Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin
Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin
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DOI：
10.1111/jpi.12063
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发表时间：
2013-10-01
影响因子：
10.3
通讯作者：
Gonzalez-Gallego, Javier
中科院分区：
文献类型：
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作者：
Tunon, Maria J.;San-Miguel, Beatriz;Gonzalez-Gallego, Javier
肝细胞凋亡在暴发性肝功能衰竭（FHF）的发生发展中起重要作用。本研究的目的是调查是否内质网（ER）的压力和未折叠蛋白反应（UPR）的抑制是一个潜在的机制褪黑激素抗凋亡作用的动物模型中的病毒来源的FHF的兔出血症病毒（RHDV）诱导。用2 × 10（4）血凝单位的RHDV分离株感染家兔，并在感染后0小时、12小时和24小时分别给予10 mg/kg和20 mg/kg两种浓度的褪黑激素。RHDV感染诱导CCAAT/增强子结合蛋白同源蛋白（CHOP）、免疫球蛋白重链结合蛋白（BiP/GRP 78）、葡萄糖调节蛋白94（GRP 94）、磷酸化c-Jun N-末端激酶（JNK）和半胱天冬酶-12的表达增加。这些作用被褪黑激素减弱。双重免疫荧光染色显示CHOP和切割的caspase-3在RHDV感染的兔肝切片中共定位，而免疫染色在褪黑素治疗后显著降低。RHDV感染导致转录激活因子6（ATF 6）、ATF 4、肌醇需要酶1（IRE 1）、剪接的X-box结合蛋白-1（XBP 1 s）和肿瘤坏死因子受体相关因子2（TRAF 2）的mRNA水平显著增加。褪黑激素减弱了变化的程度。所获得的数据提供的证据表明，在兔实验感染RHDV，减少凋亡性肝损伤的褪黑激素与衰减的ER应激通过调制的三个武器的UPR信号，并进一步支持褪黑激素在FHF的潜在的肝保护作用。
Hepatocyte apoptosis plays an important role in the development of fulminant hepatic failure (FHF). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress and unfolded protein response (UPR) inhibition is an underlying mechanism of melatonin anti-apoptotic effects in an animal model of FHF of viral origin induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2x10(4) hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10mg/kg and 20mg/kg at 0hr, 12hr and 24hr postinfection. RHDV infection induced increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin heavy chain binding protein (BiP/GRP78), glucose-regulated protein 94 (GRP94), phospho-c-Jun N-terminal kinase (JNK) and caspase-12. These effects were attenuated by melatonin. Double immunofluorescence staining showed colocalization of CHOP and cleaved caspase-3 in liver sections of RHDV-infected rabbits, while immunostaining decreased markedly with melatonin treatment. RHDV infection resulted in significant increases in the mRNA levels of activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), spliced X-box binding protein-1 (XBP1s) and tumor necrosis factor receptor-associated factor 2 (TRAF2). Melatonin attenuated the extent of the changes. Data obtained provide evidence that in rabbits with experimental infection by RHDV, reduction in apoptotic liver damage by melatonin is associated with attenuation of ER stress through a modulation of the three arms of UPR signaling and further support a potential hepatoprotective role of melatonin in FHF.