Li Kun, Wang Meichen, Hu Yaping, Xu Na, Yu Qin, Wang Qinfu
Institute of Immunology, College of Life Science & Technology, Dalian University, Dalian, Liaoning, China; College of Medicine, Dalian University, Dalian, Liaoning, China.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, United States.
Cell Immunol. 2016 Dec;310:193-198. doi: 10.1016/j.cellimm.2016.09.011. Epub 2016 Sep 21.
TGF-β activating protein kinase 1 (TAK1) belongs to the MAP kinase kinase kinase (MAP3K) family. TAK1 is involved in many signaling pathways, especially the innate and adaptive immune responses. TAK1 mediates nuclear factor κB (NF-κB) and MAPK signaling pathway in response to interleukin-1, tumor necrosis factor-α (TNFα), and toll-like receptor agonists, such as lipopolysaccharide (LPS). The regulatory roles of TAK1 in LPS-induced proinflammatory cytokines production are dependent on the cell types. In this study, we examined the effects of TAK1 on the LPS induced production of proinflammatory cytokines in myeloid cells. Knockdown of TAK1 enhanced the secretion of interleukin 1-beta (IL-1β) and TNFα induced by LPS. In addition, LPS-activated TAK1 negatively regulates mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). Moreover, TAK1 inhibited MEKK3 activation, which, in turn, activated NF-κB. These results indicate that TAK1 negatively regulates LPS-induced cytokine secretion in myeloid cells by inhibiting MEKK3 activities.
转化生长因子-β激活蛋白激酶1（TAK1）属于丝裂原活化蛋白激酶激酶激酶（MAP3K）家族。TAK1参与多种信号通路，尤其是先天性和适应性免疫反应。TAK1介导核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路，以响应白细胞介素-1、肿瘤坏死因子-α（TNFα）和Toll样受体激动剂，如脂多糖（LPS）。TAK1在LPS诱导的促炎细胞因子产生中的调节作用取决于细胞类型。在本研究中，我们检测了TAK1对LPS诱导的髓系细胞中促炎细胞因子产生的影响。敲低TAK1可增强LPS诱导的白细胞介素1-β（IL-1β）和TNFα的分泌。此外，LPS激活的TAK1对丝裂原活化蛋白激酶/细胞外信号调节激酶激酶激酶3（MEKK3）具有负调节作用。而且，TAK1抑制MEKK3的激活，进而激活NF-κB。这些结果表明，TAK1通过抑制MEKK3的活性对LPS诱导的髓系细胞细胞因子分泌起负调节作用。
