Melatonin attenuates carbon tetrachloride-induced liver fibrosis via inhibition of necroptosis.
We investigated the protective mechanisms of melatonin (MLT) associated with necroptosis signaling and damage-associated molecular patterns, which are mediated by the activation of pattern recognition receptors in liver fibrosis. Rats were given an intraperitoneal injection of carbon tetrachloride (CCl4) dissolved in olive oil (1:3, vol/vol) twice a week (0.5 mL/kg) for 8 weeks. During this period, MLT was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 administration increased hepatic hydroxyproline content and hepatocellular damage. MLT attenuated these increases. The expression levels of transforming growth factor β1 and α-smooth muscle actin that were increased by chronic CCl4 exposure were attenuated by MLT. CCl4 significantly increased receptor-interacting protein 1 (RIP1) expression, the formation of the RIP1 and RIP3 necrosome complex, and the level of mixed lineage kinase domain-like protein in liver tissue, which were attenuated by MLT. MLT also attenuated CCl4-induced increases in serum high-mobility group box 1 (HMGB1) and interleukin 1α, as well as the interaction between HMGB1 receptors for advanced glycation end products (RAGE). The increases in toll-like receptor 4 expression, p38, c-Jun N-terminal kinases phosphorylation, and nuclear factor κB translocation were suppressed by MLT. MLT attenuated the overexpression of RAGE, increased level of early growth response protein 1, and increased messenger RNA level of macrophage inflammatory protein 2. Our findings suggest MLT may prevent liver fibrosis by inhibiting necroptosis-associated inflammatory signaling.
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
Hyo-Sun
HS
Choi
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
Jung-Woo
JW
Kang
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea. Electronic address: sunmee@skku.edu.
Sun-Mee
SM
Lee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002251:Carbon Tetrachloride; D024243:HMGB1 Protein / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053582:Interleukin-1alpha / Q000097:blood; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use*; D009336:Necrosis / Q000097:blood / Q000473:pathology*; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism
D024243:HMGB1 Protein; C553108:Il33 protein, rat; D053582:Interleukin-1alpha; D000067596:Interleukin-33; D007378:Interleukins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D002251:Carbon Tetrachloride; D008550:Melatonin