Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.
Hepatocyte I kappaB kinase beta (IKK beta) inhibits hepatocarcinogenesis by suppressing accumulation of reactive oxygen species (ROS) and liver damage, whereas JNK1 activation promotes ROS accumulation, liver damage, and carcinogenesis. We examined whether hepatocyte p38 alpha, found to inhibit liver carcinogenesis, acts similarly to IKK beta in control of ROS metabolism and cell death. Hepatocyte-specific p38 alpha ablation enhanced ROS accumulation and liver damage, which were prevented upon administration of an antioxidant. In addition to elevated ROS accumulation, hepatocyte death, augmented by loss of either IKK beta or p38 alpha, was associated with release of IL-1 alpha. Inhibition of IL-1 alpha action or ablation of its receptor inhibited carcinogen-induced compensatory proliferation and liver tumorigenesis. IL-1 alpha release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.
Sakurai
Toshiharu
T
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
He
Guobin
G
Matsuzawa
Atsushi
A
Yu
Guann-Yi
GY
Maeda
Shin
S
Hardiman
Gary
G
Karin
Michael
M
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D051550:I-kappa B Kinase / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones; D009336:Necrosis; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D002273:Carcinogens; C497250:Ddit3 protein, mouse; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D053582:Interleukin-1alpha; D015850:Interleukin-6; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D004052:Diethylnitrosamine; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases