PAR1- and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes.
PAR1- and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes.
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DOI：
10.1186/1471-2172-11-53
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发表时间：
2010-10-28
期刊：
影响因子：
3
通讯作者：
Chung WO
中科院分区：
文献类型：
--
作者：
Rohani MG;DiJulio DH;An JY;Hacker BM;Dale BA;Chung WO
蛋白水解酶激活受体(PARs)是G蛋白偶联受体的一员，被多种蛋白水解酶激活。PAR1和PAR2的激活可在口腔角质形成细胞(HOK)中触发先天免疫反应，但HOK中PAR1和PAR2激活下游的信号通路尚不清楚。在这项研究中，我们旨在确定PAR1和PAR2介导的信号在通过ERK、p38和PI3K/Akt诱导天然免疫标记物CXCL3、CXCL5和CCL20方面是否存在差异。我们的数据表明，PAR1诱导的先天免疫需要p38和ERK蛋白激酶，而PAR2主要通过p38发出信号。然而，抑制PI3K主要通过抑制PAR激活信号的p38磷酸化来增强先天免疫标志物的表达。我们的数据表明，介导PAR1和PAR2激活的蛋白水解酶通过MAP激酶级联传递差异信号。此外，PI3K/Akt抑制PAR1和PAR2诱导的趋化因子的产生，从而维持HOK的天然免疫应答平衡。我们的研究结果为了解PAR激活的信号通路提供了新的视角。
Protease-Activated Receptors (PARs), members of G-protein-coupled receptors, are activated by proteolytic activity of various proteases. Activation of PAR1 and PAR2 triggers innate immune responses in human oral keratinocytes (HOKs), but the signaling pathways downstream of PAR activation in HOKs have not been clearly defined. In this study, we aimed to determine if PAR1- and PAR2-mediated signaling differs in the induction of innate immune markers CXCL3, CXCL5 and CCL20 via ERK, p38 and PI3K/Akt. Our data show the induction of innate immunity by PAR1 requires both p38 and ERK MAP kinases, while PAR2 prominently signals via p38. However, inhibition of PI3K enhances expression of innate immune markers predominantly via suppressing p38 phosphorylation signaled by PAR activation. Our data indicate that proteases mediating PAR1 and PAR2 activation differentially signal via MAP kinase cascades. In addition, the production of chemokines induced by PAR1 and PAR2 is suppressed by PI3K/Akt, thus keeping the innate immune responses of HOK in balance. The results of our study provide a novel insight into signaling pathways involved in PAR activation.
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