Human Monocytes - CD14, CD16 - Ziegler-Heitbrock

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Regulation of tumor necrosis factor-a processing by a metalloproteinase inhibitor

Abstract

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.

Authors: McGeehan, G.M., Becherer, J.D., Bast, R.C. jr., Boyer, C.M., Champion, B., Connolly, K.M., Conway, J.G., Furdon, P., Karp, S., Kidao, S., McElroy, A.B., Nichols, J., Pryzwansky, K.M., Schoenen, F., Sekut, L., Truesdale, A., Verghese, M., Warner, J., Ways,
Journal: Nature, 370: 558-561
Year: 1994
PubMed: Find in PubMed