Originally published In Press as doi:10.1074/jbc.M308093200 on October 17, 2003
J. Biol. Chem., Vol. 278, Issue 52, 53035-53044, December 26, 2003
Respiratory Syncytial Virus Up-regulates TLR4 and Sensitizes Airway Epithelial Cells to Endotoxin*
Martha M. Monick
¶,
Timur O. Yarovinsky,
Linda S. Powers,
Noah S. Butler,
A. Brent Carter,
Gunnar Gudmundsson||, and
Gary W. Hunninghake
From the
University of Iowa Roy J. and Lucille A. Carver College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52240 and the ||Department of Medicine, National University Hospital, IS-101 Reykjavik, Iceland
Airway epithelial cells are unresponsive to endotoxin (lipopolysaccharide (LPS)) exposure under normal conditions. This study demonstrates that respiratory syncytial virus (RSV) infection results in increased sensitivity to this environmental exposure. Infection with RSV results in increased expression of Toll-like receptor (TLR) 4 mRNA, protein, and increased TLR4 membrane localization. This permits significantly enhanced LPS binding to the epithelial monolayer that is blocked by disruption of the Golgi. The increased TLR4 results in an LPS-induced inflammatory response as demonstrated by increased mitogen-activated protein (MAP) kinase activity, IL-8 production, and tumor necrosis factor 
production. RSV infection also allowed for tumor necrosis factor production subsequent to TLR4 cross-linking with an immobilized antibody. These data suggest that RSV infection sensitizes airway epithelium to a subsequent environmental exposure (LPS) by altered expression and membrane localization of TLR4. The increased interaction between airway epithelial cells and LPS has the potential to profoundly alter airway inflammation.
Received for publication, July 25, 2003
, and in revised form, September 16, 2003.
* This work was supported by a Veterans Affairs Merit Review grant, National Institutes of Health Grant HL-60316, National Institutes of Health Grant HL073967-01, and National Institutes of Health Grant ES-09607, U. S. Environmental Protection Agency Grant R826711 (to G. W. H.), National Institutes of Health Grant HL-03860 (to A. B. C.) and Grant RR00059 from the General Clinical Research Centers Program, National Center for Research Resources, 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.
The on-line version of this article (available at http://www.jbc.org) contains supplementary movies showing confocal z sections of control and RSV-infected HAE cells exposed to LPS-ALEXA488.
Both authors contributed equally to this work.
¶ 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, Iowa City, IA 52242. Tel.: 319-335-759; Fax: 319-335-6530; E-mail: martha-monick{at}uiowa.edu.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
