Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha

Nature. 1989 Feb 16;337(6208):661-3. doi: 10.1038/337661a0.


Tumour necrosis factor-alpha (TNF-alpha) is secreted by macrophages in response to inflammation, infection and cancer. Sublethal doses of recombinant TNF-alpha to rats causes cachexia, anaemia and inflammation. TNF-alpha plays a major part in tissue inflammation and remodelling by stimulating production of collagenase. Cellular responses to TNF-alpha are initiated by binding to high-affinity cell surface receptors. TNF-alpha then profoundly affects gene regulation, stimulating the fos, myc, interleukin-1 and interleukin-6 genes and inhibiting the type I collagen gene. Here we demonstrate that TNF-alpha also stimulates collagenase gene transcription; this stimulation is mediated by an element of the gene that is responsive to the transcription factor AP-1, the major component of which (jun/AP-1) is encoded by the jun gene; and that TNF-alpha stimulates prolonged activation of jun gene expression. This prolonged induction of jun contrasts with its transient activation by the phorbol ester TPA and provides a physiological example of the ability of jun/AP-1 to stimulate its own transcription. This may be a key mechanism for mediating at least some of the biological effects of TNF-alpha.

Publication types

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

MeSH terms

  • Blotting, Northern
  • Cells, Cultured
  • Chloramphenicol O-Acetyltransferase / genetics
  • DNA-Binding Proteins / genetics*
  • Fibroblasts / enzymology
  • Gene Expression Regulation*
  • Genes / drug effects*
  • Humans
  • Microbial Collagenase / genetics*
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogenes*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • Transcription Factors / genetics*
  • Transcription, Genetic / drug effects*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Chloramphenicol O-Acetyltransferase
  • Protein Kinase C
  • Microbial Collagenase