Lysophospholipids and ATP mutually suppress maturation and release of IL-1 beta in mouse microglial cells using a Rho-dependent pathway.
The P2X7 receptor (P2X7R), an ATP-gated ion channel, plays essential roles in the release and maturation of IL-1beta 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-1beta mediated by P2X7R in mouse MG6 microglial cells. LPC or SPC alone induced the release of precursor (pro-IL-1beta) and mature IL-1beta (mIL-1beta) 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-1beta. Conversely, ATP inhibited the release of pro-IL-1beta and mIL-1beta induced by LPC/SPC. This suggests that lysophospholipids and ATP mutually suppressed each function to release IL-1beta. 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-1beta 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-1beta release. Mutual suppression by ATP and LPC/SPC on the maturation of IL-1beta 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-1beta from microglial cells.
Transgenic Animal Research Center, National Institute of Agrobiological Sciences, Tsukuba, Japan.
Takato
T
Takenouchi
Yoshifumi
Y
Iwamaru
Shuei
S
Sugama
Mitsuru
M
Sato
Makoto
M
Hashimoto
Hiroshi
H
Kitani
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000276:immunology*; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008246:Lysophospholipids / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008246:Lysophospholipids; C546469:P2rx7 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D000255:Adenosine Triphosphate; D020742:rhoA GTP-Binding Protein; D013110:Sphingosine