Processing of tumour necrosis factor-α precursor by metalloproteinases

• Published in: Nature (London) 1994-08, Vol.370 (6490), p.555-557
• Main Authors: Gearing, A. J. H, Beckett, P, Christodoulou, M, Churchill, M, Clements, J, Davidson, A. H, Drummond, A. H, Galloway, W. A, Gilbert, R, Gordon, J. L, Leber, T. M, Mangan, M, Miller, K, Nayee, P, Owen, K, Patel, S, Thomas, W, Wells, G, Wood, L. M, Woolley, K
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Amino acids; Analysis of the immune response. Humoral and cellular immunity; Animals; Autoimmune diseases; Biological and medical sciences; Cells, Cultured; Endotoxins; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humanities and Social Sciences; Humans; Hydroxamic Acids - pharmacology; Immunobiology; letter; Leukocytes - metabolism; Male; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - metabolism; Miscellaneous; multidisciplinary; Protein Processing, Post-Translational - physiology; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins - metabolism; Regulatory factors and their cellular receptors; Rheumatoid arthritis; Science; Science (multidisciplinary); Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - secretion; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/370555a0

TUMOUR necrosis factor-α (TNF-α) 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 1 . TNF-α is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine 2 . The processing enzyme(s) which cleave TNF-α are unknown. Here we show that the release of mature TNF-α from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-α into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-α precursor is cleaved to biologically active, mature TNF-α by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-α precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-α production.