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Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease.




 

J Gastroenterol Hepatol. 2000 Apr;15(4):349-56. Unique Identifier :

Chemokines are implicated in the pathogenesis of alcoholic liver disease in humans and in experimental models of alcohol intoxication. The major sources of these chemokines are Kupffer cells which represent more than 80% of tissue macrophages in the body. Kupffer cells are highly responsive to the effects of ethanol, endotoxin and human immunodeficiency virus (HIV)-1 glycoprotein120. These agents, either independently or in combination, may exacerbate the production of chemokines. Chemokines are agents that are highly chemotactic to mononuclear cells and granulocytes. The levels of these chemokines in sera and tissue are elevated in patients with alcoholic hepatitis, alcoholic cirrhosis, diseased livers, viral hepatitis, and in experimental models of chronic alcohol intoxication. Alcohol-induced influx of endotoxin from the gut into the portal circulation is suggested to play an important role in the activation of Kupffer cells which leads to enhanced chemokine release. The up-regulation of chemokines during alcohol consumption is selective. During the early phase of alcoholic liver disease, C-X-C or alpha-chemokines predominate. This is also associated with neutrophilic infiltration of the liver. In the later stage, up-regulation of C-C or beta-chemokine production and migration of mononuclear cells into the liver are observed, and this may lead to liver cirrhosis. Selective up-regulation of chemokine synthesis and release may involve differential modulation of the transcription factors required for chemokine gene expression. Increased cytokine release following alcohol consumption may also regulate chemokine secretion in Kupffer cells via paracrine and autocrine mechanisms and vice versa. In addition, infection with HIV-1 may further compromise the liver to more damage. During HIV-1 infection, a pre-existing liver disease superimposed on chronic alcohol consumption may also exacerbate HIV-1 replication and lymphocytic infiltration in the liver, because of the ability of HIV-1 gp120 to stimulate chemokine production by Kupffer cells and stimulate migration of inflammatory leucocytes in the liver.

JOURNAL ARTICLE REVIEW REVIEW, TUTORIAL Alcohol Drinking/ADVERSE EFFECTS Alcoholic Intoxication/COMPLICATIONS/METABOLISM Animal Cell Movement/DRUG EFFECTS Chemokines/*BIOSYNTHESIS/GENETICS Endotoxins/SECRETION Ethanol/*ADVERSE EFFECTS/TOXICITY Human Intestinal Mucosa/DRUG EFFECTS/SECRETION Kupffer Cells/DRUG EFFECTS/*METABOLISM Liver Cirrhosis, Experimental/CHEMICALLY INDUCED/METABOLISM/ PATHOLOGY Liver Diseases, Alcoholic/ETIOLOGY/*METABOLISM/PATHOLOGY Macrophage Activation/DRUG EFFECTS/GENETICS Neutrophils/DRUG EFFECTS/METABOLISM/PATHOLOGY Signal Transduction/DRUG EFFECTS Support, U.S. Gov't, P.H.S. Up-Regulation (Physiology)/DRUG EFFECTS



 




Information in this article was accurate in September 30, 2000. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.