A20 suppresses canonical Smad-dependent fibroblast activation: novel function for an endogenous inflammatory modulator.
A20 suppresses canonical Smad-dependent fibroblast activation: novel function for an endogenous inflammatory modulator.
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DOI：
10.1186/s13075-016-1118-7
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发表时间：
2016-10-03
影响因子：
4.9
通讯作者：
Varga J
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Wang W;Graham LV;Varga J
泛素编辑胞质酶A20是toll样受体（TLR）介导的细胞炎症反应的主要负调节因子，与系统性硬化症（SSc）有着紧密的遗传联系。由于最近的研究表明内源性配体驱动的TLR信号通路参与SSc的发病机制，我们试图研究A20在皮肤成纤维细胞中的调节、作用和作用机制。在外植的人皮肤成纤维细胞中评估A20的表达以及强迫A20表达或sirna介导的A20敲低对转化生长因子-ß （TGF-ß）诱导的纤维化反应的影响。此外，我们还评估了TGF-ß和脂联素（一种具有抗纤维化活性的多效脂肪因子）对A20的调节作用。在正常成纤维细胞中，TGF-ß诱导A20持续下调，并取消其tlr4依赖性诱导。A20的强制表达终止了TGF-ß诱导的胶原基因表达和肌成纤维细胞转化的刺激，并破坏了典型的Smad信号传导和Smad依赖的转录反应。相反，sirna介导的A20的下调增强了TGF-ß引发的纤维化反应的幅度。脂联素，先前被证明可以阻断tlr依赖性的纤维化反应，引发成纤维细胞中A20积累的快速和持续增加。这些结果确定了泛素编辑酶A20是一种新的内源性纤维化反应强度负调控机制。导致A20表达或功能受损的系统性硬化症相关的A20遗传变异，结合纤维化环境中TGF-ß对A20的直接抑制，可能在纤维化反应的持续中发挥重要的功能作用，而药物增强A20抑制途径的活性可能是一种新的治疗策略。本文的在线版本（doi:10.1186/s13075-016-1118-7）包含补充材料，可供授权用户使用。
The ubiquitin-editing cytosolic enzyme A20, the major negative regulator of toll-like receptor (TLR)-mediated cellular inflammatory responses, has tight genetic linkage with systemic sclerosis (SSc). Because recent studies implicate endogenous ligand-driven TLR signaling in SSc pathogenesis, we sought to investigate the regulation, role and mechanism of action of A20 in skin fibroblasts. A20 expression and the effects of forced A20 expression or siRNA-mediated A20 knockdown on fibrotic responses induced by transforming growth factor-ß (TGF-ß) were evaluated was evaluated in explanted human skin fibroblasts. Additionally, A20 regulation by TGF-ß, and by adiponectin, a pleiotropic adipokine with anti-fibrotic activity, was evaluated. In normal fibroblasts, TGF-ß induced sustained downregulation of A20, and abrogated its TLR4-dependent induction. Forced expression of A20 aborted the stimulation of collagen gene expression and myofibroblast transformation induced by TGF-ß, and disrupted canonical Smad signaling and Smad-dependent transcriptional responses. Conversely, siRNA-mediated knockdown of A20 enhanced the amplitude of fibrotic responses elicited by TGF-ß. Adiponectin, previously shown to block TLR-dependent fibrotic responses, elicited rapid and sustained increase in A20 accumulation in fibroblasts. These results identify the ubiquitin-editing enzyme A20 as a novel endogenous mechanism for negative regulation of fibrotic response intensity. Systemic sclerosis-associated genetic variants of A20 that cause impaired A20 expression or function, combined with direct suppression of A20 by TGF-ß within the fibrotic milieu, might play a significant functional role in persistence of fibrotic responses, while pharmacological augmentation of A20 inhibitory pathway activity might represent a novel therapeutic strategy. The online version of this article (doi:10.1186/s13075-016-1118-7) contains supplementary material, which is available to authorized users.
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影响因子：
8.7
作者：
Hamerman JA;Pottle J;Ni M;He Y;Zhang ZY;Buckner JH
通讯作者：
Buckner JH
影响因子：
4.9
作者：
Fang F;Liu L;Yang Y;Tamaki Z;Wei J;Marangoni RG;Bhattacharyya S;Summer RS;Ye B;Varga J
通讯作者：
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通讯作者：
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27.4
作者：
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通讯作者：
Allanore, Y.
影响因子：
30.5
作者：
Boone, DL;Turer, EE;Ma, A
通讯作者：
Ma, A