Abstract
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 alpha production. RSV infection also allowed for tumor necrosis factor alpha 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.
Highlights
Airway epithelial cells are unresponsive to endotoxin (lipopolysaccharide (LPS)) exposure under normal conditions
respiratory syncytial virus (RSV) infection allowed for tumor necrosis factor ␣ production subsequent to TLR4 cross-linking with an immobilized antibody
We found that RSV infection increased TLR4 expression and membrane localization on airway epithelial cells (A549 cells, primary human airway epithelial cells (HAE and Human tracheobronchial epithelial cells (hTBE)) and HeLa cells)
Summary
Vol 278, No 52, Issue of December 26, pp. 53035–53044, 2003 Printed in U.S.A. Respiratory Syncytial Virus Up-regulates TLR4 and Sensitizes Airway Epithelial Cells to Endotoxin*□S. They showed that this low dose effect of LPS (facilitation of Th2 responses) differs from high dose exposure that facilitates protective Th1 responses These observations suggest a complicated role for LPS in the development of asthma that may depend on a number of interacting factors, including dose, genetics, and other environmental exposures. We evaluated first the LPS responsiveness of a lung epithelial cell line and the effect of RSV infection on TLR4 expression and membrane localization. The basic observations (increased TLR4 and MD-2, as well as increased LPS binding) were confirmed in a number of other epithelial lines, including newly isolated human bronchotracheal epithelial cells As a composite, these studies suggest that RSV infection alters epithelial environmental responsiveness via an effect on expression and function of the LPS receptor, TLR4
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