TAK1 regulation of reactive oxygen species and inflammation

TAK 1激酶是天然免疫细胞内信号传导不可缺少的中间体， 应答TAK 1被多种不同的因子激活，包括Toll样受体 配体，细胞内微生物传感器（NOD样受体）配体，IL-1和TNF。 TAK 1通过激活NF-B和丝裂原上调促炎反应 激活蛋白激酶途径。因此，TAK 1通常被认为是阳性的。 炎症调节因子。然而，我们最近发现， 皮肤和肠上皮中的TAK 1导致严重的炎症。这些 TAK 1突变小鼠的炎症状况类似于慢性炎症性疾病 比如皮肤上的牛皮癣和肠道的克罗恩病。我们发现TAK 1 缺失导致活性氧簇（ROS）的积累，并且抑制ROS 可以完全挽救培养的上皮细胞中的细胞死亡。重要的是，我们发现， 在上皮特异性TAK 1缺失小鼠中给予抗氧化剂治疗可以防止 上皮细胞死亡并减少炎症。因此，我们假设消融术 TAK 1信号在上皮细胞中引起ROS的失调， 上皮细胞死亡和炎症。本提案的目标是：1）确定 ROS调节上皮细胞死亡和炎症的机制; 2）鉴定 TAK 1缺陷上皮细胞中ROS积累的原因。本项目的成果 将描绘ROS调节和慢性炎症之间的关系， 可能导致新的方法来调节炎症。

TAK1 kinase is an indispensable intermediate in the intracellular signaling of innate immune responses. TAK1 is activated by many of distinct factors including Toll-like receptor ligands, intracellular microorganism sensor (NOD like receptor) ligands, IL-1 and TNF. TAK1 upregulates proinflammatory responses through activation of NF-B and mitogen activated protein kinase pathways. Thus, TAK1 is generally considered to be a positive regulator of inflammation. However, we have recently found that the targeted deletion of TAK1 in the epithelium of skin and intestine results in severe inflammation. These inflammatory conditions in the TAK1 mutant mice resemble chronic inflammatory diseases such as psoriasis in the skin and Crohn's disease in the intestine. We have found that TAK1 deletion causes accumulation of reactive oxygen species (ROS), and that inhibition of ROS can completely rescue cell death in cultured epithelial cells. Importantly, we found that treatment of the antioxidants in the epithelial-specific TAK1 deletion mice could prevent the epithelial cell death and diminishes inflammation. Therefore, we hypothesize that ablation of TAK1 signaling in epithelial cells causes dysregulation of ROS that is involved in epithelial cell death and inflammation. The objectives of this proposal are; 1) to determine the mechanism by which ROS regulates epithelial cell death and inflammation; 2) to identify the cause of ROS accumulation in TAK1-deficient epithelium. Outcomes from this project will delineate the relationship between ROS regulation and chronic inflammation, which could result in new approaches to regulate inflammation.