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J. Biol. Chem., Vol. 278, Issue 10, 8435-8441, March 7, 2003
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From the Laboratory of Hepatobiology and Toxicology,
Curriculum of Toxicology, Department of Pharmacology, University of
North Carolina, Chapel Hill, North Carolina 27599
Ethanol is known to cause both tolerance and
sensitization to endotoxin (lipopolysaccharide). It is also
known that ethanol modulates the expression and activity of several
intracellular signaling molecules and transcription factors in
monocytes and Kupffer cells, the resident hepatic macrophages.
Expression of CD14, the endotoxin receptor, is up-regulated following
chronic exposure to endotoxin and ethanol. Ethanol-induced oxidative
stress is important in the regulation of transcription factor
activation and cytokine production by Kupffer cells. Thus, it was
hypothesized that acute ethanol increases CD14 expression through a
mechanism dependent upon oxidant production. This hypothesis was tested by overexpression of superoxide dismutase via recombinant adenovirus. Mice were infected with adenovirus (3 × 109
plaque-forming units, intravenously) containing either Cu,Zn superoxide
dismutase (Ad.SOD1) or
Up-regulation of CD14 in Liver Caused by Acute
Ethanol Involves Oxidant-dependent AP-1 Pathway*
and
-galactosidase (Ad.lacZ), which caused significant expression of Cu,Zn-SOD in hepatocytes and Kupffer
cells. Three days post-infection, mice were given saline or ethanol (5 g/kg, intragastrically). A significant increase in CD14 mRNA was
observed 3 h after ethanol, and this increase was almost
completely blocked in mice overexpressing Cu,Zn-SOD. Additionally,
overexpression of SOD also blunted ethanol-induced activation of
redox-sensitive transcription factors NF
B and AP-1 and production of
cytokines. However, only inhibition of AP-1 with dominant-negative TAK1
but not NFB by dominant-negative IB
significantly blunted
ethanol-induced increases in CD14, suggesting that AP-1 is important
for CD14 transcriptional regulation. It is also shown here that NADPH
oxidase is important in the increase in CD14 due to ethanol.
Moreover, these data suggest that acute ethanol causes sensitization to
endotoxin through mechanisms dependent upon oxidative stress.
*
This work was supported in part by grants from the National
Institute on Alcohol Abuse and Alcoholism.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.
Published in memory of R. G. Thurman (1941-2001).
To whom correspondence should be addressed: CB 7365, Mary Ellen
Jones Bldg., University of North Carolina, Chapel Hill, NC 27599. Tel.:
919-966-1154; Fax: 919-966-1893; E-mail: wheelmi@med.unc.edu.
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