S-Adenosylmethionine, cytokines, and alcoholic liver disease

McClain, Craig J; Hill, Daniell B; Song, Zhenyuan; Chawla, Rajender; Watson, Walter H; Chen, Theresa; Barve, Shirish

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Volume 27, Issue 3 , Pages 185-192, July 2002

S-Adenosylmethionine, cytokines, and alcoholic liver disease☆

Craig J McClain
- Corresponding author. Department of Internal Medicine, University of Louisville Medical Center, 550 S. Jackson St., ACB 3rd Floor, Louisville, KY 40292, USA. Tel.: +1-502-852-6991; fax: +1-502-852-0846.
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA
- Veterans Administration, Louisville, KY 40292, USA
Daniell B Hill
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA
Zhenyuan Song
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
Rajender Chawla
Walter H Watson
- Department of Biochemistry, Emory University, Atlanta, GA 30322, USA
Theresa Chen
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA
Shirish Barve
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA

Received 11 February 2002; received in revised form 18 April 2002; accepted 19 April 2002.

Abstract

Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury. AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels. Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS-induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis. Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.

Keywords: S-adenosylmethionine, Alcoholic liver disease, Tumor necrosis factor