Research Project
Grant-in-Aid for Scientific Research (B)
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.
All 2007 2006 2001 Other
All Journal Article (27 results) (of which Peer Reviewed: 12 results) Presentation (10 results)
Nature Neurosci. 10
Pages: 691-701
J. Biol. Chem. 282
Pages: 23117-23128
Proc. Natl. Acad. Sci. USA. 104
Pages: 16323-16328
Channels 1
Pages: 144-147
J. Biol. Chem 282
Proc. NatL Acad. Sci. USA 104
Proc. Natl. Acad. Sci. USA 104
Proc. Natl. Acad. Sci. USA 103
Pages: 16704-16709
J. Physiol. 570
Pages: 219-235
Proc. Natl. Acad. Sci. USA. 103
Pages: 5561-5566
EMBO J. 25
Pages: 1804-1815
Nature Chem. Biol. (Article) 2
Pages: 596-607
130007038569
Nature Chem. Biol. 2
Nature Neurosci. (Article) (in press)
