TUMOR-NECROSIS-FACTOR AND ALCOHOLIC LIVER-DISEASE

Increased levels of hepatic and serum tumor necrosis factor (TNF) have been documented in animal models of alcoholic liver disease and in hu man alcoholic liver disease. This dysregulated TNF metabolism has been postulated to play a role in many of the metabolic complications and the liver injury of alcoholic liver disease. One potential therapy for alcoholic liver disease may be agents that downregulate TNF productio n or block TNF activity. Indeed, agents such as prostaglandins and glu cocorticoids (both inhibit TNF production) have been used in both huma n liver disease and experimental models of liver injury, and anti-TNF antibody has recently been shown to attenuate the hepatotoxicity in an animal model of alcoholic-related liver disease. In this study, we de monstrate that a simple ex vivo system can be used to initially assess potential efficacy of anticytokine agents when administered to humans . Both prednisone and a prostaglandin analog were effective in downreg ulating TNF and interleukin-8 production. The liver is normally resist ant to TNF cytotoxicity. Sensitivity to TNF cytotoxicity is thought to occur when there is inadequate production of hepatic protective facto rs. In this study, we showed that, when patients with acute alcoholic hepatitis were matched with trauma patients for serum levels of interl eukin-8, they had similar depressions in the negative acute phase prot ein, albumin, but markedly different increases in the major acute phas e protein, C reactive protein. Patients with alcoholic hepatitis had a very blunted response. We also showed that inhibiting activation of t he redox sensitive transcription factor NF kappa B sensitizes to TNF-i nduced hepatocyte death in vitro. This transcription factor is importa nt for the production of both cytokines and many acute phase protectiv e factors. Several hepatic protective factors are induced by TNF. One possible mechanism for liver injury in alcoholic hepatitis may be inad equate generation of hepatic protective factors. Our future understand ing of mechanisms of alcoholic liver disease will involve understandin g the balance between noxious and protective factors in the liver, and this should lead to rational therapy for this disease process.