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J. Biol. Chem., Vol. 280, Issue 30, 28162-28168, July 29, 2005

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Genetic and Pharmacologic Evidence That Calcium-independent Phospholipase A₂ Regulates Virus-induced Inducible Nitric-oxide Synthase Expression by Macrophages^*

Jason M. Moran, R. Mark L. Buller, Jane McHowat¶, John Turk||, Mary Wohltmann||, Richard W. Gross**, and John A. Corbett

From the The Edward A. Doisy Department of Biochemistry and Molecular Biology and Departments of Molecular Microbiology and Immunology and ^¶Pathology, St. Louis University School of Medicine, St. Louis, Missouri 63104 and Divisions of ^||Endocrinology and ^**Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Recent evidence supports a regulatory role for the calcium-independent phospholipase A₂ (iPLA₂) in the antiviral response of inducible nitric-oxide synthase (iNOS) expression by macrophages. Because two mammalian isoforms of iPLA₂ (iPLA₂ and iPLA₂ ) have been cloned and characterized, the aim of this study was to identify the specific isoform(s) in macrophages that regulates the expression of iNOS in response to virus infection. Bromoenol lactone (BEL), a suicide substrate inhibitor of iPLA₂, inhibits the activity of both isoforms at low micromolar concentrations. However, the R- and S-enantiomers of BEL display 10-fold greater potency for inhibition of the enzymatic activity of iPLA₂ and iPLA₂, respectively. In this study, we show that the iPLA₂-selective (S)-BEL inhibits encephalomyocarditis virus (EMCV)-induced iNOS expression, nitric oxide production, and iPLA₂ enzymatic activity in macrophages in a concentration-related manner that closely resembles the inhibitory properties of racemic BEL. cAMP response element-binding protein (CREB) is one downstream target of iPLA₂ that is required for the transcriptional activation of iNOS in response to virus infection, and consistent with the effects of BEL enantiomers on iNOS expression, (S)-BEL more effectively inhibits EMCV-induced CREB phosphorylation than (R)-BEL in macrophages. Using macrophages isolated from iPLA₂-null mice, virus infection fails to stimulate iNOS mRNA accumulation and protein expression, thus providing genetic evidence that iPLA₂ is required for EMCV-induced iNOS expression. These findings provide evidence for a signaling role for iPLA₂ in virus-induced iNOS expression by macrophages.

Received for publication, January 1, 2005 , and in revised form, June 3, 2005.

^* This work was supported by National Institutes of Health Grants HL68588 (to J. M.), HL41250, PO1 HL57278-08 (to R. W. G.), DK34388 (to J. T.), and DK-52194 and AI-44458 (to J. A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Tel.: 314-977-9247; Fax: 314-977-9205; E-mail: corbettj{at}slu.edu.

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