title: Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion.
abstract: The cytoprotective mechanisms of melatonin in hepatic ischemia/reperfusion (I/R) injury associated with heme oxygenase-1 (HO-1) induction and type 1 interferon (IFN) signaling pathway downstream of toll-like receptor 4 (TLR4) were investigated. Rats were subjected to 60min of ischemia followed by 5-hr reperfusion. Melatonin (10mg/kg) or vehicle (5% ethanol in saline) was administered intraperitoneally 15min prior to ischemia and immediately before reperfusion. Rats were pretreated with zinc protoporphyrin (ZnPP, 10mg/kg, i.p.), a HO-1 inhibitor, at 16 and 3hr prior to ischemia. Melatonin attenuated the I/R-induced increase in serum alanine aminotransferase activity, and ZnPP reversed this attenuation. Melatonin augmented the levels of HO activity and HO-1 protein and mRNA expression, and this enhancement was reversed by ZnPP. Melatonin enhanced the level of NF-E2-related factor-2 (Nrf2) nuclear translocation, and ZnPP reversed this increase. Overexpression of TLR4 and its adaptor proteins, toll-receptor-associated activator of interferon (TRIF), and myeloid differentiation factor 88 (MyD88), induced by I/R, was attenuated by melatonin; ZnPP reversed the effect of melatonin on TLR4 and TRIF expression. Melatonin suppressed the increased interaction between TLR4/TRIF and TLR4/MyD88, which was reversed by ZnPP. Melatonin attenuated the increased levels of JAK2 and STAT1 activation as well as IFN-β, and ZnPP reversed these inhibitory effects of melatonin. Melatonin inhibited the level of chemokine (C-X-C motif) ligand 10 (CXCL-10), and ZnPP reversed this inhibition. Our findings suggest that melatonin protects the liver against I/R injury by HO-1 overexpression, which suppresses the type 1 IFN signaling pathway downstream of TLR4.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Kang
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D054357:Chemokine CXCL10 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000975:Antioxidants; D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; D004791:Enzyme Inhibitors; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011524:Protoporphyrins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C523075:Ticam1 protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C017803:zinc protoporphyrin; D016899:Interferon-beta; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D008550:Melatonin