Premium
Zonated expression of cytokines in rat liver: Effect of chronic ethanol and the cytochrome P450 2E1 inhibitor, chlormethiazole
Author(s) -
Fang Che,
Lindros Kai O.,
Badger Thomas M.,
Ronis Martin J.J.,
IngelmanSundberg Magnus
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510270516
Subject(s) - cyp2e1 , proinflammatory cytokine , alcoholic liver disease , cytokine , western blot , cytochrome p450 , chemistry , liver injury , tumor necrosis factor alpha , oxidative stress , gene expression , endocrinology , medicine , microbiology and biotechnology , biology , biochemistry , inflammation , metabolism , cirrhosis , gene
Abstract The release of proinflammatory cytokines by endotoxins and during oxidative stress is considered to be an early key step in the pathogenesis of alcoholic liver disease (ALD). Ethanol‐inducible cytochrome P450 2E1 (CYP2E1) has potentially pro‐oxidative and toxicological properties, and its expression is restricted to the perivenous region of liver. We investigated zonal differences of cytokine expression in rat liver and how these are affected by alcohol exposure and by chlormethiazole (CMZ), a transcriptional and posttranslational inhibitor of hepatic CYP2E1. Periportal and perivenous cell lysates were obtained by the digitonin pulse technique from livers of rats treated with ethanol and CMZ for 38 days. Cytokine expression on the mRNA and protein levels was quantified using competitive polymerase chain reaction (PCR) and Western blot, respectively. Chronic ethanol treatment significantly increased the expression of CYP2E1, microsomal p ‐nitrophenol hydroxylase activity (indicative for CYP2E1 enzyme activity), and the expression of transforming growth factor β 1 (TGF‐β 1 ), tumor necrosis factor α (TNF‐α), and interleukin (IL)‐1β (1.4‐ to 4.6‐fold). In contrast, ethanol caused a decrease in IL‐4 expression and had no influence on IL‐6 expression. CMZ treatment caused a reduction in hepatic CYP2E1 expression and in the ethanol‐induced cytokine expression by 40% to 60%. Expression of IL‐6, IL‐2, and IL‐4 mRNA occurred preferentially in the periportal region, whereas ethanol caused a pronounced increase in the perivenous expression of TGF‐β 1 , which was inhibited by CMZ as monitored both on the mRNA and protein levels. These results show the zonated expression of several cytokines and the counteraction of CMZ on all effects of ethanol on cytokine expression. The data further strengthen a link between increased CYP2E1 expression and enhanced cytokine expression as important events in the development of ALD.