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J. Biol. Chem., Vol. 280, Issue 3, 2147-2158, January 21, 2005

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Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis^*

Martha M. Monick, Kelli Cameron, Janice Staber, Linda S. Powers, Timur O. Yarovinsky, John G. Koland¶, and Gary W. Hunninghake

From the Department of Internal Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52242 and the ^¶Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242

Respiratory syncytial virus (RSV) preferentially infects lung epithelial cells. Infection by RSV leads to an extended inflammatory response, characterized by the release of interleukin-8 (IL-8). Activation of ERK MAP kinase is required for both RSV-induced inflammation and the extended survival of infected cells. In this study, we analyzed the role of the epidermal growth factor receptor (EGFR) in RSV activation of ERK. We demonstrate for the first time that RSV activates EGFR in lung epithelial cells. Activation of EGFR results in increased ERK activity, contributing to both the inflammatory response (IL-8 release) and prolonging the survival of RSV-infected cells. Inhibition of EGFR with siRNA decreased both ERK activation and IL-8 production after RSV. In analyzing the effect of EGFR activation on survival of RSV-infected cells, we found that EGFR activation by RSV resulted in ERK-dependent alterations in the balance of pro- versus anti-apoptotic Bcl2 proteins. RSV altered the balance between pro- and anti-apoptotic Bcl2 proteins (increased BclxL and decreased BimEL) increasing the relative amount of pro-survival proteins. This occurred in an EGFR-dependent manner. This study supports an important role for EGFR activity in the lifespan and inflammatory potential of RSV-infected epithelial cells.

Received for publication, August 2, 2004 , and in revised form, November 4, 2004.

^* This work was supported by a Veterans Affairs merit review grant and by National Institutes of Health Grants HL-60316, HL-077431, and RR00059 from the General Clinical Research Centers Program, NCRR, National Institutes of Health. 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: Division of Pulmonary, Critical Care, and Occupational Medicine, Rm. 100, EMRB, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, IA City, IA 52242. Tel.: 319-335-7590; Fax: 319-335-6530; E-mail: martha-monick{at}uiowa.edu.

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