PROCESSING OF TUMOR-NECROSIS-FACTOR-ALPHA PRECURSOR BY METALLOPROTEINASES

被引：1111

作者：

GEARING, AJH ^{[1
]}

BECKETT, P ^{[1
]}

CHRISTODOULOU, M ^{[1
]}

CHURCHILL, M ^{[1
]}

CLEMENTS, J ^{[1
]}

DAVIDSON, AH ^{[1
]}

DRUMMOND, AH ^{[1
]}

GALLOWAY, WA ^{[1
]}

GILBERT, R ^{[1
]}

GORDON, JL ^{[1
]}

LEBER, TM ^{[1
]}

MANGAN, M ^{[1
]}

MILLER, K ^{[1
]}

NAYEE, P ^{[1
]}

OWEN, K ^{[1
]}

PATEL, S ^{[1
]}

THOMAS, W ^{[1
]}

WELLS, G ^{[1
]}

WOOD, LM ^{[1
]}

WOOLLEY, K ^{[1
]}

机构：

[1] BRITISH BIOTECHNOL LTD, OXFORD OX4 5LY, ENGLAND

来源：

NATURE | 1994年 / 370卷 / 6490期

关键词：

D O I：

10.1038/370555a0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

TUMOUR necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha are unknown. Here we show that the release of mature TNF-alpha from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-alpha into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-alpha precursor is cleaved to biologically active, mature TNF-alpha by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-alpha precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-alpha production.

引用

页码：555 / 557

页数：3

共 21 条

[1] SYSTEMIC ADMINISTRATION OF TIMP IN THE TREATMENT OF COLLAGEN-INDUCED ARTHRITIS IN MICE [J].