A proinflammatory role for IL-18 in rheumatoid arthritis

IL-18 is a novel cytokine with pleiotropic activities critical to the devel opment of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein wi thin rheumatoid arthritis (RA) synovial tissues in significantly higher lev els than in osteoarthritis controls. Similarly IL-18 receptor expression wa s detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues i n vitro. IL-18 independently promoted GM-CSF and nitric oxide production, a nd it induced significant TNF-alpha synthesis by CD14(+) macrophages in syn ovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-al pha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 pro duction in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1 beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membra ne. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant- immunized DBA/1 mice facilitated the development of an erosive, inflammator y arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together , these data indicate that synergistic combinations of IL-18, IL-12, and IL -15 may be of importance in sustaining both Th1 responses and monokine prod uction in RA.