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Inhibition of suppressor of cytokine signaling 1 mediates the profibrotic effect of TWEAK/Fn14 signaling on kidney cells.
Cellular Signalling ( IF 4.8 ) Pub Date : 2020-03-23 , DOI: 10.1016/j.cellsig.2020.109615
Jingyun Chen 1 , Fangyan Jia 2 , Kaixuan Ren 1 , Mai Luo 3 , Xiaoyun Min 3 , Ping Wang 4 , Shengxiang Xiao 1 , Yumin Xia 1
Affiliation  

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) engagement with the receptor Fn14 contributes to the fibrotic process of kidney cells in systemic lupus erythematosus. Downregulation of the protein suppressor of cytokine signaling 1 (SOCS1) correlates with amplified production of proinflammatory factors and cell apoptosis, which participate in the pathogenesis of lupus nephritis. To elucidate the potential role of SOCS1 in TWEAK/Fn14 signaling, we determined the SOCS1 levels in primary kidney cells from MRL/MpJ (control strain) or MRL/lpr (lupus-prone) mice. These cells (mesangial cells, glomerular endothelial cells, and tubular epithelial cells) were also evaluated after stimulation with TWEAK (0 to 250 ng/mL). The results showed that the lupus-prone cells exhibited reduced SOCS1 expression. TWEAK induced the production of profibrotic factors (laminin, fibronectin, (CC motif) ligand 20, etc.) in kidney cells from both mouse strains. TWEAK stimulation also decreased both the mRNA and protein levels of SOCS1 in all cells. Moreover, the effect of TWEAK on mesangial cells was amplified by pre-transfection of SOCS1 siRNA but was partly reduced with SOCS1 overexpression by adenoviral delivery. Therefore, TWEAK/Fn14 activation contributes to renal fibrosis in lupus nephritis involving the depression of SOCS1 function.

中文翻译:

抑制细胞因子信号传导抑制因子 1 介导 TWEAK/Fn14 信号传导对肾细胞的促纤维化作用。

肿瘤坏死因子样细胞凋亡弱诱导剂 (TWEAK) 与受体 Fn14 的结合有助于系统性红斑狼疮肾细胞的纤维化过程。细胞因子信号转导蛋白抑制因子 1 (SOCS1) 的下调与促炎因子和细胞凋亡的扩增产生相关,这些因子参与狼疮性肾炎的发病机制。为了阐明 SOCS1 在 TWEAK/Fn14 信号传导中的潜在作用,我们确定了来自 MRL/MpJ(对照品系)或 MRL/lpr(易患狼疮)小鼠的原代肾细胞中的 SOCS1 水平。这些细胞(系膜细胞、肾小球内皮细胞和肾小管上皮细胞)在用 TWEAK(0 至 250 ng/mL)刺激后也进行了评估。结果表明,狼疮易发细胞表现出降低的 SOCS1 表达。TWEAK 在来自两种小鼠品系的肾细胞中诱导促纤维化因子(层粘连蛋白、纤连蛋白、(CC 基序)配体 20 等)的产生。TWEAK 刺激还降低了所有细胞中 SOCS1 的 mRNA 和蛋白质水平。此外,TWEAK 对系膜细胞的影响通过 SOCS1 siRNA 的预转染被放大,但通过腺病毒传递的 SOCS1 过表达而部分降低。因此,TWEAK/Fn14 激活有助于狼疮性肾炎的肾纤维化,包括 SOCS1 功能的抑制。TWEAK 对系膜细胞的影响通过 SOCS1 siRNA 的预转染被放大,但通过腺病毒递送的 SOCS1 过表达而部分减弱。因此,TWEAK/Fn14 激活有助于狼疮性肾炎的肾纤维化,包括 SOCS1 功能的抑制。TWEAK 对系膜细胞的影响通过 SOCS1 siRNA 的预转染被放大,但通过腺病毒递送的 SOCS1 过表达而部分减弱。因此,TWEAK/Fn14 激活有助于狼疮性肾炎的肾纤维化,包括 SOCS1 功能的抑制。
更新日期:2020-03-26
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