concanavalin aifn-gamma triggers autophagy-related necrotic hepatocyte death through irgm1-mediated lysosomal membrane disruption伴刀豆球蛋白aifn-gamma触发autophagy-related坏死肝细胞死亡通过irgm1-mediated溶酶体膜的破坏.pdfVIP

Concanavalin A/IFN-Gamma Triggers Autophagy-Related Necrotic Hepatocyte Death through IRGM1-Mediated Lysosomal Membrane Disruption 1,3 2 1,2,3 Chih-Peng Chang , Ming-Chen Yang , Huan-Yao Lei * 1 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 2 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 3 Infectious Disease and Signaling Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan Abstract Interferon-gamma (IFN-c), a potent Th1 cytokine with multiple biological functions, can induce autophagy to enhancethe 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-c 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-c 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-c. Cathepsin B and L were released from lysosomes to cause cell death. Furthermore, IFN-c 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-c/Con A-induced LMP change and cell death. Furthermore, IFN-c2/ 2 mice are resistant to Con A-induced autophagy-associated necrotic hepatocyte death. We conclude that IFN-c enhances Con A-induced