Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor

Nature. 1994 Aug 18;370(6490):558-61. doi: 10.1038/370558a0.


Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory agent produced primarily by activated monocytes and macrophages. TNF-alpha is synthesized as a precursor protein of M(r) 26,000 (26K) which is processed to a secreted 17K mature form by cleavage of an Ala-Val bond between residues 76-77. The enzyme(s) responsible for processing pro-TNF-alpha has yet to be identified. Here, we describe the capacity of a metalloproteinase inhibitor, GI 129471, to block TNF-alpha secretion both in vitro and in vivo. The inhibition is specific to TNF-alpha; the production of other secreted cytokines, such as the interleukins IL-1 beta, IL-2, or IL-6, is not inhibited. The mechanism of inhibition occurs at a post-translational step in TNF-alpha production. Our data suggest that TNF-alpha processing is mediated by a unique Zn2+ endopeptidase which is inhibited by GI 129471 and would represent a novel target for therapeutic intervention in TNF-alpha associated pathologies.

MeSH terms

  • Animals
  • Cell Line
  • Coumarins / pharmacology
  • Female
  • Humans
  • Interleukins / metabolism
  • Isocoumarins
  • Macrophages / metabolism
  • Metalloendopeptidases / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C3H
  • Monocytes / metabolism
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Protein Processing, Post-Translational / drug effects*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism*


  • Coumarins
  • Interleukins
  • Isocoumarins
  • Tumor Necrosis Factor-alpha
  • GI 129471
  • Phenylalanine
  • 3,4-dichloroisocoumarin
  • Metalloendopeptidases