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

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Abstract
TUMOUR necrosis factor-αa (TNF-α) is a potent pro-inflammatory agent produced primarily by activated monocytes and macrophages1. TNF-α is synthesized as a precursor protein of Mr 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-α has yet to be identified. Here, we describe the capacity of a metalloproteinase inhibitor, GI129471, to block TNF-α secretion both in vitro and in vivo. The inhibition is specific to TNF-α; the production of other secreted cytokines, such as the interleukins IL-1β, IL-2, or IL-6, is not inhibited. The mechanism of inhibition occurs at a post-translational step in TNF-α production. Our data suggest that TNF-α 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-α associated pathologies.