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* Transgenic Animal Research Center, National Institute of Agrobiological Sciences, Tsukuba;
Research Center for Prion Diseases, National Institute of Animal Health, Tsukuba, Japan;
Department of Physiology, Nippon Medical School, Tokyo, Japan; and
Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
The P2X7 receptor (P2X7R), an ATP-gated ion channel, plays essential roles in the release and maturation of IL-1β in microglial cells in the brain. Previously, we found that lysophosphatidylcholine (LPC) potentiated P2X7R-mediated intracellular signals in microglial cells. In this study, we determined whether the lysophospholipids, i.e., LPC and sphingosylphosphorylcholine (SPC), modulate the ATP-induced release and processing of IL-1β mediated by P2X7R in mouse MG6 microglial cells. LPC or SPC alone induced the release of precursor (pro-IL-1β) and mature IL-1β (mIL-1β) from LPS-primed MG6 cells, possibly due to lytic functions. However, these lysophospholipids inhibited ATP-induced caspase-1 activation that is usually followed by the release of mIL-1β. Conversely, ATP inhibited the release of pro-IL-1β and mIL-1β induced by LPC/SPC. This suggests that lysophospholipids and ATP mutually suppressed each function to release IL-1β. P2X7R activation resulted in microtubule reorganization in the MG6 cells that was blocked in the presence of LPC and SPC. LPC/SPC reduced the amount of activated RhoA after stimulation with ATP, implying that these lysophospholipids block ATP-induced microtubule reorganization by interfering with RhoA activation. In addition, the microtubule inhibitor colchicine inhibited ATP-induced release of mIL-1β similar to that of LPC and SPC. This suggests that the impairment of the microtubule reassembly may be associated with the inhibitory effects of LPC/SPC on ATP-induced mIL-1β release. Mutual suppression by ATP and LPC/SPC on the maturation of IL-1β was observed in LPS-primed primary microglia. Collectively, these data suggest opposing functions by lysophospholipids, either proinflammatory or anti-inflammatory, in regard to the maturation and release of IL-1β from microglial cells.
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1 This work was supported by a research grant and Grant-in-Aid from the BSE Control Project of the Ministry of Agriculture, Forestry, and Fisheries in Japan, and a Grant-in-Aid for Young Scientists (Category B) from the Ministry of Education, Science, Sports and Technology of Japan. This work was also supported by a research grant from The Naito Foundation.
2 Address correspondence and reprint requests to Dr. Hiroshi Kitani, Transgenic Animal Research Center, National Institute of Agrobiological Sciences, Ohwashi 1-2, Tsukuba, Ibaraki 305-8634, Japan. E-mail address: kitani{at}affrc.go.jp
3 Abbreviations used in this paper: mIL-1β, mature IL-1β; LPC, lysophosphatidylcholine; SPC, sphingosylphosphorylcholine; PLA2, phospholipase A2; oATP, oxidized ATP; PVDF, polyvinylidene difluoride.
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