title: Concanavalin A/IFN-gamma triggers autophagy-related necrotic hepatocyte death through IRGM1-mediated lysosomal membrane disruption.
abstract: Interferon-gamma (IFN-γ), a potent Th1 cytokine with multiple biological functions, can induce autophagy to enhance the clearance of the invading microorganism or cause cell death. We have reported that Concanavalin A (Con A) can cause autophagic cell death in hepatocytes and induce both T cell-dependent and -independent acute hepatitis in immunocompetent and immunodeficient mice, respectively. Although IFN-γ is known to enhance liver injury in Con A-induced hepatitis, its role in autophagy-related hepatocyte death is not clear. In this study we report that IFN-γ can enhance Con A-induced autophagic flux and cell death in hepatoma cell lines. A necrotic cell death with increased lysosomal membrane permeabilization (LMP) is observed in Con A-treated hepatoma cells in the presence of IFN-γ. Cathepsin B and L were released from lysosomes to cause cell death. Furthermore, IFN-γ induces immunity related GTPase family M member 1(IRGM1) translocation to lysosomes and prolongs its activity in Con A-treated hepatoma cells. Knockdown of IRGM1 inhibits the IFN-γ/Con A-induced LMP change and cell death. Furthermore, IFN-γ(-/-) mice are resistant to Con A-induced autophagy-associated necrotic hepatocyte death. We conclude that IFN-γ enhances Con A-induced autophagic flux and causes an IRGM1-dependent lysosome-mediated necrotic cell death in hepatocytes.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Peng
authors.initials: CP
authors.lastname: Chang
authors.forename: Ming-Chen
authors.initials: MC
authors.lastname: Yang
authors.forename: Huan-Yao
authors.initials: HY
authors.lastname: Lei
mesh_terms: D000818:Animals; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003208:Concanavalin A / Q000378:metabolism*; D004705:Endocytosis; D019204:GTP-Binding Proteins / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D010539:Permeability
chemical_list: C096000:Ifi1 protein, mouse; D003208:Concanavalin A; D007371:Interferon-gamma; D002401:Cathepsin B; D056668:Cathepsin L; D019204:GTP-Binding Proteins