Role of Neutrophil NADPH Oxidase in the Mechanism of Tumor Necrosis Factor-α-induced NF-κB Activation and Intercellular Adhesion Molecule-1 Expression in Endothelial Cells*

In this study, we explored a novel function of polymorphonuclear neutrophils (PMN) NAD(P)H oxidase in the mechanism of tumor necrosis factor-α (TNFα)-induced NF-κB activation and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells. Studies were made in mice lacking the p47 phox subunit of NAD(P)H oxidase as well as in cultured mouse lung vascular endothelial cells (MLVEC) from these mice. In response to TNFα challenge, NF-κB activation and ICAM-1 expression were significantly attenuated in lungs of p47 phox −/− mice as compared with wild-type (WT) mice. The attenuated NF-κB activation in p47 phox −/− mice was secondary to inhibition of NIK activity and subsequent IκBα degradation. Induction of neutropenia using anti-PMN serum prevented the initial TNFα-induced NF-κB activation and ICAM-1 expression in WT mice, indicating the involvement of PMN NAD(P)H oxidase in signaling these responses. Moreover, the responses were restored upon repletion with PMN obtained from WT mice but not with PMN from p47 phox −/−mice. These findings were recapitulated in MLVEC co-cultured with PMN, suggesting that NF-κB activation and resultant ICAM-1 expression in endothelial cells occurred secondary to oxidants generated by the PMN NAD(P)H oxidase complex. The functional relevance of the PMN NAD(P)H oxidase in mediating TNFα-induced ICAM-1-dependent endothelial adhesivity was evident by markedly reduced adhesion of p47 phox −/− PMN in co-culture experiments. Thus, oxidant signaling by the PMN NAD(P)H oxidase complex is an important determinant of TNFα-induced NF-κB activation and ICAM-1 expression in endothelial cells.

• Publication year

  2002

• Venue

  Journal of Biological Chemistry

• Publication date

  2002-02-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.M110054200
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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