Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase.

Abstract

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.

• Authors: Barbara Wegiel, David Gallo, Eva Csizmadia, Thierry Roger, Elzbieta Kaczmarek, Clair Harris, Brian S Zuckerbraun, Leo E Otterbein
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 46 Pg. 18849-54 (Nov 15 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 22042868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Transcription Factor AP-1
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Oxidoreductases Acting on CH-CH Group Donors
• biliverdin reductase
• Biliverdine

Topics

• 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)