Transforming growth factor-β differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling
Transforming growth factor-β differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling
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DOI：
10.1074/jbc.c400503200
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发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Arditi, M
中科院分区：
文献类型：
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作者：
Naiki, Y;Michelsent, KS;Arditi, M
转化生长因子-β1是一种多功能的、有效的抗炎细胞因子，由多种细胞产生，调节细胞的增殖、凋亡和免疫反应。Toll样受体识别多种病原体相关的分子模式，因此是先天免疫系统的关键组成部分。在这项研究中，我们发现转化生长因子-β1阻断了TLR2、-4和-5配体刺激的核因子-KB的激活和细胞因子的释放。我们进一步证明，转化生长因子-β1可以特异性地干扰TLR2、-4或-5配体诱导的涉及到连接分子MyD88(髓系分化因子88)的反应，但不能通过剂量和时间依赖的方式降低MyD88的蛋白水平而不改变其mRNA的表达来干扰TRAM/TRIF信号通路。蛋白酶体抑制剂环氧米星可阻断转化生长因子-β1诱导的MyD88降解。此外，转化生长因子-β1导致MyD88蛋白的泛素化，提示转化生长因子-β1促进MyD88的泛素化和蛋白酶体的降解，从而通过降低MyD88蛋白的细胞水平而减弱MyD88依赖的信号转导。这些发现有助于我们理解转化生长因子-β1介导免疫反应抗炎调节的分子机制。
Transforming growth factor-beta1 (TGF-beta1) is a multifunctional, potent anti-inflammatory cytokine produced by many cell types that regulates cell proliferation, apoptosis, and immune responses. Toll-like receptors (TLRs) recognize various pathogen-associated molecular patterns and are therefore a pivotal component of the innate immune system. In this study we show that TGF-beta1 blocks the NF-KB activation and cytokine release that is stimulated by ligands for TLRs 2, 4, and 5. We further show that TGF-beta1 can specifically interfere with TLR2, -4, or -5 ligand-induced responses involving the adaptor molecule MyD88 (myeloid differentiation factor 88) but not the TRAM/TRIF signaling pathway by decreasing MyD88 protein levels in a dose- and time-dependent manner without altering its mRNA expression. The proteasome inhibitor epoxomicin abolished the MyD88 degradation induced by TGF-beta1. Furthermore, TGF-beta1 resulted in ubiquitination of MyD88 protein, suggesting that TGF-beta1 facilitates ubiquitination and proteasomal degradation of MyD88 and thereby attenuates MyD88-dependent signaling by decreasing cellular levels of MyD88 protein. These findings importantly contribute to our understanding of molecular mechanisms mediating anti-inflammatory modulation of immune responses by TGF-beta1.