IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-γ

摘要

IL-18 shares with IL-1 the same family of receptors and several identical signal transduction pathways. Because of these similarities, IL-18 was investigated for its ability to induce prostaglandin E2 (PGE2) synthesis in human peripheral blood mononuclear cells (PBMC), a prominent, proinflammatory property of IL-1. IL-18 was highly active in PBMC by inducing the synthesis of the chemokine IL-8; however, no induction of PGE2 synthesis nor cyclooxygenase type-2 gene expression was observed in PBMC stimulated with IL-18. In the same cultures, IL-1β induced a 12-fold increase in PGE2. Although IL-1β-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1β-induced PGE2 production by 40%. The suppressive effect of IL-18 on PGE2 production was mediated by interferon (IFN)-γ because anti-human IFN-γ-antibody prevented IL-18-induced reduction in PGE2. Consistent with these observations, IL-12, a known inducer of IFN-γ, augmented IL-1β-induced IFN-γ but suppressed IL-1β-induced PGE2 by 75%. IL-18 binding protein (IL-18BP) is a naturally occurring and specific inhibitor of IL-18. When recombinant IL-18BP was added to PBMC cultures, unexpectedly, spontaneous PGE2 production increased. PGE2 production was also increased by the addition of IL-18BP to PBMC stimulated with either IL-1β or IL-12 and also in whole blood cultures stimulated with Staphylococcus epidermidis. These studies demonstrate that IL-18BP decreases endogenous IL-18 activity by reducing IFN-γ-mediated responses.