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Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin
Author(s) -
Tuñón María J.,
SanMiguel Beatriz,
Crespo Irene,
Laliena Almudena,
Vallejo Daniela,
Álvarez Marcelino,
Prieto Jesús,
GonzálezGallego Javier
Publication year - 2013
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/jpi.12063
Subject(s) - endoplasmic reticulum , unfolded protein response , melatonin , fulminant , viral hepatitis , medicine , virology , biology , endocrinology , immunology , microbiology and biotechnology
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 2 × 10 4 hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10 mg/kg and 20 mg/kg at 0 hr, 12 hr and 24 hr postinfection. RHDV infection induced increased expression of CCAAT /enhancer‐binding protein homologous protein ( CHOP ), immunoglobulin heavy chain binding protein ( BiP / GRP 78), glucose‐regulated protein 94 ( GRP 94), 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 ( ATF 6), ATF 4, inositol‐requiring enzyme 1 ( IRE 1), spliced X ‐box binding protein‐1 ( XBP 1s) and tumor necrosis factor receptor‐associated factor 2 ( TRAF 2). 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 .