Inhibition of suppressor of cytokine signaling 1 mediates the profibrotic effect of TWEAK/Fn14 signaling on kidney cells.
Inhibition of suppressor of cytokine signaling 1 mediates the profibrotic effect of TWEAK/Fn14 signaling on kidney cells.
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DOI：
10.1016/j.cellsig.2020.109615
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发表时间：
2020-03
影响因子：
4.8
通讯作者：
Jingyun Chen;Fangyan Jia;K. Ren;Mai Luo;X. Min;Ping Wang;S. Xiao;Yumin Xia
中科院分区：
文献类型：
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作者：
Jingyun Chen;Fangyan Jia;K. Ren;Mai Luo;X. Min;Ping Wang;S. Xiao;Yumin Xia
肿瘤坏死因子样弱凋亡诱导因子（TWEAK）与受体Fn 14的结合促进了系统性红斑狼疮肾细胞的纤维化过程。细胞因子信号转导抑制蛋白1（SOCS 1）的下调与参与狼疮肾炎发病机制的促炎因子的扩增产生和细胞凋亡相关。为了阐明SOCS 1在TWEAK/Fn 14信号传导中的潜在作用，我们测定了来自MRL/MpJ（对照品系）或MRL/lpr（狼疮倾向）小鼠的原代肾细胞中的SOCS 1水平。还在用TWEAK（0 - 250 ng/mL）刺激后评价了这些细胞（系膜细胞、肾小球内皮细胞和肾小管上皮细胞）。结果显示，狼疮倾向细胞表现出SOCS 1表达减少。TWEAK诱导纤维化因子（层粘连蛋白、纤连蛋白、（C单键C基序）配体20等）的产生。在两种小鼠的肾细胞中。TWEAK刺激还降低了所有细胞中SOCS 1的mRNA和蛋白水平。此外，TWEAK对系膜细胞的作用通过预先转染SOCS 1 siRNA被放大，但通过腺病毒递送的SOCS 1过表达被部分降低。因此，TWEAK/Fn 14激活有助于狼疮性肾炎中的肾纤维化，涉及SOCS 1功能的抑制。
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, (Csingle bondC 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.