Processing of tumour necrosis factor-α precursor by metalloproteinases

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Abstract
TUMOUR necrosis factor-α (TNF-α) 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 infection1. TNF-α is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine2. The processing enzyme(s) which cleave TNF-α are unknown. Here we show that the release of mature TNF-α from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-α into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-α precursor is cleaved to biologically active, mature TNF-α by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-α precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-α production.