TAK1 targeting by glucocorticoids determines JNK and IκB regulation in Toll-like receptor-stimulated macrophages
TAK1 targeting by glucocorticoids determines JNK and IκB regulation in Toll-like receptor-stimulated macrophages
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DOI：
10.1182/blood-2009-06-224782
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发表时间：
2010-03-11
期刊：
影响因子：
20.3
通讯作者：
Muglia, Louis J.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Sandip;Ratajczak, Christine K.;Muglia, Louis J.
糖皮质激素有效地减弱巨噬细胞产生炎症介质，巨噬细胞是先天免疫的主要效应物。不同的巨噬细胞Toll样受体（TLR）的激活各自的配体提出了一个强大的系统，通过它来评估刺激依赖性糖皮质激素在相同的细胞类型的影响。在这里，我们测试的假设，糖皮质激素，通过糖皮质激素受体，调节巨噬细胞活化优先依赖于TLR-选择性配体和TLR适配器。我们确定，2种衔接子（Trif、MyD 88或两者）决定了糖皮质激素抑制kappa B（I kappa B）降解或Janus激酶（JNK）激活抑制剂的能力。此外，转化生长因子β激活激酶1（TAK 1）激活对糖皮质激素的敏感性决定了这些作用。这些发现将TAK 1确定为糖皮质激素的新靶点，糖皮质激素将其抗炎作用整合到先天免疫信号通路中。（血。2010; 115：1921-1931）
Glucocorticoids potently attenuate the production of inflammatory mediators by macrophages, a primary effector of innate immunity. Activation of different macrophage Toll-like receptors (TLRs) by their respective ligands presents a powerful system by which to evaluate stimulus-dependent glucocorticoid effects in the same cell type. Here, we test the hypothesis that glucocorticoids, acting through the glucocorticoid receptor, modulate macrophage activation preferentially depending upon the TLR-selective ligand and TLR adapters. We established that 2 adapters, Trif, MyD88, or both, determine the ability of glucocorticoids to suppress inhibitor of kappa B (I kappa B) degradation or Janus kinase (JNK) activation. Moreover, the sensitivity of transforming growth factor beta-activated kinase 1 (TAK1) activation to glucocorticoids determines these effects. These findings identify TAK1 as a novel target for glucocorticoids that integrates their anti-inflammatory action in innate immunity signaling pathways. (Blood. 2010; 115: 1921-1931)