Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor.
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.
McGeehan
G M
GM
Glaxo Inc. Research Institute, Research Triangle Park, North Carolina 27709.
Becherer
J D
JD
Bast
R C
RC
Boyer
C M
CM
Champion
B
B
Connolly
K M
KM
Conway
J G
JG
Furdon
P
P
Karp
S
S
Kidao
S
S
D000818:Animals; D002460:Cell Line; D003374:Coumarins / Q000494:pharmacology; D005260:Female; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D049934:Isocoumarins; D008264:Macrophages / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D003374:Coumarins; D007378:Interleukins; D049934:Isocoumarins; D014409:Tumor Necrosis Factor-alpha; C088672:GI 129471; D010649:Phenylalanine; C046235:3,4-dichloroisocoumarin; D008666:Metalloendopeptidases