RESUMO
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.
Assuntos
Etanol/farmacologia , Fígado/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Proteínas do Core Viral/fisiologia , Proteínas Virais Reguladoras e Acessórias/fisiologia , Acetaldeído/farmacologia , Animais , Antígenos CD/genética , Antígenos CD/fisiologia , Células Cultivadas , Proteínas de Ligação ao GTP/metabolismo , Vetores Genéticos/genética , Genótipo , Vírus da Hepatite B/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Quinase I-kappa B , Proteínas I-kappa B/genética , Proteínas I-kappa B/fisiologia , Fígado/citologia , Fígado/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Toxina Pertussis , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/fisiologia , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral , Transdução de Sinais/efeitos dos fármacos , Transativadores , Transfecção , Células Tumorais Cultivadas , Proteínas do Core Viral/genética , Proteínas Virais Reguladoras e Acessórias/genética , Fatores de Virulência de Bordetella/farmacologia , Quinase Induzida por NF-kappaBRESUMO
In the present study, we have studied the level of oxidative DNA base damage in lymphocytes of HIV-infected intravenous drug users (IDUs) and a seronegative control group. Chromatin was isolated from the lymphocytes and then analyzed by gas chromatography/isotope-dilution mass spectrometry with selected-ion monitoring (GC/IDMS-SIM). Significantly greater levels of four oxidatively modified DNA bases were observed in chromatin samples from the symptomatic HIV-infected patients than in those from the seronegative patients. These were 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyadenine and 8-hydroxyguanine. In the case of 5-hydroxyuracil and 8-hydroxyguanine, a statistically significant difference was also found between the control group and the asymptomatic HIV-positive patients. These results suggest that oxidative stress may play an important role in the pathogenesis of acquired immune deficiency syndrome (AIDS), and that administration of antioxidant drugs to HIV-infected patients may offer protection against AIDS-related carcinogenesis.
