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Keywords:

  • Alcohol;
  • cirrhosis;
  • hepatitis C;
  • IL-6;
  • normal liver;
  • TNFα;
  • transcription factor

Eur J Clin Invest 2010; 40 (7): 575–584

Abstract

Background/aims  Conflicting observations exist concerning the role of nuclear factor kappa B (NFκB) in alcoholic liver disease (ALD) in animal models. To date no studies have examined this aspect in human liver tissue. We here assessed cytokines and toll-like receptors (TLRs) expressions in conjunction with NFκB activation in non-active end-stage human ALD compared with normal livers and hepatitis C virus (HCV) related end-stage disease.

Methods  mRNA and protein expression were examined by quantitative PCR and Western blotting, DNA-binding by electrophoretic mobility shift assays and NFκB sub-cellular localization by immunofluorescent staining of livers.

Results  NFκB mRNA and protein expression as well as strong DNA-binding were preserved in ALD but significantly down-regulated in HCV compared with normal livers. P50 immunofluorescence was found in hepatocytes and bile ducts in ALD and normal livers, whereas a shift was observed in p65 staining from non-parenchymal cells in normal livers to hepatocytes in ALD. NFκB responsive genes mRNA levels IkBα and interleukin 6 were significantly higher in ALD compared with HCV. Tumour necrosis factor alpha (TNFα), TLRs 3 and 7 mRNA were up-regulated in ALD and HCV compared with normal liver with TNFα and TLR7 being the highest in HCV. Strong induction of interferon beta was found in HCV but not in ALD or normal liver tissue.

Conclusions  Persistent NFκB activation together with high pro-inflammatory cytokine expression and upregulation of TLR3 and TLR7 is associated with end-stage ALD in humans and could contribute to disease progression even in absence of alcohol intake.