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Institute of Molecular Biology and Genetics, Spanish National Research Council and University of Valladolid School of Medicine, Valladolid, Spain
dsRNA is a by-product of viral replication capable of inducing an inflammatory response when recognized by phagocyte cells. In this study, we identify group IVA cytosolic phospholipase A2 (cPLA2
) as an effector of the antiviral response. Treatment of RAW 264.7 murine macrophage-like cells with the dsRNA analog polyinosinic:polycytidylic acid (poly-IC) promotes the release of free arachidonic acid that is subsequently converted into PGE2 by the de novo-synthesized cyclooxygenase-2 (COX-2) enzyme. These processes are blocked by the selective cPLA2 inhibitor pyrrophenone, pointing out to cPLA2 as the effector involved. In keeping with this observation, the cPLA2 phosphorylation state increases after cellular treatment with poly-IC. Inhibition of cPLA2 expression and activity by either small interfering RNA (siRNA) or pyrrophenone leads to inhibition of the expression of the inducible NO synthase (iNOS) gene. Moreover, COX-2-derived PGE2 production appears to participate in iNOS expression, because siRNA inhibition of COX-2 also leads to inhibition of iNOS, the latter of which is restored by exogenous addition of PGE2. Finally, cellular depletion of TLR3 by siRNA inhibits COX-2 expression, PGE2 generation, and iNOS induction by poly-IC. Collectively, these findings suggest a model for macrophage activation in response to dsRNA, whereby engagement of TLR3 leads to cPLA2-mediated arachidonic acid mobilization and COX-2-mediated PGE2 production, which cooperate to induce the expression of iNOS.
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.
1 This work was supported by the Spanish Ministry of Education and Science (Grants BFU2004-01886/BMC and SAF2004-04676), the Fundación La Caixa (Grant BM05-248-0), and the Spanish Ministry of Health (ISCIII-RETIC RD06).
2 Address correspondence and reprint requests to Dr. Jesús Balsinde, Instituto de Biología y Genética Molecular (Consejo Superior de Investigaciones Cientificas), Calle Sanz y Forés s/n, 47003 Valladolid, Spain; E-mail address: jbalsinde{at}ibgm.uva.es or Dr. María A. Balboa, Instituto de Biología y Genética Molecular (Consejo Superior de Investigaciones Cientificas), Calle Sanz y Forés s/n, 47003 Valladolid, Spain. E-mail address: mbalboa{at}ibgm.uva.es
3 Abbreviations used in this paper: poly-IC, polyinosinic:polycytidylic acid; PLA2, phospholipase A2; AA, arachidonic acid; sPLA2, secreted PLA2; cPLA2, cytosolic PLA2; iPLA2, calcium-independent PLA2; cPLA2, group IVA cytosolic PLA2; COX-2, cyclooxygenase-2; iNOS, inducible NO synthase; LTB4, leukotriene B4; siRNA, small interfering RNA.
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