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KMID : 0620920080400010019
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Experimental & Molecular Medicine
2008 Volume.40 No. 1 p.19 ~ p.26
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Cross talk between P2 purinergic receptors modulates extracellular ATP-mediated interleukin-10 production in rat microglial cells
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Seo Dong-Reoyl
Lee Hwan-Goo
Lee Yong-Beom
Moon Ju-Hyun
Kim Soo-Yoon
Kim Seung-U
Kim Kyung-You
Lee Jae-Souk
Lee Se-Hoon
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Abstract
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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 μM) and bell-shaped. The concentrations of ATP, ATP-γS, ADP, and ADP-β S that showed maximal IL-10 release were 100, 10, 100, and 100 μM 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), α,β-methylene ATP (α,β-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 Ca2+ 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 P2Y1 antagonist) or 5’-AMPS (a P2Y11 antagonist), indicating that both the P2Y1 and P2Y11 receptors are major receptors involved in IL-10 expression. In addition, we found that inhibition of IL-10 production by high concentrations of ATP-γS (100 μM) was restored by TNP-ATP (an antagonist of the P2X1, P2X3, and P2X4 receptors), and that IL-10 production by 2-meSADP was restored by 2meSAMP (a P2Y12 receptor antagonist) or pertussis toxin (PTX; a Gi protein inhibitor), indicating that the P2X1, P2X3, P2X4 receptor group, or the P2Y12 receptor, negatively modulate the P2Y11 receptor or the P2Y1 receptor, respectively.
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KEYWORD
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adenosine diphosphate, adenosine triphosphate, calcium, cyclic AMP, cyclic AMP-dependent protein kinases, inositol 3-phosphate, interleukin-10, microglia, receptors, purinergic P2
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