TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis
TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis
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DOI：
10.1074/jbc.m603384200
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发表时间：
2006-07-14
影响因子：
4.8
通讯作者：
Ninomiya-Tsuji, Jun
中科院分区：
文献类型：
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作者：
Omori, Emily;Matsumoto, Kunihiro;Ninomiya-Tsuji, Jun
转化生长因子β激活激酶1（TAK 1）在炎性细胞因子的下游发挥作用，以激活几种细胞类型中的c-Jun N-末端激酶（JNK）以及NF-κ B。然而，TAK 1在体内环境中的功能作用尚未确定。在这里，我们已经证明了TAK 1是皮肤炎症以及角质形成细胞死亡的主要调节因子。TAK 1的表皮特异性缺失导致出生后第6-8天的严重炎症性皮肤病。突变皮肤也表现出大量角质细胞死亡。从突变皮肤分离的角质形成细胞的分析表明，TAK 1缺陷导致细胞凋亡响应肿瘤坏死因子（TNF）的显着增加。TAK 1缺陷型角质形成细胞在TNF处理后不能激活NF-κ B或JNK。这些结果表明，TNF诱导TAK 1缺陷型角质形成细胞死亡，因为缺乏NF-κ B（可能还有JNK）介导的细胞存活信号。最后，我们已经表明，在表皮特异性TAK 1缺陷小鼠中，TNF受体的缺失可以在很大程度上挽救角质形成细胞死亡以及炎症性皮肤病。我们的研究结果表明，TAK 1是皮肤中TNF信号传导的主要调节因子，并调节皮肤炎症和角质形成细胞死亡。
Transforming growth factor beta-activated kinase 1 (TAK1) functions downstream of inflammatory cytokines to activate c-Jun N-terminal kinase (JNK) as well as NF-kappa B in several cell types. However, the functional role of TAK1 in an in vivo setting has not been determined. Here we have demonstrated that TAK1 is the major regulator of skin inflammation as well as keratinocyte death in vivo. Epidermal-specific deletion of TAK1 causes a severe inflammatory skin condition by postnatal day 6-8. The mutant skin also exhibits massive keratinocyte death. Analysis of keratinocytes isolated from the mutant skin revealed that TAK1 deficiency results in a striking increase in apoptosis in response to tumor necrosis factor (TNF). TAK1-deficient keratinocytes cannot activate NF-kappa B or JNK upon TNF treatment. These results suggest that TNF induces TAK1-deficient keratinocyte death because of the lack of NF-kappa B (and possibly JNK)-mediated cell survival signaling. Finally, we have shown that deletion of the TNF receptor can largely rescue keratinocyte death as well as inflammatory skin condition in epidermal-specific TAK1-deficient mice. Our results demonstrate that TAK1 is a master regulator of TNF signaling in skin and regulates skin inflammation and keratinocyte death.