Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor
Kim, B; Jeong, HK; Kim, JH; Lee, SY; Jou, I; Joe, EH
Journal of immunology (Baltimore, Md. : 1950), 186(6):3701-3709, 2011
Journal of immunology (Baltimore, Md. : 1950)
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.
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