title: Regulation of cyclooxygenase-2 expression by macrophages in response to double-stranded RNA and viral infection.
abstract: 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 PGE(2). Similar to dsRNA, encephalomyocarditis virus (EMCV) infection of RAW 264.7 cells stimulates COX-2 expression and PGE(2) 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 PGE(2) production. Furthermore, dsRNA and EMCV stimulate COX-2 expression and PGE(2) 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 A(2) (iPLA(2)) in the regulation of inducible NO synthase expression by macrophages in response to virus infection has been identified. The selective iPLA(2) 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-kappaB activation prevents dsRNA-stimulated COX-2 expression and PGE(2) 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-kappaB and that is independent of PKR or iPLA(2) activation.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, MO 63104, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Steer
authors.forename: Jason M
authors.initials: JM
authors.lastname: Moran
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Maggi
authors.forename: R Mark L
authors.initials: RM
authors.lastname: Buller
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D051546:Cyclooxygenase 2; D004686:Encephalomyocarditis virus / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D010741:Phospholipases A / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019892:eIF-2 Kinase; D010741:Phospholipases A; D002118:Calcium