Interleukin-6 enhances acid-induced apoptosis via upregulating acid-sensing ion channel 1a expression and function in rat articular chondrocytes.
Interleukin-6 enhances acid-induced apoptosis via upregulating acid-sensing ion channel 1a expression and function in rat articular chondrocytes.
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DOI：
10.1016/j.intimp.2015.08.044
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发表时间：
2015-12
影响因子：
5.6
通讯作者：
Renpeng Zhou;Xiao-shan Wu;Zhisen Wang;J. Ge;Fei-hu Chen
中科院分区：
文献类型：
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作者：
Renpeng Zhou;Xiao-shan Wu;Zhisen Wang;J. Ge;Fei-hu Chen
炎症细胞因子白细胞介素 6 (IL-6) 是类风湿性关节炎 (RA) 的致病因子，类风湿性关节炎是一种伴有退行性关节炎软骨的慢性炎症性疾病。然而，IL-6影响软骨细胞凋亡的确切机制尚不清楚。酸敏感离子通道 (ASIC) 是细胞外 H+ 激活的阳离子通道家族，可以被细胞外酸短暂激活，并在酸诱导的细胞损伤中发挥关键作用。在本研究中，为了研究IL-6在调节酸诱导的关节软骨细胞凋亡中的作用，在酸存在下对原代大鼠关节软骨细胞进行有或没有IL-6的不同处理。结果显示，佐剂性关节炎（AA）大鼠的关节软骨和软骨细胞中ASIC1a的mRNA和蛋白表达显着增加。 IL-6能够以时间和剂量依赖性方式显着上调ASIC1a的水平，并诱导关节软骨细胞中JAK2、STAT3、ERK、JNK和NF-κB的激活。此外，这些信号通路的各自抑制剂和针对 IL-6 受体的特异性抗体（托珠单抗）都可以部分消除 IL-6 诱导的 ASIC1a 上调。此外，IL-6 抑制细胞活力，增强酸诱导的关节软骨细胞中 LDH 的释放、[Ca2+] 升高和细胞凋亡，而这些变化可以通过使用 ASIC1a 的特异性拮抗剂 psalmotoxin 1 (PcTX1) 来逆转。此外，PcTX1预处理可抑制酸诱导的关节软骨细胞中IL-6诱导的Bcl-2表达下调和Bax表达上调。综上所述，这些结果表明IL-6可以增强酸诱导的关节软骨细胞凋亡，其机制可能部分涉及其调节ASIC1a依赖性JAK2/STAT3和MAPK/NF-κB信号通路激活的能力。
The inflammatory cytokine interleukin-6 (IL-6) is a causative agent of rheumatoid arthritis (RA), a chronic inflammatory disease complicated with degenerative arthritic cartilage. However, the precise mechanism of IL-6 on chondrocyte apoptosis is largely unclear. Acid-sensing ion channels (ASICs), a family of extracellular H+-activated cation channels, can be transiently activated by extracellular acid and play a pivotal role in acid-induced cell injury. In the present study, to investigate the role of IL-6 in regulating acid-induced articular chondrocyte apoptosis, primary rat articular chondrocytes were subjected to different treatments with or without IL-6 in the presence of acid. The results showed that the mRNA and protein expressions of ASIC1a were significantly increased in articular cartilage and chondrocytes of adjuvant arthritis (AA) rats. IL-6 could dramatically upregulate the level of ASIC1a in a time- and dose-dependent manner, and induce the activation of JAK2, STAT3, ERK, JNK and NF-κB in articular chondrocytes. Moreover, both the respective inhibitors of these signaling pathways and the specific antibody against IL-6 receptor (tocilizumab) could partially abrogate the ASIC1a upregulation induced by IL-6. Furthermore, IL-6 inhibited the cell viability and enhanced LDH release, [Ca2 +]ielevation, and apoptosis in acid-induced articular chondrocytes, and these changes could be reversed by using psalmotoxin 1(PcTX1), which is the specific antagonist of ASIC1a. In addition, pretreatment with PcTX1 could inhibit the downregulated expression of Bcl-2 and the upregulated expression of Bax induced by IL-6 in acid-induced articular chondrocytes. Taken together, these results indicated that IL-6 could enhance acid-induced articular chondrocyte apoptosis, the mechanism of which might partially be involved with its ability of regulating the activation of ASIC1a-dependent JAK2/STAT3 and MAPK/NF-κB signaling pathways.