lpha production. Together, these data define a novel role for IL-18 in acti vating neutrophils and thereby promoting early innate immune responses.