Processing of tumour necrosis factor-α precursor by metalloproteinases (original) (raw)

Nature volume 370, pages 555–557 (1994)Cite this article

Abstract

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 infection1. TNF-α is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine2. 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.

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Authors and Affiliations

  1. British Biotech, Watlington Road, Cowley, Oxford, 0X4 SLY, UK
    A. J. H. Gearing, P. Beckett, M. Christodoulou, M. Churchill, J. Clements, A. H. Davidson, A. H. Drummond, W. A. Galloway, R. Gilbert, J. L. Gordon, T. M. Leber, M. Mangan, K. Miller, P. Nayee, K. Owen, S. Patel, W. Thomas, G. Wells, L. M. Wood & K. Woolley

Authors

  1. A. J. H. Gearing
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  2. P. Beckett
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  3. M. Christodoulou
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  4. M. Churchill
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  5. J. Clements
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  6. A. H. Davidson
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  7. A. H. Drummond
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  8. W. A. Galloway
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  9. R. Gilbert
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  10. J. L. Gordon
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  11. T. M. Leber
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  12. M. Mangan
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  13. K. Miller
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  14. P. Nayee
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  15. K. Owen
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  16. S. Patel
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  17. W. Thomas
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  18. G. Wells
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  19. L. M. Wood
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  20. K. Woolley
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Gearing, A., Beckett, P., Christodoulou, M. et al. Processing of tumour necrosis factor-α precursor by metalloproteinases.Nature 370, 555–557 (1994). https://doi.org/10.1038/370555a0

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