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Tumor necrosis factor and alcoholic liver disease
C J McClain1, S Barve, S Barve
1Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington 40536-0084, USA.
Alcoholism, Clinical and Experimental Research
|September 4, 1998
Summary
Tumor necrosis factor (TNF) plays a role in alcoholic liver disease. Agents that downregulate TNF, like prednisone, show promise in treating this condition by reducing harmful cytokine production.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Elevated tumor necrosis factor (TNF) is observed in alcoholic liver disease (ALD), contributing to liver injury and metabolic complications.
- Dysregulated TNF metabolism is implicated in ALD pathogenesis, suggesting therapeutic targets to modulate TNF activity.
- Existing treatments like prostaglandins and glucocorticoids inhibit TNF production, showing potential in liver disease models.
Purpose of the Study:
- To evaluate an ex vivo system for assessing the efficacy of anti-cytokine agents in humans for ALD.
- To investigate the role of protective factors and transcription factors in TNF-induced hepatotoxicity in ALD.
- To explore mechanisms underlying liver injury in alcoholic hepatitis and identify rational therapeutic strategies.
Main Methods:
- Utilized an ex vivo system to test prednisone and a prostaglandin analog for their ability to downregulate TNF and interleukin-8.
- Compared acute alcoholic hepatitis patients with trauma patients to assess acute phase protein responses (albumin, C-reactive protein) relative to interleukin-6 levels.
- Investigated the effect of inhibiting NF-kappaB activation on TNF-induced hepatocyte death in vitro.
Main Results:
- Prednisone and a prostaglandin analog effectively reduced TNF and interleukin-8 production in the ex vivo system.
- Patients with alcoholic hepatitis exhibited a blunted acute phase protein response (C-reactive protein) compared to trauma patients, despite similar interleukin-6 levels.
- Inhibition of NF-kappaB activation sensitized hepatocytes to TNF-induced death, highlighting its role in protection.
Conclusions:
- An ex vivo system can effectively assess anti-cytokine therapies for ALD.
- Inadequate generation of hepatic protective factors, potentially linked to NF-kappaB dysfunction, may contribute to liver injury in alcoholic hepatitis.
- Understanding the balance of noxious and protective factors in ALD is crucial for developing targeted therapies.