Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 5, Pages 3404-3411Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110054200
Keywords
-
Categories
Funding
- NHLBI NIH HHS [T32 HL07829, HL60678, HL45638, HL27016] Funding Source: Medline
Ask authors/readers for more resources
In this study, we explored a novel function of polymorphonuclear neutrophils (PMN) NAD(P)H oxidase in the mechanism of tumor necrosis factor-a (TNFalpha)-induced NF-KB 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 TNFa challenge, NTF-K3 activation and ICAM-1 expression were significantly attenuated in lungs of p47(phox-/-)mice as compared with wild-type (V;T) mice. The attenuated NF-KB activation in p47(phox-/-) mice was secondary to inhibition of NIK activity and subsequent IKBalpha degradation. Induction of neutropenia using anti-PMN serum prevented the initial TNFalpha-induced NF-KB 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 MILVEC co-cultured with PMN, suggesting that NF-KB 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 TNFa-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 TNFa-induced NF-KB activation and ICAM-1 expression in endothelial cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available