Alcohol drinking and infection with hepatitis virus accelerate liver injury, but the underlying mechanism is not fully understood. 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-kB, a critical signal in hepatic injury and tumor transformation. Acute ethanol or acetaldehyde exposure potentiates HBX or HCV core protein activation of NF-kB in primary mouse hepatocytes. The ethanol metabolism inhibitor 4-methylprazole abolishes such potentiation. Overexpression of dominant negative NIK, IKK, or IkB attenuates HBX, HCV core protein, or acetaldehyde activation of NF-kB. Induction of NF-kB by HBX and HCV core protein but not ethanol is completely abolished in TNF receptor 1 (TNFR1) -/- hepatocytes, whereas pertussis toxin attenuates acetaldehyde activation of NF-kB. Finally, chronic ethanol consumption induces hepatic CYP2E1 protein expression and potentiates HBX or HCV core protein activation of NF-kB in the liver. These findings suggest that ethanol activates hepatic NF-kB via its metabolism and HBX or HCV core protein activates hepatic NF-kB via TNFR1. In view of the essential role of TNFR1 in alcoholic liver injury, targeting TNFR1 by hepatitis viral proteins could contribute to cooperative effects of alcohol drinking and viral hepatitis on liver disease. We have also demonstrated that elevated interleukin-6 levels during alcohol consumption protect alcohol-induced apoptosis in the liver. Currently, we are continuing to investigate the molecular mechanism underlying the synergistic effect of alcohol drinking and viral hepatitis infection on liver injury.
| Bi, Xiaolin; Jones, Tamara; Abbasi, Fatima et al. (2005) Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells. Oncogene 24:8229-39 |
| Kim, W H; Hong, F; Jaruga, B et al. (2001) 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. FASEB J 15:2551-3 |
| Neuman, M G; Brenner, D A; Rehermann, B et al. (2001) Mechanisms of alcoholic liver disease: cytokines. Alcohol Clin Exp Res 25:251S-253S |
