PROCESSING OF TUMOR-NECROSIS-FACTOR-ALPHA PRECURSOR BY METALLOPROTEINASES
PROCESSING OF TUMOR-NECROSIS-FACTOR-ALPHA PRECURSOR BY METALLOPROTEINASES
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DOI：
10.1038/370555a0
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发表时间：
1994-08-18
期刊：
影响因子：
64.8
通讯作者：
WOOLLEY, K
中科院分区：
文献类型：
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作者：
GEARING, AJH;BECKETT, P;WOOLLEY, K
肿瘤坏死因子- α (tnf - α)是一种有效的促炎和免疫调节细胞因子，与炎症有关，如类风湿关节炎、克罗恩病、多发性硬化症和与癌症或人类免疫缺陷病毒感染相关的恶病质(1)。tnf - α最初以233个氨基酸的膜锚定前体表达，经过蛋白水解处理后产生成熟的157个氨基酸的细胞因子(2)。切割tnf -的加工酶是未知的。本研究表明，合成羟肟酸金属蛋白酶抑制剂可以特异性地阻止体外培养的白细胞释放成熟的tnf - α，这也可以阻止tnf - α释放到内毒素挑战大鼠的循环中。重组，截断的tnf - α前体被几种基质金属蛋白酶裂解成具有生物活性的成熟tnf - α。这些结果表明，tnf - α前体的加工依赖于至少一种基质金属蛋白酶样酶，抑制这种酶代表了干扰tnf - α产生的一种新的治疗机制。
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.