白细胞介素-6通过JAK2-STAT3信号通路对瞬时受体电位阳离子通道亚家族M成员7功能的调控
Regulation of TRPM7 Function by IL-6 through the JAK2-STAT3 Signaling Pathway.
作者信息
Liu Aifen, Zhao Fengbo, Wang Jing, Zhao Yin, Luo Zhenzhao, Gao Yan, Shi Jing
机构信息
Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Basic Medical Research Centre, Medical College of Nantong University, Nantong, Jiangsu, P.R. China.
出版信息
PLoS One. 2016 Mar 24;11(3):e0152120. doi: 10.1371/journal.pone.0152120. eCollection 2016.
AIMS
Previous studies have demonstrated that expression of the TRPM7 channel, which may induce delayed cell death by mediating calcium influx, is precisely regulated. However, functional regulation of TRPM7 channels by endogenous molecules has not been elucidated. The proinflammatory cytokine IL-6 contributes to regulation of Ca2+ influx in cerebral ischemia, but the role of IL-6 in regulating TRPM7 functioning is unknown. Thus, we here investigated the interaction between IL-6 and TRPM7 channels and the relevant mechanisms.
MATERIALS AND METHODS
Using whole-cell patch-clamping, we first investigated the effect of IL-6 on TRPM7-like currents in primary cultured cortical neurons. Next, TRPM7-overexpressing HEK293 cells were used to confirm the effect of IL-6/sIL-6R on TRPM7. Finally, we used specific signaling pathway inhibitors to investigate the signaling pathways involved.
RESULTS
IL-6 or IL-6/sIL-6R dose-dependently inhibited inward TRPM7 currents, in both primary cultured neurons and HEK293 cells overexpressing TRPM7. In intracellular Mg2+-free conditions, extracellular Ca2+ or the α-kinase domain of TRPM7 did not participate in this regulation. The inhibitory effect of IL-6 on TRPM7 could be blocked by specific inhibitors of the JAK2-STAT3 pathway, but not of the PI3K, ERK1/2, or PLC pathways.
CONCLUSIONS
IL-6 inhibits the inward TRPM7 current via the JAK2-STAT3 signaling pathway.
目的
以往研究表明，可通过介导钙内流诱导延迟性细胞死亡的瞬时受体电位通道M7（TRPM7）通道的表达受到精确调控。然而，内源性分子对TRPM7通道的功能调节尚未阐明。促炎细胞因子白细胞介素-6（IL-6）参与脑缺血时Ca2+内流的调节，但IL-6在调节TRPM7功能中的作用尚不清楚。因此，我们在此研究了IL-6与TRPM7通道之间的相互作用及相关机制。
材料与方法
采用全细胞膜片钳技术，我们首先研究了IL-6对原代培养皮层神经元中TRPM7样电流的影响。接下来，使用过表达TRPM7的人胚肾293（HEK293）细胞来证实IL-6/可溶性IL-6受体（sIL-6R）对TRPM7的作用。最后，我们使用特异性信号通路抑制剂来研究其中涉及的信号通路。
结果
在原代培养神经元和过表达TRPM7的HEK293细胞中，IL-6或IL-6/sIL-6R均剂量依赖性地抑制内向TRPM7电流。在细胞内无镁离子的条件下，细胞外钙离子或TRPM7的α激酶结构域不参与此调节。IL-6对TRPM7的抑制作用可被JAK2-STAT3信号通路的特异性抑制剂阻断，但不能被磷脂酰肌醇-3激酶（PI3K）、细胞外信号调节激酶1/2（ERK1/2）或磷脂酶C（PLC）信号通路的抑制剂阻断。
结论
IL-6通过JAK2-STAT3信号通路抑制内向TRPM7电流。
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