Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.
Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.
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DOI：
10.1186/ar4577
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发表时间：
2014-06-12
影响因子：
4.9
通讯作者：
Sluka KA
中科院分区：
文献类型：
--
作者：
Gong W;Kolker SJ;Usachev Y;Walder RY;Boyle DL;Firestein GS;Sluka KA
酸敏感离子通道3（ASIC 3）在滑膜细胞中表达，通过pH值降低而激活，并减少炎症性关节炎动物模型中的炎症。本研究的目的是表征成纤维细胞样滑膜细胞（FLS）中ASIC 3控制炎症的潜在机制。实验在来自野生型（WT）和ASIC 3-/-小鼠、ASIC 1-/-小鼠和患有类风湿性关节炎的人的培养的FLS中进行。我们评估了在有和没有白细胞介素-1 β的情况下酸性pH对FLS的影响，以及ASICs在调节细胞内钙离子浓度、丝裂原激活激酶（MAP激酶）表达和细胞死亡中的作用。[Ca2+]i通过荧光钙成像评估，MAP激酶通过蛋白质印迹测量; ASIC、细胞因子和蛋白酶mRNA表达通过定量PCR测量，细胞死亡通过LIVE/DEAD测定测量。在WT FLS中，酸性pH增加[Ca 2 +]i并降低p-ERK表达;在ASIC 3-/- FLS中，这些作用显著较小，并可通过阻断[Ca 2 +]i来防止。阻断蛋白磷酸酶2A（PP 2A）可防止pH诱导的p-ERK降低。在WT FLS中，IL-1β增加ASIC 3 mRNA，并且当与酸性pH组合时，增加[Ca 2 +]i、p-ERK、IL-6和金属蛋白酶mRNA以及细胞死亡。在WT FLS中，[Ca 2 +]i和ERK抑制剂可预防pH 6.0与IL-1β联合诱导的细胞死亡。pH降低激活ASIC 3，导致[Ca 2 +]i增加和p-ERK降低。在炎症条件下，酸性pH导致[Ca 2 +]i增加和细胞外信号调节激酶的磷酸化，导致细胞死亡。因此，通过来自发炎关节的酸性pH激活FLS上的ASIC 3可以限制滑膜增殖，从而减少炎症介质的积累和随后的关节损伤。
Acid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS). Experiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca2+]i, mitogen activated kinase (MAP kinase) expression, and cell death. [Ca2+]i was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay. Acidic pH increased [Ca2+]i and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca2+]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca2+]i, p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca2+]i and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS. Decreased pH activates ASIC3 resulting in increased [Ca2+]i, and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca2+]i and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage.
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影响因子：
4.4
作者：
Kim, Wan-Uk;Kang, Soon Suk;Cho, Chul-Soo
通讯作者：
Cho, Chul-Soo
DOI：
10.1016/j.bbrc.2008.02.155
发表时间：
2008-05-16
影响因子：
3.1
作者：
Hu, Fen;Sun, Wen Wu;Yang, Wen Xiu
通讯作者：
Yang, Wen Xiu
影响因子：
5.5
作者：
Eshcol, Jayasheel O.;Harding, Anne Marie S.;Benson, Christopher J.
通讯作者：
Benson, Christopher J.
影响因子：
5.6
作者：
Liu, Wen-Hsin;Chang, Long-Sen
通讯作者：
Chang, Long-Sen
影响因子：
27.4
作者：
Kolker SJ;Walder RY;Usachev Y;Hillman J;Boyle DL;Firestein GS;Sluka KA
通讯作者：
Sluka KA