Journal of Biological Chemistry
Volume 278, Issue 52, 26 December 2003, Pages 53035-53044
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Molecular Basis of Cell and Developmental Biology
Respiratory Syncytial Virus Up-regulates TLR4 and Sensitizes Airway Epithelial Cells to Endotoxin*

https://doi.org/10.1074/jbc.M308093200Get rights and content
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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 α production. RSV infection also allowed for tumor necrosis factor α 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.

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*

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.