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Cross talk between P2 purinergic receptors modulates extracellular ATP-mediated interleukin-10 production in rat microglial cells.

Seo, DR; Kim, SY; Kim, KY; Lee, HG; Moon, JH; Lee, JS; Lee, SH; Kim, SU; Lee, YB
Experimental & molecular medicine, 40(1):19-26, 2008
Journal Title
Experimental & molecular medicine
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.
MeSH terms
Adenosine Diphosphate/analogs & derivativesAdenosine Diphosphate/pharmacologyAdenosine Triphosphate/analogs & derivativesAdenosine Triphosphate/pharmacology*Adenylate Cyclase/antagonists & inhibitorsAnimalsCalcium/metabolismChelating Agents/pharmacologyCyclic AMP-Dependent Protein Kinases/antagonists & inhibitorsEnzyme Inhibitors/pharmacologyExtracellular Space/drug effectsExtracellular Space/metabolism*Gene Expression Regulation/drug effectsInterleukin-10/biosynthesis*Microglia/drug effects*Microglia/enzymologyMicroglia/metabolism*Purinergic P2 Receptor AgonistsPurinergic P2 Receptor AntagonistsRNA, Messenger/geneticsRNA, Messenger/metabolismRatsRats, Sprague-DawleyReceptor Cross-Talk/drug effects*Receptors, Purinergic P2/geneticsReceptors, Purinergic P2/metabolism*Thionucleotides/pharmacology
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