Negative regulation of inducible nitric-oxide synthase expression mediated through transforming growth factor-beta-dependent modulation of transcription factor TCF11

Inducible nitric-oxide synthase (iNOS) plays a central role in the regulation of vascular function and response to injury. A central mediator controlling iNOS expression is transforming growth factor-beta (TGF-beta), which represses its expression through a mechanism that is poorly understood. We ha...

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Bibliographic Details
Published in:The Journal of biological chemistry Vol. 282; no. 51; p. 36837
Main Authors: Berg, David T, Gupta, Akanksha, Richardson, Mark A, O'Brien, Lee A, Calnek, David, Grinnell, Brian W
Format: Journal Article
Language:English
Published: United States 21.12.2007
Subjects:
Animals
Carcinogens - pharmacology
Cells, Cultured
Dimerization
Disease Models, Animal
Endotoxemia - enzymology
Endotoxemia - genetics
Enzyme Inhibitors - pharmacology
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - genetics
Hepatocyte Nuclear Factor 1-beta - antagonists & inhibitors
Hepatocyte Nuclear Factor 1-beta - genetics
Hepatocyte Nuclear Factor 1-beta - metabolism
Humans
Inflammation - enzymology
Inflammation - genetics
MafG Transcription Factor - genetics
MafG Transcription Factor - metabolism
Male
Mutation
Naphthalenes - pharmacology
Nitric Oxide Synthase Type II - biosynthesis
Nitric Oxide Synthase Type II - genetics
Protein Kinase C - antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Repressor Proteins - genetics
Repressor Proteins - metabolism
Response Elements - genetics
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
Signal Transduction - drug effects
Signal Transduction - genetics
Smad6 Protein - genetics
Smad6 Protein - metabolism
Smad7 Protein - genetics
Smad7 Protein - metabolism
Staurosporine - pharmacology
Tetradecanoylphorbol Acetate - pharmacology
Transforming Growth Factor beta1 - metabolism
Transforming Growth Factor beta1 - pharmacology
ISSN:0021-9258
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Summary:Inducible nitric-oxide synthase (iNOS) plays a central role in the regulation of vascular function and response to injury. A central mediator controlling iNOS expression is transforming growth factor-beta (TGF-beta), which represses its expression through a mechanism that is poorly understood. We have identified a binding site in the iNOS promoter that interacts with the nuclear heterodimer TCF11/MafG using chromatin immunoprecipitation and mutation analyses. We demonstrate that binding at this site acts to repress the induction of iNOS gene expression by cytokines. We show that this repressor is induced by TGF-beta1 and by Smad6-short, which enhances TGF-beta signaling. In contrast, the up-regulation of TCF11/MafG binding could be suppressed by overexpression of the TGF-beta inhibitor Smad7, and a small interfering RNA to TCF11 blocked the suppression of iNOS by TGF-beta. The binding of TCF11/MafG to the iNOS promoter could be enhanced by phorbol 12-myristate 13-acetate and suppressed by the protein kinase C inhibitor staurosporine. Moreover, the induction of TCF11/MafG binding by TGF-beta and Smad6-short could be blocked by staurosporine, and the effect of TGF-beta was blocked by the selective protein kinase C inhibitor calphostin C. Consistent with the in vitro data, we found suppression of TCF11 coincident with iNOS up-regulation in a rat model of endotoxemia, and we observed a highly significant negative correlation between TCF11 and nitric oxide production. Furthermore, treatment with activated protein C, a serine protease effective in septic shock, blocked the down-regulation of TCF11 and suppressed endotoxin-induced iNOS. Overall, our results demonstrate a novel mechanism by which iNOS expression is regulated in the context of inflammatory activation.
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ISSN:0021-9258
DOI:10.1074/jbc.M706909200