TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase

J Clin Invest. 2003 Oct;112(8):1234-43. doi: 10.1172/JCI18696.


Interactions of polymorphonuclear neutrophils (PMNs) with endothelial cells may contribute to the activation of endothelial cell responses involved in innate immunity. We explored a novel function of PMN NADPH oxidase in the mechanism of Toll-like receptor-2 (TLR2) upregulation induced by LPS-TLR4 signaling in endothelial cells. We showed that LPS induced TLR2 up-regulation through TLR4- and MyD88-dependent signaling. In neutropenic mice, the LPS-induced NF-kB activation and TLR2 expression were significantly reduced, and both responses were restored upon repletion by PMN obtained from WT mice but not by PMNs from NADPH oxidase gp91pho(-/-) mice. These findings were recapitulated in mouse lung vascular endothelial cells cocultured with PMNs, indicating that the augmented NF-kB activation and the resultant TLR2 upregulation in endothelial cells were secondary to oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in endothelial cells was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and peptidoglycan. Thus, PMN NADPH oxidase-derived oxidant signaling is an important determinant of the cross talk between TLR4 and TLR2 and the control of endothelial cell activation.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Movement
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Lipopolysaccharides / pharmacology
  • Lung / metabolism
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase 2
  • NADPH Oxidases / physiology*
  • NF-kappa B / physiology
  • Neutrophils / enzymology*
  • Neutrophils / physiology
  • Phosphoproteins / physiology
  • Receptors, Cell Surface / physiology*
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Phosphoproteins
  • Receptors, Cell Surface
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Intercellular Adhesion Molecule-1
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • neutrophil cytosolic factor 1