Anti-dsDNA antibodies induce inflammation via endoplasmic reticulum stress in human mesangial cells.
Anti-dsDNA antibodies induce inflammation via endoplasmic reticulum stress in human mesangial cells.
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抗 dsDNA 抗体通过人系膜细胞内质网应激诱导炎症
DOI：
10.1186/s12967-015-0536-7
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发表时间：
2015-06-04
影响因子：
7.4
通讯作者：
Yang N
中科院分区：
文献类型：
--
作者：
Zhang H;Zhao C;Wang S;Huang Y;Wang H;Zhao J;Yang N
抗dsDNA抗体在狼疮性肾炎（LN）的发病中起重要作用。内质网应激是应激状态下的一种生理反应，在持续刺激下可引起炎症反应。本研究探讨内质网应激在抗dsDNA抗体诱导的人肾小球系膜细胞炎症反应中的作用。从LN患者中分离的抗dsDNA抗体用于刺激HMC。Western blot检测GRP 78、PERK、p-PERK、p-eIF 2 α、ATF 4、p-IRE 1 α、ATF 6和CHOP在HMCs中的表达。通过检测NF-κB p65的核转位来检测NF-κB活化。qPCR和ELISA检测IL-1β、TNF-α和MCP-1的表达和产生。流式细胞术和细胞ELISA显示抗dsDNA抗体可与HMCs结合。Fc受体的阻断不抑制结合。抗dsDNA抗体刺激后，GRP 78、p-PERK、p-eIF 2 α和ATF 4的表达明显增强。另外，抗dsDNA抗体还能显著增强NF-κB的活化，上调IL-1β、TNF-α和MCP-1的表达，而化学ER应激抑制剂4-PBA则能抑制这些蛋白的表达。转染特异性ATF 4 siRNA也能显著降低NF-κB的活化和促炎细胞因子的表达。抗dsDNA抗体通过PERK-eIF 2 α-ATF 4 ER应激途径诱导HMC中NF-κB活化和炎症。
Anti-dsDNA antibodies play an important role in the pathogenesis of lupus nephritis (LN). Endoplasmic reticulum (ER) stress is a physical reaction under stressful condition and can cause inflammation when stimulation is sustained. This study investigated the roles of ER stress in anti-dsDNA antibody-induced inflammation response in human mesangial cells (HMCs). Anti-dsDNA antibodies isolated from LN patients were used to stimulate HMCs. The expression of GRP78, PERK, p-PERK, p-eIF2α, ATF4, p-IRE1α, ATF6 and CHOP in HMCs was measured by western blot. NF-κB activation was detected by examining nuclear translocation of NF-κB p65. The expression and production of IL-1β, TNF-α and MCP-1 were examined by qPCR and ELISA. Flow cytometry and cellular ELISA showed that anti-dsDNA antibodies can bind to HMCs. The binding was not inhibited by blockage of Fc receptor. Anti-dsDNA antibody stimulation significantly enhanced the expression of GRP78, p-PERK, p-eIF2α and ATF4 in HMCs. However, no significant increase in the expression of p-IRE1α and ATF6 was found. In addition, anti-dsDNA antibodies also significantly increased the activation of NF-κB and upregulated the expression of IL-1β, TNF-α and MCP-1, which were suppressed by pretreatment of HMCs with chemical ER stress inhibitor 4-PBA. Transfection of specific ATF4 siRNA also significantly reduced the activation of NF-κB and expression of proinflammatory cytokines. Anti-dsDNA antibodies induce NF-κB activation and inflammation in HMCs via PERK-eIF2α-ATF4 ER stress pathway.
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影响因子：
2
作者：
Kaneko, M;Niinuma, Y;Nomura, Y
通讯作者：
Nomura, Y
影响因子：
4.3
作者：
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通讯作者：
Khullar, Madhu
影响因子：
11.4
作者：
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通讯作者：
BAEUERLE, PA
影响因子：
4.4
作者：
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通讯作者：
Harigae, Hideo
影响因子：
5.3
作者：
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通讯作者：
Exton, JH