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: Jung-Woo Kang, Sun-Mee Lee
• Journal: Journal of pineal research (J Pineal Res) Vol. 53 Issue 1 Pg. 67-76 (Aug 2012) ISSN: 1600-079X [Electronic] England
• PMID: 22288937 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 John Wiley & Sons A/S.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Antioxidants
• Chemokine CXCL10
• Cxcl10 protein, rat
• Enzyme Inhibitors
• Myd88 protein, rat
• Myeloid Differentiation Factor 88
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• Protoporphyrins
• STAT1 Transcription Factor
• STAT1 protein, human
• Ticam1 protein, rat
• Tlr4 protein, rat
• Toll-Like Receptor 4
• zinc protoporphyrin
• Interferon-beta
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat
• Jak2 protein, rat
• Janus Kinase 2
• Melatonin

Topics

• Active Transport, Cell Nucleus (drug effects)
• Adaptor Proteins, Vesicular Transport
• Animals
• Antioxidants (pharmacology)
• Cell Nucleus (metabolism, pathology)
• Chemokine CXCL10 (metabolism)
• Enzyme Inhibitors (pharmacology)
• Heme Oxygenase (Decyclizing) (antagonists & inhibitors, metabolism)
• Interferon-beta (metabolism)
• Janus Kinase 2 (metabolism)
• Liver (metabolism, pathology)
• Male
• Melatonin (pharmacology)
• Myeloid Differentiation Factor 88 (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Protoporphyrins (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism, pathology, prevention & control)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Toll-Like Receptor 4 (metabolism)