Processing of tumour necrosis factor-alpha precursor by metalloproteinases.
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.
Gearing
A J
AJ
British Biotech, Cowley, Oxford, UK.
Beckett
P
P
Christodoulou
M
M
Churchill
M
M
Clements
J
J
Davidson
A H
AH
Drummond
A H
AH
Galloway
W A
WA
Gilbert
R
R
Gordon
J L
JL
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C088670:BB 2116; C088671:BB 2275; C088669:BB 2284; D006877:Hydroxamic Acids; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases