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Regulation of gene expression and nitric oxide production in murine macrophages by the serine/threonine phosphatase inhibitor okadaic acid

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

C.A. Salkowski

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

M.J. Fultz

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

P-Y. Perera

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

R. McNally

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

S.N. Vogel

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

LPS-stimulated macrophages produce cytokines which, at appropriate levels, direct successful immune responses against harmful pathogens. However, excessive cytokine production, as seen in endotoxemia, results in pathophysiological damage to the host. Therefore, understanding mechanisms of cytokine regulation may aid the development of strategies designed to control cytokine production during an ongoing immune response. We have examined the role of okadaic acid-sensitive phosphatases in the production of cytokines and nitric oxide by macrophages. Okadaic acid induces TNF, IL-1β, IL-6, IFN-β, and IP-10, but not IL-10 or IL-12 (p40) mRNA. Okadaic acid differentially regulates the expression 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-.

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