Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-kappaB and STAT3 signaling pathways.
Alcohol consumption is a major risk factor accelerating the progression of liver disease in patients with chronic hepatitis virus infection. However, the mechanism underlying the enhanced susceptibility of alcoholics to liver injury is not fully understood. Here, we demonstrate that chronic ethanol consumption increases the susceptibility of C57BL/6 mice to concanavalin A (Con A)-induced T cell-mediated hepatitis. Injection of a low dose of Con A (5 microg/g) causes severe liver damage in ethanol-fed mice as evidenced by a significant elevation of serum alanine aminotransaminase levels, massive necrosis, and infiltration of leukocytes but only slightly induces liver injury in control pair-fed mice. In ethanol-fed mice, the activation and cytotoxicity of natural killer T cells, cells that play key roles in Con A-induced T cell hepatitis, are not significantly enhanced relative to pair-fed mice. Moreover, Con A-induced activation of hepatic NF-kappaB is increased, whereas activation of STAT1 and STAT3 is attenuated in ethanol-fed mice. Consistent with this result, the expression of chemokines and adhesion molecules [such as ICAM-1, macrophage inflammatory protein (MIP)-1, MIP-2, and MCP-1] controlled by NF-kappaB is upregulated, whereas STAT1-controlled expression of chemokines (such as MIG and IP-10) is downregulated in ethanol-fed mice compared with pair-fed mice. In conclusion, chronic alcohol consumption accelerates T cell-mediated hepatitis via upregulation of the NF-kappaB signaling pathway and subsequently enhances expression of chemokines/adhesive molecules and recruitment of leukocytes into the liver. Downregulation of the antiapoptotic STAT3 signal may also contribute to alcohol potentiation of T cell hepatitis.
Jaruga
Barbara
B
Section on Liver Biology, NIAAA/NIH, Park Bldg. Rm. 120, 12420 Parklawn Dr., MSC 8115, Bethesda, MD 20892, USA.
Hong
Feng
F
Kim
Won-Ho
WH
Sun
Rui
R
Fan
Saijun
S
Gao
Bin
B
D000428:Alcohol Drinking; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D018925:Chemokines / Q000378:metabolism; D003208:Concanavalin A / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes; D007694:Killer Cells, Natural / Q000187:drug effects; D007962:Leukocytes / Q000473:pathology; D008099:Liver / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes; D016328:NF-kappa B / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D018925:Chemokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D003208:Concanavalin A; D000431:Ethanol