Article: article d'un périodique ou d'un magazine.
Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase.
Proceedings of the National Academy of Sciences of the United States of America
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Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
The cellular response to an inflammatory stressor requires a proinflammatory cellular activation followed by a controlled resolution of the response to restore homeostasis. We hypothesized that biliverdin reductase (BVR) by binding biliverdin (BV) quells the cellular response to endotoxin-induced inflammation through phosphorylation of endothelial nitric oxide synthase (eNOS). The generated NO, in turn, nitrosylates BVR, leading to nuclear translocation where BVR binds to the Toll-like receptor-4 (TLR4) promoter at the Ap-1 sites to block transcription. We show in macrophages that BV-induced eNOS phosphorylation (Ser-1177) and NO production are mediated in part by Ca(2+)/calmodulin-dependent kinase kinase. Furthermore, we show that BVR is S-nitrosylated on one of three cysteines and that this posttranslational modification is required for BVR-mediated signaling. BV-induced nuclear translocation of BVR and inhibition of TLR4 expression is lost in macrophages derived from Enos(-/-) mice. In vivo in mice, BV provides protection from acute liver damage and is dependent on the availability of NO. Collectively, we elucidate a mechanism for BVR in regulating the inflammatory response to endotoxin that requires eNOS-derived NO and TLR4 signaling in macrophages.
Active Transport, Cell Nucleus, Animals, Biliverdine/metabolism, Cell Nucleus/metabolism, Endotoxins/metabolism, Gene Expression Regulation, Enzymologic, Liver/pathology, Macrophages/metabolism, Mice, Mice, Transgenic, Nitric Oxide/metabolism, Nitric Oxide Synthase Type III/metabolism, Oxidoreductases Acting on CH-CH Group Donors/metabolism, Toll-Like Receptor 4/metabolism, Transcription Factor AP-1/metabolism
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