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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #217335
Title: Cytokine and Chemokine Expression Associated with Steatohepatitis and Hepatocyte Proliferation in Rats Fed Ethanol Via Total Enteral Nutrition

Author
item RONIS, MARTIN - ACNC/UAMS
item BUTURA, ANGELICA - KAROLINSKA INST, SWEDEN
item KOROURIAN, SOHEILA - UAMS
item SHANKAR, KARTIK - ACNC/UAMS
item JO, CHAN-HE - UAMS
item SIMPSON, PIPPA - UAMS
item ALBANO, EMANUELE - U OF E PIEDMOTE, ITALY
item INGELMAN-SUNDBERG, MAGNUS - KAROLINSKA INST, SWEDEN
item BADGER, THOMAS - ACNC/UAMS

Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/29/2008
Publication Date: 3/10/2008
Citation: Ronis, M.J., Butura, A., Korourian, S., Shankar, K., Jo, C., Simpson, P., Albano, E., Ingelman-Sundberg, M., Badger, T.M. 2008. Cytokine and chemokine expression associated with steatohepatitis and hepatocyte proliferation in rats fed ethanol via total enteral nutrition [abstract]. The Toxicologist. 102(S1):173. Program No. 844.

Interpretive Summary: Chronic and excessive alcohol consumption cause liver damage and can lead to hepatitis. This can lead to increased sensitivity to infections by reducing the activity of various parts of the immune system. This process is highly dependent upon nutritional status and dietary content. We have been interested in the nutrition/alcohol interactions. In the current report, we studied liver factors (cytokine and chemokine peptides) that control inflammatory processes during chronic alcohol intake in rats fed by total enteral nutrition and correlated with appearance of liver injury. We found that appearance of excess fat preceded development of liver damage, and there was a specific profile of the cytokines and chemokines that appears to be important for this damage to occur. One chemokine, CXCL-2, increased progressively up to 35 days and before the appearance of inflammation. These data suggest that liver fat accumulation, increased ethanol breakdown, and a specific profile of cytokines and chemokines must develop in order to cause alcohol-induces liver damage.

Technical Abstract: Sprague-Dawley rats were intragastrically fed low carbohydrate-containing ethanol (EtOH) diets via total enteral nutrition 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 alpha) and interferon gamma (IFN gamma) was observed at 14 d, followed by reduced expression of TNF alpha, IFN gamma, and 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, a second peak of TNF alpha 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 TGF beta. 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, necrosis, apoptosis, and a late peak of TNF alpha only occurred after 6-7 weeks of ethanol, coincided with the appearance of inflammatory infiltrates, and were associated with stimulation of hepatocyte proliferation.