P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways.
Microglia plays an important role in many neurodegenerative conditions. ATP leaked or released by damaged cells triggers microglial activation through P2 receptors, and stimulates the release of oxygen radicals, proinflammatory cytokines and chemokines from activated microglia. However, little is known about mechanisms underlying ATP-induced chemokine release from microglia. In this study, we found that a high concentration of ATP induces the mRNA expression and release of CXCL2 from microglia. A similar effect was observed following treatment of microglia with a P2X7 receptor (P2X7R) agonist, 2'-and 3'-O-(4-benzoylbenzoyl) ATP, and this was inhibited by pre-treatment with a P2X7R antagonist, Brilliant Blue G. ATP induced both activation of nuclear factor of activated T cells (NFAT) and MAPKs (p38, ERK, and JNK) through P2X7R. ATP-induced mRNA expression of CXCL2 was inhibited by INCA-6 (an NFAT inhibitor), SB203580 (a p38 inhibitor), U0126 (a MEK-ERK inhibitor) and JNK inhibitor II (a JNK inhibitor). However, MAPK inhibitors did not inhibit activation of NFAT. In addition, protein kinase C inhibitors suppressed ATP-induced ERK and JNK activation, and also inhibited ATP-induced CXCL2 expression in microglia. These results suggest that ATP increased CXCL2 production via both NFAT and protein kinase C/MAPK signaling pathways through P2X7 receptor stimulation in microglia.
Shiratori
Miho
M
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Tozaki-Saitoh
Hidetoshi
H
Yoshitake
Mai
M
Tsuda
Makoto
M
Inoue
Kazuhide
K
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism* / Q000502:physiology; D058486:Receptors, Purinergic P2X7; D015854:Up-Regulation / Q000502:physiology
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D050778:NFATC Transcription Factors; C546469:P2rx7 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D011493:Protein Kinase C