REGULATION OF GENE-EXPRESSION AND NITRIC-OXIDE PRODUCTION IN MURINE MACROPHAGES BY THE SERINE THREONINE PHOSPHATASE INHIBITOR OKADAIC ACID/

LPS-stimulated macrophages produce cytokines which, at appropriate lev els, direct successful immune responses against harmful pathogens. How ever, excessive cytokine production, as seen in endotoxemia, results i n pathophysiological damage to the host. Therefore, understanding mech anisms of cytokine regulation may aid the development of strategies de signed to control cytokine production during an ongoing immune respons e. We have examined the role of okadaic acid-sensitive phosphatases in the production of cytokines and nitric oxide by macrophages. Okadaic acid induces TNF alpha, IL-1 beta, IL-6, IFN-beta, and IP-10, but not IL-10 or IL-12 (p40) mRNA. Okadaic acid differentially regulates the e xpression of LPS-inducible IL-10 and IL-12 (p40) mRNA. These findings suggest that okadaic acid-sensitive phosphatases are key regulators of cytokine production in unstimulated and immune-activated macrophages. Finally, okadaic acid inhibits iNOS mRNA and nitric oxide production by macrophages activated by LPS and IFN-gamma.