Omori Emily, Matsumoto Kunihiro, Sanjo Hideki, Sato Shintaro, Akira Shizuo, Smart Robert C, Ninomiya-Tsuji Jun
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633, USA.
J Biol Chem. 2006 Jul 14;281(28):19610-7. doi: 10.1074/jbc.M603384200. Epub 2006 May 4.
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-kappaB 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-kappaB or JNK upon TNF treatment. These results suggest that TNF induces TAK1-deficient keratinocyte death because of the lack of NF-kappaB (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.
转化生长因子β激活激酶1（TAK1）在多种细胞类型中，于炎性细胞因子下游发挥作用，激活c-Jun氨基末端激酶（JNK）以及核因子κB（NF-κB）。然而，TAK1在体内环境中的功能作用尚未确定。在此，我们证明了TAK1是体内皮肤炎症以及角质形成细胞死亡的主要调节因子。TAK1的表皮特异性缺失在出生后第6至8天会导致严重的炎性皮肤病症。突变皮肤还表现出大量角质形成细胞死亡。对从突变皮肤分离的角质形成细胞的分析显示，TAK1缺陷导致对肿瘤坏死因子（TNF）应答时细胞凋亡显著增加。TNF处理后，TAK1缺陷的角质形成细胞无法激活NF-κB或JNK。这些结果表明，由于缺乏NF-κB（可能还有JNK）介导的细胞存活信号，TNF诱导TAK1缺陷的角质形成细胞死亡。最后，我们表明，在表皮特异性TAK1缺陷小鼠中，TNF受体的缺失可在很大程度上挽救角质形成细胞死亡以及炎性皮肤病症。我们的结果证明，TAK1是皮肤中TNF信号的主要调节因子，并调节皮肤炎症和角质形成细胞死亡。
