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Melatonin inhibits type 1 interferon signaling of toll‐like receptor 4 via heme oxygenase‐1 induction in hepatic ischemia/reperfusion
Author(s) -
Kang JungWoo,
Lee SunMee
Publication year - 2012
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2012.00972.x
Subject(s) - melatonin , trif , zinc protoporphyrin , tlr4 , chemistry , endocrinology , pharmacology , medicine , receptor , heme oxygenase , toll like receptor , biology , heme , biochemistry , innate immune system , enzyme
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.