Tumor Necrosis Factor and Alcoholic Liver Disease

Authors

  • Craig J. McClain,

    Corresponding author
    1. Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
      Reprint requests: Craig J. McClain, M.D., Director, Division of Digestive Diseases and Nutrition, MN 655, University of Kentucky Medical Center, Lexington, KY 40536-0084.
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  • Shirish Barve,

    1. Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
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  • Swati Barve,

    1. Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
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  • Ion Deaciuc,

    1. Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
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  • Daniell B. Hill

    1. Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, Kentucky.
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  • Presented at the Alcohol-Induced Immunopathology Symposium, New Orleans, LA, October 17–18, 1997.

  • This research is supported by the National Institutes of Health Grants 1K21 AA00205-01, 1K20 AA00190-01, 1P01 NS31220-01A1, R01 AA010762, M01 RR02602, and by the Veterans Administration.

Reprint requests: Craig J. McClain, M.D., Director, Division of Digestive Diseases and Nutrition, MN 655, University of Kentucky Medical Center, Lexington, KY 40536-0084.

Abstract

Increased levels of hepatic and serum tumor necrosis factor (TNF) have been documented in animal models of alcoholic liver disease and in human 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 down-regulate TNF production or block TNF activity. Indeed, agents such as prostaglandins and glucocorticoids (both inhibit TNF production) have been used in both human 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 demonstrate 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 downregulating TNF and interleukin-8 production. The liver is normally resistant to TNF cytotoxicity. Sensitivity to TNF cytotoxicity is thought to occur when there is inadequate production of hepatic protective factors. In this study, we showed that, when patients with acute alcoholic hepatitis were matched with trauma patients for serum levels of interleukin-6, they had similar depressions in the negative acute phase protein, albumin, but markedly different increases in the major acute phase protein, C reactive protein. Patients with alcoholic hepatitis had a very blunted response. We also showed that inhibiting activation of the redox sensitive transcription factor NFKB sensitizes to TNF-induced hepatocyte death in vitro. This transcription factor is important for the production of both cytokines and many acute phase protective factors. Several hepatic protective factors are induced by TNF. One possible mechanism for liver injury in alcoholic hepatitis may be inadequate generation of hepatic protective factors. Our future understanding of mechanisms of alcoholic liver disease will involve understanding the balance between noxious and protective factors in the liver, and this should lead to rational therapy for this disease process.

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