Control of ER stress by a chemical chaperone counteracts apoptotic signals in IFN-gamma-treated murine hepatocytes.
Apoptosis of hepatocytes plays a key role in the pathogenesis of immune-mediated hepatitis. However, the detailed mechanisms of apoptotic signaling remain unclear. In this study, we investigated the involvement of ER stress in a model of IFN-gamma-induced apoptosis of hepatocytes in vitro, using a chemical chaperone reagent, glycerol. IFN-gamma-induced apoptotic events (mitochondrial release of cytochrome c, enzymatic activation of caspase-3 and -9) were markedly inhibited by glycerol. Glycerol induced partial inhibition of cytotoxicity indicated by lactate dehydrogenase release from the cytosol but had no inhibitory effect on the induction of IRF-1 gene expression and reactive oxygen species, required for hepatocyte apoptosis by IFN-gamma. Induction of caspase-4 and -12 gene expression, positively correlated with ER stress, was attenuated by glycerol. Gene analysis revealed that induction of ER stress-related genes, C/EBP homologue protein (CHOP/GADD153) and TRB3, was suppressed completely by glycerol treatment. These results suggest that ER stress plays a crucial role in mediating apoptosis of hepatocytes induced by IFN-gamma, and a chemical chaperone is an effective inhibitor of the ER stress.
Kanki
Keita
K
Department of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo, Tokyo, Japan.
Kawamura
Takeshi
T
Watanabe
Yoshifumi
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005990:Glycerol / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D018832:Molecular Chaperones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051742:Transcription Factor CHOP / Q000187:drug effects / Q000378:metabolism
C497250:Ddit3 protein, mouse; D050856:Interferon Regulatory Factor-1; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D051742:Transcription Factor CHOP; D007371:Interferon-gamma; D045304:Cytochromes c; D020169:Caspases; D005990:Glycerol