IL-18 binding protein increases spontaneous and IL-1-induced prostaglandinproduction via inhibition of IFN-gamma

IL-18 shares with IL-1 the same family of receptors and several identical s ignal transduction pathways. Because of these similarities, IL-18 was inves tigated for its ability to induce prostaglandin E-2 (PGE(2)) synthesis in h uman peripheral blood mononuclear cells (PBMC), a prominent, proinflammator y property of IL-1. IL-18 was highly active in PBMC by inducing the synthes is of the chemokine IL-8; however, no induction of PGE(2) synthesis nor cyc looxygenase type-2 gene expression was observed in PBMC stimulated with IL- 18. In the same cultures, IL-1 beta induced a 12-fold increase in PGE(2). A lthough IL-1 beta-induced IL-8 synthesis was augmented 3-fold by IL-18, IL- 18 suppressed IL-1 beta-induced PGE(2) production by 40%. The suppressive e ffect of IL-18 on PGE(2) production was mediated by interferon (IFN)-gamma because anti-human IFN-gamma-antibody prevented IL-18-induced reduction in PGE(2). Consistent with these observations, IL-12, a known inducer of IFN-g amma augmented IL-1 beta-induced IFN-gamma but suppressed IL-1 beta-induced PGE(2) by 75%. IL-18 binding protein (IL-18BP) is a naturally occurring an d specific inhibitor of IL-18. When recombinant IL-18BP was added to PBMC c ultures, unexpectedly, spontaneous PGE(2) production increased. PGE(2) prod uction was also increased by the addition of IL-18BP to PBMC stimulated wit h either IL-1 beta or IL-12 and also in whole blood cultures stimulated wit h Staphylococcus epidermidis. These studies demonstrate that IL-18BP decrea ses endogenous IL-18 activity by reducing IFN-gamma-mediated responses.