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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 46; pp. 18849 - 18854
• Main Authors: Wegiel, Barbara, Gallo, David, Csizmadia, Eva, Roger, Thierry, Kaczmarek, Elzbieta, Harris, Clair, Zuckerbraun, Brian S, Otterbein, Leo E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.11.2011; National Acad Sciences
• Subjects: Activator protein 1; Active Transport, Cell Nucleus; Animals; Antiinflammatories; Bacterial vaginosis; biliverdin; Biliverdin reductase; Biliverdine - metabolism; Biological Sciences; Calcium; Cell membranes; Cell Nucleus - metabolism; Cysteine; Endothelial cells; Endotoxins; Endotoxins - metabolism; Gene expression; Gene Expression Regulation, Enzymologic; Hepatocytes; Homeostasis; Inflammation; Kinases; Liver; Liver - pathology; Macrophages; Macrophages - metabolism; Mice; Mice, Transgenic; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Nuclear transport; Oxides; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Phosphorylation; post-translational modification; Promoters; Rodents; T cell receptors; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription; Transcription Factor AP-1 - metabolism; Transcription factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1108571108

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 Ca2+/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.