title: Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor.
abstract: Chemokines play critical roles in inflammation by recruiting inflammatory cells to injury sites. In this study, we found that UDP induced expression of chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) in microglia, astrocytes, and slice cultures by activation of P2Y(6). Interestingly, CCL2 was more highly expressed than CCL3. However, CCL2 synthesis kinetics in response to UDP differed in microglia and astrocytes; microglia rapidly produced small amounts of CCL2, whereas astrocytes continuously synthesized large amounts of CCL2, resulting in a high ultimate level of the chemokine. UDP-induced chemokine expression was reduced in the presence of a specific antagonist of P2Y(6) (MRS2578) or small interfering RNA directed against the P2Y(6) gene. Inhibition of phospholipase C and calcium increase, downstream signaling pathways of Gq-coupled P2Y(6), reduced UDP-induced chemokine expression. UDP activated two calcium-activated transcription factors, NFATc1 and c2. Furthermore, inhibitors of calcineurin (a phosphatase activating NFAT) and NFAT reduced UDP-induced chemokine synthesis. We also found, using a transmigration assay, that UDP-treated astrocytes recruited monocytes. These results suggest that UDP induces chemokine expression in microglia and astrocytes of the injured brain by activation of P2Y(6) receptors.
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Beomsue
authors.initials: B
authors.lastname: Kim
authors.forename: Hey-kyeong
authors.initials: HK
authors.lastname: Jeong
authors.forename: Jong-hyeon
authors.initials: JH
authors.lastname: Kim
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Lee
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.forename: Eun-hye
authors.initials: EH
authors.lastname: Joe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D054405:Chemokine CCL3 / Q000096:biosynthesis*; D017628:Microglia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009000:Monocytes / Q000276:immunology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014530:Uridine Diphosphate / Q000378:metabolism / Q000502:physiology*
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate