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Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection¹

Sarah A. Steer^*, Jason M. Moran^*,, Leonard B. Maggi, Jr.^*, R. Mark L. Buller, Harris Perlman and John A. Corbett^2,*,

^* Edward A. Doisy Department of Biochemistry and Molecular Biology and Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine, St. Louis, MO 63104

In this study the regulation of macrophage expression of cyclooxygenase-2 (COX-2) in response to dsRNA and virus infection was examined. Treatment of RAW 264.7 macrophages with dsRNA results in COX-2 mRNA accumulation and protein expression and the production of PGE₂. Similar to dsRNA, encephalomyocarditis virus (EMCV) infection of RAW 264.7 cells stimulates COX-2 expression and PGE₂ accumulation. The dsRNA-dependent protein kinase (PKR), which has been shown to participate in the regulation of gene expression in response to dsRNA and virus infection, does not appear to participate in the regulation of COX-2 expression by macrophages. Expression of dominant negative mutants of PKR in RAW 264.7 cells fails to attenuate dsRNA- and EMCV-induced COX-2 expression or PGE₂ production. Furthermore, dsRNA and EMCV stimulate COX-2 expression and PGE₂ accumulation to similar levels in macrophages isolated from wild-type and PKR-deficient mice. Recently, a novel PKR-independent role for the calcium-independent phospholipase A₂ (iPLA₂) in the regulation of inducible NO synthase expression by macrophages in response to virus infection has been identified. The selective iPLA₂ suicide substrate inhibitor bromoenol lactone prevents dsRNA- and EMCV-stimulated inducible NO synthase expression; however, bromoenol lactone does not attenuate dsRNA- or EMCV-induced COX-2 expression by macrophages. In contrast, inhibition of NF-B activation prevents dsRNA-stimulated COX-2 expression and PGE₂ accumulation by macrophages. These findings indicate that virus infection and treatment with dsRNA stimulate COX-2 expression by a mechanism that requires the activation of NF-B and that is independent of PKR or iPLA₂ activation.

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