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ORIGINAL RESEARCH ARTICLE

Cytokine and Chemokine Expression Associated with Steatohepatitis and Hepatocyte Proliferation in Rats Fed Ethanol via Total Enteral Nutrition

Martin J. J. Ronis^*,,1, Angelica Butura, Soheila Korourian^,, Kartik Shankar^*,, Pippa Simpson^||, Jamie Badeaux, Emanuele Albano^¶, Magnus Ingelman-Sundberg and Thomas M. Badger^,#

^* Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; Arkansas Children’s Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202; Department of Pharmacology, Institute of Physiology & Pharmacology, Karolinska Institute, 17177 Stockholm, Sweden; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; ^|| Department of Pediatrics, Little Rock, Arkansas 72202; ^¶ Department of Medical Sciences, University "A Avogadro" of East Piedmont, I-28100 Novara, Italy; and ^# Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

To whom requests for reprints should be addressed at ¹ Arkansas Children’s Nutrition Center, Slot 512–20B, University of Arkansas for Medical Sciences, 1120 Marshall Street, Little Rock, AR 72202. E-mail: RonisMartinJ{at}uams.edu

To determine the temporal relationship between alcohol-induced changes in cytokines and chemokines, development of liver pathology and stimulation of hepatocyte proliferation, male Sprague-Dawley rats were intragastrically fed low carbohydrate-containing ethanol (EtOH) diets via total enteral nutrition (TEN) for up to 49 d. Induction of EtOH metabolism and appearance of steatosis preceded development of oxidative stress, inflammation, and cell death. A transitory peak of tumor necrosis factor (TNF) and interferon gamma (IFN) was observed at 14 d followed by reduced expression of TNF, IFN and another Th1 cytokine IL-12 accompanied by reduced expression of the Th1 regulators T-bet and STAT4. After 35–49 d of EtOH, at a time when hepatocyte proliferation was stimulated, IL-12 returned to control values and a second peak of TNF occurred. The Th2 cytokine IL-4 remained suppressed throughout the study and was accompanied by reductions in the Th2 regulator GATA3. There was no temporal effect of EtOH on expression of IL-6 or TGFβ. IL-5 and IL-13 mRNA were undetectable. Chemokine CXCL-2 expression increased progressively up to 35 d and preceded the appearance of inflammatory infiltrates. These data suggest that steatosis, increased ethanol metabolism, a transient induction of the innate immune response and suppression of Th2 responses were acute consequences of ethanol treatment and were followed by suppression of Th1 responses. However, the majority of necrosis, apoptosis and a late peak of TNF only occurred after 6–7 weeks of ethanol, coincided with the appearance of inflammatory infiltrates and were associated with stimulation of hepatocyte proliferation.

Key Words: alcohol • cytokine • TNF • • IL-4 • proliferation