Regulation of signals by TRP channels audits physiological significauce

趋化因子介导炎症细胞如中性粒细胞和单核细胞在损伤或感染的炎症部位的募集。近年来，活性氧（ROS）在炎症趋化因子表达中的病理生理意义已被认识到。在这里，我们证明了质膜Ca^<2+>-渗透性阳离子通道TRPM2控制了单核细胞对ROS的趋化因子产生。在人单核细胞系U937中，过氧化氢（H202）通过TRPM2通道诱导Ca^<2+>内流，触发Ca^<2+>依赖的Pyk2激活，并以ras依赖的方式放大Erk激活。Erk信号的扩增导致核因子-_KB （NF_KB）的核易位以及随后趋化因子白介素-8 （IL-8）的产生，提示TRPM2在ros诱导的单核细胞IL-8的产生中起关键作用。从TRPM2敲除小鼠中分离的单核细胞显示，在H2O2刺激下，细胞内Ca^<2+>浓度升高和巨噬细胞炎症蛋白2 （MIP-2）的产生显著抑制，MIP-2是小鼠IL-8的对应物。在葡聚糖硫酸钠诱导的实验性结肠炎作为炎症模型中，缺乏TRPM2可显著减轻MIP-2的产生、中性粒细胞浸润和溃疡。这些研究结果表明，Ca^<2+>通过TRPM2通道注入可放大ros诱导的Erk/NF_KB激活，从而控制趋化因子的产生，在炎症加重中起关键作用。

Chemokines mediate the recruitment of inflammatory cells such as neutrophils and monocytes at inflamed sites in injury or infection. Recently, patho-physiological significance of reactive oxygen species (ROS) has been recognized in inflammatory chemokine expression. Here, we demonstrate that the plasma membrane Ca^<2+>-permeable cation channel TRPM2 controls chemokine production in response to ROS in monocytes. In human monocytic cell line U937, hydrogen peroxide (H202) induces Ca^<2+> influx via TRPM2 channels that triggers Ca^<2+>-dependent activation of Pyk2 and amplifies Erk activation in Ras-dependent manner. The amplification of Erk signal leads to the nuclear translocation of nuclear factor-_KB (NF_KB) and the subsequence production of the chemokine interleukine-8 (IL-8), suggesting a pivotal role played by TRPM2 in ROS-induced IL-8 production in monocytes. Monocytes isolated from TRPM2 knockout mice show significantly suppressed elevation of intracellular Ca^<2+> concentration and production of the macrophage inflammatory protein 2 (MIP-2), a murine counterpart of IL-8, upon stimulation with H2O2. In dextran sulfate sodium-induced experimental colitis used as a model for inflammation, MIP-2 production, neutrophil infiltration, and ulceration were significantly attenuated by TRPM2 defeciency. These findings suggest that Ca^<2+> inflax via TRPM2 channels amplifies ROS-induced Erk/NF_KB activation to control chemokine production, playing a key role in aggravation of inflammation.