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J. Biol. Chem., Vol. 276, Issue 45, 41930-41937, November 9, 2001
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From the Department of Nutrition, Case Western Reserve University,
Cleveland, Ohio 44106-4906
Increased expression of tumor necrosis factor
Stabilization of Tumor Necrosis Factor
mRNA by Chronic
Ethanol
ROLE OF A + U-RICH ELEMENTS AND p38 MITOGEN-ACTIVATED PROTEIN
KINASE SIGNALING PATHWAY*
(TNF) in response to chronic ethanol has been implicated in the
pathogenesis of alcoholic liver disease. However, the molecular
mechanisms by which ethanol increases the levels of TNF are not well
characterized. Utilizing Kupffer cells isolated from rats fed an
ethanol containing diet and a murine macrophage cell line, RAW264.7,
exposed to ethanol in culture, we have demonstrated that exposure to
chronic ethanol results in an enhanced expression of lipopolysaccharide
(LPS)-induced TNF. While chronic ethanol had no effect on the rate
of LPS-induced TNF transcription as measured by nuclear run-on
experiments, TNF mRNA half-life was increased by chronic
ethanol. Chronic ethanol also potentiated the activation of LPS-induced
p38 mitogen-activated protein (MAP) kinase in Kupffer cells, as well as
in RAW264.7 cells. Specific inhibition of p38 MAP kinase activation by
SB203580 in Kupffer cells or by overexpression of dominant negative p38 MAP kinase in RAW264.7 cells blocked ethanol-mediated TNF mRNA stabilization. Furthermore, using chimeric reporter constructs, we have
shown that A + U-rich elements in the 3'-untranslated region of TNF
mRNA are not sufficient to impart ethanol-mediated stabilization on
TNF mRNA.
*
This work was supported by National Institutes of Health
Grant AA 11975 (to L. E. N.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Nutrition,
2123 Abington Rd., Rm. 201, Case Western Reserve University, Cleveland,
OH 44106-4906. Tel.: 216-368-6230; Fax: 216-368-6644; E-mail:
len2@po.cwru.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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