Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2-induced neutrophil migration by regulating IL-8 secretion
Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2-induced neutrophil migration by regulating IL-8 secretion
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DOI：
10.1002/eji.200939347
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发表时间：
2009-10-01
影响因子：
5.4
通讯作者：
Sevigny, Jean
中科院分区：
文献类型：
--
作者：
Ben Yebdri, Fethia;Kukulski, Filip;Sevigny, Jean
细胞外核苷酸通过激活P2受体调节炎症中涉及的多种细胞反应。在这里，我们表明，核苷酸调节TLR 2诱导的中性粒细胞迁移在体内和体外。核苷酸清除剂腺苷三磷酸双磷酸酶抑制注射TLR 2激动剂Pam（3）CSK（4）的小鼠气囊中的中性粒细胞募集。一致地，当在腺苷三磷酸双磷酸酶存在下处理前一种细胞时，用Pam（3）CSK（4）处理的人原代单核细胞或单核细胞（THP-1和U937）的上清液募集显著更少的中性粒细胞。如用抑制性Ab所证明的，由于IL-8分泌，这些上清液诱导中性粒细胞迁移。此外，非选择性P2受体拮抗剂活性蓝2和苏拉明以及选择性P2 Y（6）拮抗剂MRS 2578显著减少了IL-8的分泌。P2 Y（1）（MRS 2500）和P2 Y（11）（NF 157）的选择性拮抗剂不影响IL-8的释放。用特异性shRNA敲低P2 Y（2）或P2 Y（6）减少了Pam（3）CSK（4）处理的THP-1细胞的IL-8分泌。总之，这些结果表明，细胞外核苷酸，通过P2 Y2和P2 Y 6受体，通过控制TLR 2诱导的IL-8从人单核细胞的释放，调节中性粒细胞迁移。与我们之前对TLR 4的研究一致，这项研究进一步支持了核苷酸在细菌诱导的中性粒细胞迁移中的重要性。
Extracellular nucleotides regulate a variety of cellular responses involved in inflammation via the activation of P2 receptors. Here, we show that nucleotides regulate TLR2-induced neutrophil migration both in vivo and in vitro. The nucleotide scavenger apyrase inhibited neutrophil recruitment in murine air pouches injected with the TLR2 agonist Pam(3)CSK(4). In agreement, the supernatants of either human primary monocytes or monocytic cells (THP-1 and U937) treated with Pam(3)CSK(4) recruited significantly fewer neutrophils when the former cells were treated in the presence of apyrase. As demonstrated with inhibitory Ab, these supernatants induced neutrophil migration due to IL-8 secretion. In addition, IL-8 secretion was markedly diminished by the non-selective P2 receptor antagonists reactive blue 2 and suramin, and by a selective P2Y(6) antagonist, MRS2578. Selective antagonists of P2Y(1) (MRS2500) and P2Y(11) (NF157) did not affect IL-8 release. The knockdown of either P2Y(2) or P2Y(6) with specific shRNA diminished IL-8 secretion from Pam(3)CSK(4)-treated THP-1 cells. Altogether, these results show that extracellular nucleotides, via P2Y2 and P2Y6 receptors, regulate neutrophil migration by controlling TLR2-induced IL-8 release from human monocytes. In line with our previous work on TLR4, this study further supports the importance of nucleotides in bacterial-induced neutrophil migration.