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J. Biol. Chem., Vol. 280, Issue 9, 7477-7486, March 4, 2005

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Roles of an IB Kinase-related Pathway in Human Cytomegalovirus-infected Vascular Smooth Muscle Cells

A MOLECULAR LINK IN PATHOGEN-INDUCED PROATHEROSCLEROTIC CONDITIONS^*

Simon-Pierre Gravel and Marc J. Servant

From the Faculty of Pharmacy, University of Montreal, Montreal, Quebec H3C 3J7, Canada

Viral and bacterial pathogens have long been suspected to affect atherogenesis directly. However, mechanisms linking innate immunity to chronic inflammatory diseases such as atherosclerosis are still poorly defined. Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with human cytomegalovirus (HCMV) leads to activation of the novel IB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector of the cellular innate immune response. We demonstrate that part of the HCMV inflammatory response is most likely mediated via this novel kinase because the canonical IKK complex was only poorly activated upon infection of HAOSMC. An increase in TBK1 phosphotransferase activity led to a strong activation of the interferon regulatory factor (IRF)-3 transcription factor as measured by its C-terminal phosphorylation, dimerization, and DNA binding activity. In addition to TBK1, HAOSMC also express another IKK-related kinase isoform, IKK, albeit at a lower level. Nevertheless, both isoforms were required for full activation of IRF-3 by HCMV. The transcripts of proatherosclerotic genes Ccl5 (encoding for the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted)) and Cxcl10 (encoding for the chemokine IP-10 (interferon--inducible protein 10)) were induced in an IRF-3-dependent manner after HCMV infection of smooth muscle cells. In addition, cytokine arrays analysis showed that RANTES and IP-10 were the predominant chemokines present in the supernatant of HCMV-infected HAOSMC. Activation of the TBK1/IRF-3 pathway was independent of epidermal growth factor receptor and pertussis toxin-sensitive G protein-coupled receptor activation. Our results thus add additional molecular clues to a possible role of HCMV as a modulator of atherogenesis through the induction of a proinflammatory response that is, in part, dependent of an IKK-related kinase pathway.

Received for publication, September 10, 2004 , and in revised form, December 2, 2004.

^* This work was supported by a research grant from the Canadian Institutes of Health Research. 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.

Scholar of the Fonds de la Recherche en Santé du Québec and recipient of a research Career Award in Health Sciences from the Canada's Research-based Pharmaceutical Companies Health Research Foundation/Canadian Institutes of Health Research. To whom correspondence should be addressed: Faculté de Pharmacie, Université de Montréal, P.O. Box 6128, Station Centre-ville Montreal, QC H3C 3J7, Canada. Tel.: 514-343-7966; Fax: 514-343-2102; E-mail: marc.servant{at}umontreal.ca.

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