Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin

J Biol Chem. 2003 Dec 26;278(52):53035-44. doi: 10.1074/jbc.M308093200. Epub 2003 Oct 17.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Separation
  • Cells, Cultured
  • Cross-Linking Reagents / pharmacology
  • Dose-Response Relationship, Drug
  • Endotoxins / metabolism
  • Epithelial Cells / metabolism
  • Epithelium / metabolism*
  • Flow Cytometry
  • Golgi Apparatus / metabolism
  • HeLa Cells
  • Humans
  • Inflammation
  • Interleukin-8 / metabolism
  • Lipopolysaccharides / metabolism
  • Lung / pathology
  • MAP Kinase Signaling System
  • Macrophages, Alveolar / cytology
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / chemistry
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Models, Biological
  • Monocytes / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / biosynthesis*
  • Receptors, Cell Surface / chemistry
  • Respiratory Syncytial Viruses / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation*

Substances

  • Cross-Linking Reagents
  • Endotoxins
  • Interleukin-8
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha