Melatonin protects liver against ischemia and reperfusion injury through inhibition of toll‐like receptor signaling pathway

Abstract

This study investigated the immunomodulating effect of melatonin on toll-like receptor (TLR)-stimulated signal transduction. Rats were subjected to 60 min of ischemia followed by 1 or 5 hr of reperfusion. Melatonin (10 mg/kg) or the vehicle was administered intraperitoneally 15 min prior to ischemia and immediately before reperfusion. Melatonin treatment significantly reduced the level of serum alanine aminotransferase activity. Increased levels of TLR3 and TLR4 protein expression induced by ischemia/reperfusion (I/R) were attenuated by melatonin. Serum level of high-mobility group box 1 (HMGB1), a potent alarmin of the TLR system, increased significantly in the I/R group, and melatonin inhibited this release. Melatonin suppressed the increase in myeloid differentiation factor 88 (MyD88) protein expression, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation and nuclear translocation of nuclear factor κB (NF-κB) and phosphorylated c-Jun, a component of activator protein 1. The increased level of toll-receptor-associated activator of interferon (TRIF) expression, phosphorylation of interferon (IFN) regulatory factor 3 (IRF3) and serum IFN-β was attenuated by melatonin. Melatonin attenuated the levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) protein and mRNA expression, while the level of heme oxygenase-1 (HO-1) was augmented. Our results suggest that melatonin ameliorates I/R-induced liver damage by modulation of TLR-mediated inflammatory responses.

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…Recent studies show that Bβ15-42 (the fibrin-derived peptide), PNU-282987 (a selective α7 nicotinic acetylcholine receptor agonist), EPC-K1 (the vitamin E derivative), melatonin, cisplatin and glycyrrhizin attenuate warm liver I/R damage partly through inhibition of HMGB1 release (47)(48)(49)(50)(51)(52). Interestingly, pretreatment of mice with HMGB1 protein significantly decreased liver I/R injury through upregulation of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling (53).…”

Мелатонін Як Гепатопротектор При Цукровому Діабеті

“…Ïîêàçàíî, ùî ³ìóíîìîäóëþþ÷à ä³ÿ ìåëàòîí³íó ìîaeå áóòè ïîâÿçàíà ç ³íã³áóâàííÿì ïðîäóêö³¿ îêñèäó àçîòó øëÿõîì ïðè-ãí³÷åííÿ àêòèâíîñò³ ³íäóöèáåëüíî¿ NO-ñèíòàçè ³ çìåí-øåííÿ ³íäóêîâàíî¿ ïðîäóêö³¿ NFkB [37]. Çäàòí³ñòü ìå-ëàòîí³íó çíèaeóâàòè âì³ñò ïðîçàïàëüíèõ öèòîê³í³â ïðè ²Ð ìîaeå áóòè çóìîâëåíà çäàòí³ñòþ öüîãî ãîðìîíó âïëèâàòè íà Toll-ïîä³áí³ ðåöåïòîðè (êëàñ á³ëê³â, ùî â³ä³ãðàþòü êëþ÷îâó ðîëü â ³í³ö³àö³¿ ³ìóííî¿ â³äïîâ³ä³) TLR3 òà TLR4 [38].…”

Ischemia-Reperfusion Injury Associated with Liver Transplantation in 2011: Past and Future

“…The loss of TLR4 in steatotic livers from TLR4-knockout HFD animals reduces pro-inflammatory cytokines and liver injury and improves survival (Ellett et al, 2009). Although TLR4 signaling is relevant in hepatic I/R injury, there is some controversy over which of the pathways [(myeloid differentiation factor 88 (My-D88)-dependent) or Toll/IL-1 receptor domain-containing adaptor inducing interferon-(TRIF/IRF-3 signalling pathway)] is activated in hepatic I/R (Kang et al, 2011). Neutrophils have been involved in the increased vulnerability of steatotic livers to I/R injury, especially in alcoholic steatotic livers.…”