抄録
Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells at inflamed sites in injury or infection. Here, we demonstrate that the plasma membrane Ca2+-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, H2O2 evokes Ca2+ influx through TRPM2 to activate Ca2+-dependent tyrosine kinase Pyk2 and amplify Erk signal via Ras. This elicits nuclear translocation of NF-kB essential for the production of the chemokine interleukine-8 (CXCL8). In monocytes from TRPM2-defecient mice, H2O2-induced Ca2+ influx and production of the macrophage inflammatory protein 2 (MIP-2/CXCL2), the murine CXCL8 functional homologue, were significantly impaired. In the inflammation model dextran sulfate sodium-induced colitis, CXCL2 expression, neutrophil infiltration, and ulceration were significantly attenuated by TRPM2 disruption. Thus, TRPM2 Ca2+ influx controls the ROS-induced signal cascade responsible for chemokine production which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases. [J Physiol Sci. 2008;58 Suppl:S10]
