PDF(Pubmed)
Abstract：
P2Y11 is a G protein-coupled ATP receptor that activates IL-1 receptor (IL-1R) in a cyclic AMP dependent manner. In human macrophages, P2Y11/IL-1R crosstalk with CCL20 as a prime target is controlled by phosphodiesterase 4 (PDE4), which mediates breakdown of cyclic AMP. Here, we used gene expression analysis to identify activation of CXCR4 and CXCR7 as a hallmark of P2Y11 signaling. We found that PDE4 inhibition with rolipram boosts P2Y11/IL-1R-induced upregulation of CXCR7 expression and CCL20 production in an epidermal growth factor receptor dependent manner. Using an astrocytoma cell line, naturally expressing CXCR7 but lacking CXCR4, P2Y11/IL-1R activation effectively induced and CXCR7 agonist TC14012 enhanced CCL20 production even in the absence of PDE4 inhibition. Moreover, CXCR7 depletion by RNA interference suppressed CCL20 production. In macrophages, the simultaneous activation of P2Y11 and CXCR7 by their respective agonists was sufficient to induce CCL20 production with no need of PDE4 inhibition, as CXCR7 activation increased its own and eliminated CXCR4 expression. Finally, analysis of multiple CCL chemokines in the macrophage secretome revealed that CXCR4 inactivation and CXCR7 activation selectively enhanced P2Y11/IL-1R-mediated secretion of CCL20. Altogether, our data establish CXCR7 as an integral component of the P2Y11/IL-1R-initiated signaling cascade and CXCR4-associated PDE4 as a regulatory checkpoint.
摘要：
P2Y11是G蛋白偶联的ATP受体,其以环AMP依赖性方式激活IL-1受体(IL-1R)。在人类巨噬细胞中，以CCL20为主要靶标的P2Y11/IL-1R串扰受磷酸二酯酶4（PDE4）控制，介导环AMP的分解。这里,我们使用基因表达分析来确定CXCR4和CXCR7的激活是P2Y11信号的标志。我们发现，用咯利普兰抑制PDE4以表皮生长因子受体依赖性方式增强P2Y11/IL-1R诱导的CXCR7表达上调和CCL20产生。使用星形细胞瘤细胞系，天然表达CXCR7但缺乏CXCR4，P2Y11/IL-1R激活有效诱导，CXCR7激动剂TC14012即使在不存在PDE4抑制的情况下也能增强CCL20的产生。此外，通过RNA干扰消除CXCR7抑制CCL20产生。在巨噬细胞中，P2Y11和CXCR7通过其各自的激动剂同时激活足以诱导CCL20的产生，而不需要PDE4抑制，因为CXCR7激活增加其自身并消除CXCR4表达。最后,对巨噬细胞分泌组中多种CCL趋化因子的分析表明，CXCR4失活和CXCR7活化选择性地增强了P2Y11/IL-1R介导的CCL20分泌。总之,我们的数据将CXCR7确立为P2Y11/IL-1R启动的信号传导级联的组成部分,并将CXCR4相关的PDE4确立为监管检查点.
