Chemokines Induce Wnt-Frizzled Gene Expression in Human T Cells

趋化因子在体外和体内都能诱导和指导人和啮齿动物白细胞的黏附、趋化、激活和脱颗粒。CXCL12和CCL19是两种重要的趋化因子，在正常和炎症条件下调节T细胞的运动和激活。尽管有许多研究趋化因子功能的报道，但对其中涉及的转录事件知之甚少。我们最近对CXCL12和CCL19处理的T细胞进行了微阵列分析，发现Wnt蛋白家族在CXCL12处理过程中显著上调。在CXCL12的研究中，我们发现在T细胞的配体刺激过程中，Wnt5A和其他非典范Wnt途径成员的表达特异性上调，而β-连环素和典型Wnt家族成员的表达选择性下调。研究发现，WNT5A通过激活蛋白激酶C(PKC)，通过CXCL12-CXCR4轴增强信号传导。此外，我们的数据显示，在CXCL12的反应中，Wnt5A的表达是介导T细胞定向迁移所必需的，并且重组Wnt5A处理人T细胞会使T细胞对CXCL12诱导的迁移敏感。此外，CXCR4在转录和翻译上的持续表达也需要Wnt5A的表达。有趣的是，在CCL19处理的T细胞中，我们发现Wnt10A而不是Wnt5A在CCL19介导的趋化作用和维持T细胞上CCR7的表达方面发挥作用。这项工作最近已经完成，关于这些数据的手稿也已经完成。这些发现可能揭示了多种趋化因子与Wnt受体和配体之间的新的合作信号网络，该网络可能控制细胞极化和定向迁移。此外，内源性Wnt途径调节因子Klotho的功能作用目前也在研究中。 此外，在这些研究中，我们还验证和表征了其他几个基因家族，这些基因家族在T细胞迁移后高表达，对CXCL12、CCL19、gp120和HIV-1病毒的反应或简单刺激。此外，脂筏在趋化因子生物学和艾滋病毒感染性中的作用也正在通过微阵列分析进行检查。更好地理解不同趋化因子受体连接诱导的转录信号可能提供一种手段来剖析这些趋化因子诱导细胞迁移和激活的途径，以及任何在HIV进入和复制中重要的宿主转录信号。

Chemokines have been shown to induce and direct adhesion, chemotaxis, activation, and degranulation of human and rodent leukocytes both in vitro and in vivo. CXCL12 and CCL19 are two important chemokines that regulate T cell motility and activation under normal and inflammatory conditions. Despite numerous reports examining the function of chemokines, little is known about the transcriptional events involved therein. We have recently performed microarray analysis on CXCL12- and CCL19-treated T-cells, and found that the Wnt family of proteins was significantly upregulated during CXCL12 treatment. In the CXCL12 studies, we found that the expression of Wnt5A and other members of the non-canonical Wnt pathway were specifically upregulated during ligand stimulation of T cells, while beta-catenin and canonical Wnt family members were selectively downregulated. Wnt5A was found to augment signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C (PKC). Moreover, our data has revealed that Wnt5A expression is required to mediate directional T-cell migration in response to CXCL12, and that the treatment of human T-cells with recombinant Wnt5A sensitized T-cells to CXCL12-induced migration. Furthermore,Wnt5A expression was also required for the sustained expression of CXCR4, both transcriptionally and translationally. Interestingly, in CCL19-treated T cells, we found that Wnt10A, not Wnt5A plays a role in CCL19-mediated chemotaxis and in the maintenance of CCR7 expression on T cells. This work has recently been completed and a manuscript on these data has been completed. These findings may reveal a novel cooperative signaling network between various chemokine and Wnt receptors and ligands that may control cell polarization and directional migration. Also, the functional role of the endogenous Wnt pathway regulator, Klotho, is also currently being examined. Moreover, under these studies, we have also been verifying and characterizing several additional gene families that are highly expressed in T cells after migration in response to or simply stimulation with CXCL12, CCL19, gp120 and HIV-1 virus. Moreover, the role of lipid rafts in chemokine biology and HIV infectivity are also under examination using microarray analysis. A greater understanding of the transcriptional signals differentially induced by the ligation of various chemokine receptors may provide a means to dissect the pathways by which these chemoattractants induce cell migration and activation as well as any host transcriptional signals important in HIV entry and replication.