title: Cross talk between P2 purinergic receptors modulates extracellular ATP-mediated interleukin-10 production in rat microglial cells.
abstract: Previously we demonstrated that ATP released from LPS-activated microglia induced IL-10 expression in a process involving P2 receptors, in an autocrine fashion. Therefore, in the present study we sought to determine which subtype of P2 receptor was responsible for the modulation of IL-10 expression in ATP-stimulated microglia. We found that the patterns of IL-10 production were dose-dependent (1, 10, 100, 1,000 microM) and bell-shaped. The concentrations of ATP, ATP-gammaS, ADP, and ADP-betaS that showed maximal IL-10 release were 100, 10, 100, and 100 microM respectively. The rank order of agonist potency for IL-10 production was 2'-3'-O-(4-benzoyl)-benzoyl ATP (BzATP)=dATP>2-methylthio-ADP (2-meSADP). On the other hand, 2-methylthio-ATP (2-meSATP), alpha,beta-methylene ATP (alpha,beta-meATP), UTP, and UDP did not induce the release of IL-10 from microglia. Further, we obtained evidence of crosstalk between P2 receptors, in a situation where intracellular Ca(2+) release and/or cAMP-activated PKA were the main contributors to extracellular ATP-(or ADP)-mediated IL-10 expression, and IL-10 production was down-regulated by either MRS2179 (a P2Y(1) antagonist) or 5'-AMPS (a P2Y(11) antagonist), indicating that both the P2Y(1) and P2Y(11) receptors are major receptors involved in IL-10 expression. In addition, we found that inhibition of IL-10 production by high concentrations of ATP-gammaS (100 microM) was restored by TNP-ATP (an antagonist of the P2X(1), P2X(3), and P2X(4) receptors), and that IL-10 production by 2-meSADP was restored by 2meSAMP (a P2Y(12) receptor antagonist) or pertussis toxin (PTX; a Gi protein inhibitor), indicating that the P2X(1), P2X(3), P2X(4)receptor group, or the P2Y(12) receptor, negatively modulate the P2Y(11) receptor or the P2Y(1) receptor, respectively.
authors.affiliation: Neuroscience Graduate Program, Ajou University School of Medicine, Suwon 443-721, Korea.
authors.forename: Dong Reoyl
authors.initials: DR
authors.lastname: Seo
authors.forename: Soo Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Kyung You
authors.initials: KY
authors.lastname: Kim
authors.forename: Hwan Goo
authors.initials: HG
authors.lastname: Lee
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Moon
authors.forename: Jae Souk
authors.initials: JS
authors.lastname: Lee
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Yong Beom
authors.initials: YB
authors.lastname: Lee
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis*; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; D016753:Interleukin-10; C030812:adenosine 5'-O-(2-thiodiphosphate); C022571:adenosine 5'-O-(3-thiotriphosphate); D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium