Regulation of signals by TRP channels audits physiological significauce

趋化因子介导炎性细胞如中性粒细胞和单核细胞在损伤或感染的发炎部位的募集。最近，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TRPM 2控制单核细胞中响应ROS的趋化因子的产生。在人单核细胞系U937中，过氧化氢（H2 O2）通过TRPM 2通道诱导Ca ^2+内流，其触发Pyk 2的Ca^2+依赖性激活并以Ras依赖性方式放大Erk激活。Erk信号的放大导致核因子-KB（NF_KB）的核转位和随后的趋化因子白细胞介素-8（IL-8）的产生，表明TRPM 2在ROS诱导的单核细胞IL-8产生中起关键作用。从TRPM 2敲除小鼠中分离的单核细胞显示，在用H2 O2刺激时，细胞内Ca^2+浓度的升高和巨噬细胞炎性蛋白2（MIP-2，IL-8的鼠对应物）的产生受到显著抑制。在葡聚糖硫酸钠诱导的实验性结肠炎作为炎症模型，MIP-2的生产，中性粒细胞浸润，溃疡显着减弱TRPM 2缺陷。这些结果表明，Ca^<2+>通过TRPM 2通道放大ROS诱导的Erk/NF_κ B活化，从而控制趋化因子的产生，在炎症的加重中起关键作用。

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.