Cutting edge:: TNF-α-cinverting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock
Cutting edge:: TNF-α-cinverting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock
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DOI：
10.4049/jimmunol.179.5.2686
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Blobel, Carl P.
中科院分区：
文献类型：
--
作者：
Horiuchi, Keisuke;Kimura, Tokuhiro;Blobel, Carl P.
TNF-α是一种有效的促炎细胞因子，作为膜锚定的前体合成并从细胞中蛋白水解释放。可溶性TNF是诸如类风湿性关节炎、克罗恩病和内毒素休克等病理的主要介质。TNF-α转化酶（TACE），一种解整合素和金属蛋白酶17（ADAM 17），已成为最佳候选TNF脱落酶，但其它蛋白酶也可释放TNF。由于TACE缺陷小鼠在出生后不久死亡，我们产生了条件性TACE缺陷小鼠，以解决TACE是否是成年小鼠中TNF的相关脱落酶。在这项研究中，我们报告说，TACE灭活骨髓细胞或暂时灭活在6周内提供了强大的保护，从内毒素休克致死小鼠通过防止增加TNF血清水平。这些发现证实了TACE是体内小鼠骨髓细胞中主要的内毒素刺激的TNF脱落酶，从而进一步验证了TACE作为治疗TNF依赖性病变的主要靶点。
TNF-alpha, a potent proinflammatory cytokine, is synthesized as a membrane-anchored precursor and proteolytically released from cells. Soluble TNF is the primary mediator of pathologies such as rheumatoid arthritis, Crohn's disease, and endotoxin shock. The TNF-a converting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17), has emerged as the best candidate TNF sheddase, but other proteinases can also release TNF. Because TACE-deficient mice die shortly, afterbirth, we generated conditional TACE-deficient mice to address whether TACE is the relevant sheddase for TNF in adult mice. In this study, we report that TACE inactivation in myeloid cells or temporal inactivation at 6wk offers strong protection from endotoxin shock lethality in mice by preventing increased TNF serum levels. These findings corroborate that TACE is the major endotoxin-stimulated TNF sheddase in mouse myeloid cells in vivo, thereby further validating TACE as a principal target for the treatment of TNF-dependent pathologies.