title: 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: Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Barbara
authors: B
authors: Wegiel
authors: David
authors: D
authors: Gallo
authors: Eva
authors: E
authors: Csizmadia
authors: Thierry
authors: T
authors: Roger
authors: Elzbieta
authors: E
authors: Kaczmarek
authors: Clair
authors: C
authors: Harris
authors: Brian S
authors: BS
authors: Zuckerbraun
authors: Leo E
authors: LE
authors: Otterbein
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001664:Biliverdine / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D004731:Endotoxins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D001664:Biliverdine