REGULATION OF TUMOR-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(1). TN F-alpha is synthesized as a precursor protein of M(r) 26,000 (26K) whi ch is processed to a secreted 17K mature form by cleavage of an Ala-Va l bond between residues 76-77. The enzyme(s) responsible for processin g pro-TNF-alpha has yet to be identified. Here, we describe the capaci ty of a metalloproteinase inhibitor, GI 129471, to block TNF-alpha sec retion both in vitro and in vivo. The inhibition is specific to TNF-al pha; the production of other secreted cytokines, such as the interleuk ins IL-1 beta, IL-2, or IL-6, is not inhibited. The mechanism of inhib ition occurs at a post-translational step in TNF-alpha production. Our data suggest that TNF-alpha processing is mediated by a unique Zn2+ e ndopeptidase which is inhibited by GI 129471 and would represent a nov el target for therapeutic intervention in TNF-alpha associated patholo gies.