Processing of tumour necrosis factor-alpha precursor by metalloproteinases

Nature. 1994 Aug 18;370(6490):555-7. doi: 10.1038/370555a0.


Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and immunomodulatory cytokine implicated in inflammatory conditions such as rheumatoid arthritis, Crohn's disease, multiple sclerosis and the cachexia associated with cancer or human immunodeficiency virus infection. TNF-alpha is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine. The processing enzyme(s) which cleave TNF-alpha are unknown. Here we show that the release of mature TNF-alpha from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-alpha into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-alpha precursor is cleaved to biologically active, mature TNF-alpha by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-alpha precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-alpha production.

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Hydroxamic Acids / pharmacology
  • Leukocytes / metabolism
  • Male
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / metabolism*
  • Protein Processing, Post-Translational / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*


  • BB 2116
  • BB 2275
  • BB 2284
  • Hydroxamic Acids
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • Metalloendopeptidases