Cytokine-mediated differential induction of hepatic activator protein-1 genes

Surgery. 1998 Feb;123(2):191-8.


Background: Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) increase the synthesis of hepatic acute-phase proteins; these effects appear mediated by activation of transcription factors. The purpose of this study was to determine the effects of TNF-alpha and IL-6 on expression of the jun family of activator protein-1 (AP-1) transcription factors with the human hepatoma cell line HepG2, a well-characterized model of the hepatic acute-phase response.

Methods: HepG2 cells, treated with either TNF-alpha (100 ng/ml) or IL-6 (10 ng/ml), were extracted for RNA and protein (total and nuclear) and analyzed.

Results: TNF-alpha increased c-jun and junD mRNA and c-Jun and JunD protein levels, as well as AP-1 binding activity. IL-6 increased c-jun mRNA, c-Jun protein, and AP-1 binding activity but did not affect either junD or junB expression.

Conclusions: TNF-alpha and IL-6 induce a differential pattern of AP-1 expression in HepG2 cells; TNF-alpha increases both c-Jun and JunD, whereas IL-6 stimulates only c-Jun. Neither TNF-alpha nor IL-6 stimulates JunB. Multiple cytokines, released during stress, may act in concert to stimulate the AP-1 proteins, which ultimately culminate in the downstream synthesis of a variety of acute-phase proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cytokines / physiology*
  • Gene Expression Regulation / physiology*
  • Humans
  • Interleukin-6 / pharmacology
  • Liver / physiology*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Transcription Factor AP-1 / genetics*
  • Transcription Factor AP-1 / metabolism
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology


  • Cytokines
  • Interleukin-6
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha