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Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion


Address reprint requests to Sun-Mee Lee, Ph.D., School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.


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 60 min of ischemia followed by 5-hr reperfusion. Melatonin (10 mg/kg) or vehicle (5% ethanol in saline) was administered intraperitoneally 15 min prior to ischemia and immediately before reperfusion. Rats were pretreated with zinc protoporphyrin (ZnPP, 10 mg/kg, i.p.), a HO-1 inhibitor, at 16 and 3 hr 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.