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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (401)	3/2/2000 10:36:00 PM
From: Miljenko Zuanic	Respond to of 1169

pnas.org Immunology IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN- Leonid L. Reznikov, Soo-Hyun Kim, Jay Y. Westcott, Jordan Frishman, Giamila Fantuzzi, Daniela Novick, Menachem Rubinstein, and Charles A. Dinarello,õ Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206; and Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100 Israel Contributed by Charles A. Dinarello, December 28, 1999 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-1 induced a 12-fold increase in PGE2. Although IL-1-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1-induced PGE2 production by 40%. The suppressive effect of IL-18 on PGE2 production was mediated by interferon (IFN)- because anti-human IFN--antibody prevented IL-18-induced reduction in PGE2. Consistent with these observations, IL-12, a known inducer of IFN-, augmented IL-1-induced IFN- but suppressed IL-1-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-1 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--mediated responses. --------------------------------------------------------------------------------