Additive activation of hepatic NF-kappaB by ethanol and hepatitis B protein X (HBX) or HCV core protein: involvement of TNF-alpha receptor 1-independent and -dependent mechanisms.

Abstract	Alcohol consumption and viral hepatitis infection synergistically accelerate liver injury, but the underlying mechanism is not fully understood. Here we have examined the effects of ethanol on hepatitis B protein X (HBX)- or hepatitis C core protein (HCV core protein)-mediated activation of NF-kappaB, a critical signal in hepatic injury, regeneration, and tumor transformation. Acute ethanol or acetaldehyde exposure potentiates HBX or HCV core protein activation of NF-kappaB in primary mouse hepatocytes. Such potentiation can be abolished by blocking ethanol metabolism or overexpression of dominant negative NF-kappaB-inducing kinase (NIK), IkappaB kinase (IKK), or IkappaB. Moreover, pertussis toxin attenuates NF-kappaB activation induced by acetaldehyde but not by HBX or HCV core protein, whereas HBX or HCV core protein-mediated activation of NF-kappaB is abolished completely in tumor necrosis factor a receptor 1 (TNFR1) (-/-) hepatocytes. Finally, chronic ethanol consumption induces hepatic CYP2E1 protein expression and potentiates HBX or HCV core protein activation of NF-kappaB in the liver. These findings suggest that ethanol activates hepatic NF-kappaB via its metabolism and that HBX or HCV core protein activates hepatic NF-kappaB via TNFR1. With the essential role of TNFR1 in alcoholic liver injury, targeting TNFR1 by hepatitis viral proteins could contribute to cooperative effects of alcohol consumption and viral hepatitis on liver disease.
Authors	W H Kim, F Hong, B Jaruga, Z Hu, S Fan, T J Liang, B Gao
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 15 Issue 13 Pg. 2551-3 (Nov 2001) ISSN: 1530-6860 [Electronic] United States
PMID	11641261 (Publication Type: Journal Article)
Chemical References	Antigens, CD I-kappa B Proteins NF-kappa B Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Trans-Activators Viral Core Proteins Viral Regulatory and Accessory Proteins Virulence Factors, Bordetella hepatitis B virus X protein nucleocapsid protein, Hepatitis C virus Ethanol Pertussis Toxin Protein Serine-Threonine Kinases CHUK protein, human Chuk protein, mouse I-kappa B Kinase IKBKB protein, human IKBKE protein, human Ikbkb protein, mouse Ikbke protein, mouse NF-kappa B kinase GTP-Binding Proteins Acetaldehyde
Topics	Acetaldehyde (pharmacology) Animals Antigens, CD (genetics, physiology) Cells, Cultured Ethanol (pharmacology) GTP-Binding Proteins (metabolism) Genetic Vectors (genetics) Genotype Hepatitis B virus (genetics) Hepatocytes (drug effects, metabolism) Humans I-kappa B Kinase I-kappa B Proteins (genetics, physiology) Liver (cytology, drug effects, metabolism) Mice Mice, Knockout NF-kappa B (drug effects, metabolism) Pertussis Toxin Protein Serine-Threonine Kinases (genetics, physiology) Receptors, Tumor Necrosis Factor (genetics, physiology) Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Signal Transduction (drug effects) Trans-Activators Transfection Tumor Cells, Cultured Viral Core Proteins (genetics, physiology) Viral Regulatory and Accessory Proteins (genetics, physiology) Virulence Factors, Bordetella (pharmacology)

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