TAK1 regulation of reactive oxygen species and inflammation

TAK1激酶是天然免疫细胞内信号转导中不可缺少的中间产物 回应。TAK1被许多不同的因素激活，包括Toll样受体 配体、细胞内微生物感受器(NOD样受体)配体、IL-1和肿瘤坏死因子。 TAK1通过激活核因子-B和丝裂原上调促炎反应 活化的蛋白激酶通路。因此，TAK1通常被认为是积极的 炎症调节剂。然而，我们最近发现，定向删除 在皮肤和肠道上皮细胞中的TAK1会导致严重的炎症。这些 TAK1突变小鼠的炎症状态类似于慢性炎症性疾病 例如皮肤的牛皮癣和肠道的克罗恩病。我们发现TAK1 缺失会导致活性氧物种(ROS)的积累，而ROS的抑制 可以完全挽救培养上皮细胞的死亡。重要的是，我们发现 上皮特异性TAK1缺失小鼠的抗氧化剂治疗可防止 上皮细胞死亡，消炎消炎。因此，我们假设消融 上皮细胞中TAK1信号的缺失导致ROS的失调，参与了 上皮细胞死亡和炎症。这项提案的目标是：1)确定 ROS调节上皮细胞死亡和炎症的机制；2)识别 TAK1缺陷上皮细胞内ROS积聚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，其中 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.