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- Title
TRPM2-mediated Ca<sup>2+</sup> influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration.
- Authors
Yamamoto, Shinichiro; Shimizu, Shunichi; Kiyonaka, Shigeki; Takahashi, Nobuaki; Wajima, Teruaki; Hara, Yuji; Negoro, Takaharu; Hiroi, Toshihito; Kiuchi, Yuji; Okada, Takaharu; Kaneko, Shuji; Lange, Ingo; Fleig, Andrea; Penner, Reinhold; Nishi, Miyuki; Takeshima, Hiroshi; Mori, Yasuo
- Abstract
Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca2+-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H2O2) evokes Ca2+ influx through TRPM2 to activate Ca2+-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-κB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H2O2-induced Ca2+ influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca2+ influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.
- Publication
Nature Medicine, 2008, Vol 14, Issue 7, p738
- ISSN
1078-8956
- Publication type
Academic Journal
- DOI
10.1038/nm1758