Interleukin-1β and tumor necrosis factor-α augment acidosis-induced rat articular chondrocyte apoptosis via nuclear factor-kappaB-dependent upregulation of ASIC1a channel.
Interleukin-1β and tumor necrosis factor-α augment acidosis-induced rat articular chondrocyte apoptosis via nuclear factor-kappaB-dependent upregulation of ASIC1a channel.
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DOI：
10.1016/j.bbadis.2017.10.004
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Renpeng Zhou;Beibei Dai;Ya-Ya Xie-Ya;Xiao-shan Wu;Zhisen Wang;Yue Li;Zhi-qiang Wang;S. Zu;J. Ge-J.
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文献类型：
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作者：
Renpeng Zhou;Beibei Dai;Ya-Ya Xie-Ya;Xiao-shan Wu;Zhisen Wang;Yue Li;Zhi-qiang Wang;S. Zu;J. Ge-J.
急性期促炎细胞因子白细胞介素-1β (IL-1β) 和肿瘤坏死因子-α (TNF-α) 表现出高水平表达和多效性生物学效应，并有助于类风湿性关节炎 (RA) 的进展和持续。酸性关节积水也是RA的重要病理特征，酸敏感离子通道1a（ASIC1a）在酸中毒引起的软骨细胞细胞毒性中发挥着关键作用。然而，IL-1β和TNF-α在酸诱导的软骨细胞凋亡中的作用仍不清楚。大鼠佐剂关节炎和原代关节软骨细胞分别用作体内和体外模型系统。关节软骨中ASIC1a表达增加，且与体内核因子(NF)-κB表达高度共定位。IL-1β和TNF-α可上调ASIC1a表达。这些细胞因子激活软骨细胞中的丝裂原激活蛋白激酶和 NF-κB 通路，而这些信号通路各自的抑制剂可以部分逆转 IL-1β 和 TNF-α 诱导的 ASIC1a 上调。双荧光素酶和凝胶位移测定以及染色质免疫沉淀-聚合酶链反应表明，IL-1β和TNF-α通过增加NF-κB DNA结合活性来增强软骨细胞中的ASIC1a启动子活性，而NF-κB抑制剂吡咯烷二硫代氨基甲酸铵又可以阻止这种活性。 IL-1β 和 TNF-α 也会降低细胞活力，但会增强 LDH 释放、细胞内 Ca2+ 浓度升高、线粒体膜电位丧失、裂解的 PARP 和裂解的 caspase-3/9 表达以及酸刺激的软骨细胞凋亡，这些作用可以通过特异性 ASIC1a 抑制剂 psalmotoxin-1 (PcTX-1)、ASIC1a-短发夹 RNA 或钙螯合剂消除BAPTA-AM。这些结果表明，IL-1β 和 TNF-α 可以通过 NF-κB 依赖性上调原代关节软骨细胞中 ASIC1a 通道的表达来增强酸中毒诱导的细胞毒性。
The acute-phase proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) demonstrate high-level expression and pleiotropic biological effects, and contribute to the progression and persistence of rheumatoid arthritis (RA). Acid hydrarthrosis is also an important pathological characteristic of RA, and the acid-sensing ion channel 1a (ASIC1a) plays a critical role in acidosis-induced chondrocyte cytotoxicity. However, the roles of IL-1β and TNF-α in acid-induced apoptosis of chondrocytes remain unclear. Rat adjuvant arthritis and primary articular chondrocytes were used as in vivo and in vitro model systems, respectively. ASIC1a expression in articular cartilage was increased and highly colocalized with nuclear factor (NF)-κB expression in vivo.IL-1β and TNF-α could upregulate ASIC1a expression. These cytokines activated mitogen-activated protein kinase and NF-κB pathways in chondrocytes, while the respective inhibitors of these signaling pathways could partially reverse the ASIC1a upregulation induced by IL-1β and TNF-α. Dual luciferase and gel-shift assays and chromatin immunoprecipitation-polymerase chain reaction demonstrated that IL-1β and TNF-α enhanced ASIC1a promoter activity in chondrocytes by increasing NF-κB DNA-binding activities, which was in turn prevented by the NF-κB inhibitor ammonium pyrrolidinedithiocarbamate. IL-1β and TNF-α also decreased cell viability but enhanced LDH release, intracellular Ca2+concentration elevation, loss of mitochondrial membrane potential, cleaved PARP and cleaved caspase-3/9 expression, and apoptosis in acid-stimulated chondrocytes, which effects could be abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1), ASIC1a-short hairpin RNA or calcium chelating agent BAPTA-AM. These results indicate that IL-1β and TNF-α can augment acidosis-induced cytotoxicity through NF-κB-dependent up-regulation of ASIC1a channel expression in primary articular chondrocytes.