Chemokines Induce Wnt-Frizzled Gene Expression in Human T Cells

趋化因子已被证明在体外和体内诱导和指导人和啮齿动物白细胞的粘附、趋化、活化和脱粒。CXCL 12和CCL 19是两种重要的趋化因子，在正常和炎症条件下调节T细胞运动和活化。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CXCL 12和CCL 19处理的T细胞进行了微阵列分析，发现Wnt蛋白家族在CXCL 12处理期间显著上调。在CXCL 12研究中，我们发现在T细胞的配体刺激期间，Wnt 5A和非经典Wnt通路的其他成员的表达特异性上调，而β-连环蛋白和经典Wnt家族成员选择性下调。发现Wnt 5A通过蛋白激酶C（PKC）的活化增强通过CXCL 12-CXCR 4轴的信号传导。此外，我们的数据显示，Wnt 5A表达是介导响应CXCL 12的定向T细胞迁移所必需的，并且用重组Wnt 5A处理人T细胞使T细胞对CXCL 12诱导的迁移敏感。此外，Wnt 5A的表达也需要CXCR 4的持续表达，无论是转录还是转录。有趣的是，在CCL 19处理的T细胞中，我们发现Wnt 10A而不是Wnt 5A在CCL 19介导的趋化性和维持T细胞上CCR 7表达中起作用。 这项工作最近已经完成，关于这些数据的手稿已经完成。 这些发现可能揭示了各种趋化因子与Wnt受体和配体之间的新型合作信号网络，该网络可能控制细胞极化和定向迁移。此外，内源性Wnt途径调节剂Klotho的功能作用目前也正在研究中。 此外，在这些研究中，我们还验证和表征了几个额外的基因家族，这些基因家族在迁移后在T细胞中高度表达，以响应或简单地刺激CXCL 12，CCL 19，gp 120和HIV-1病毒。此外，脂筏在趋化因子生物学和HIV感染性中的作用也正在使用微阵列分析进行检查。 更好地了解不同的转录信号诱导的各种趋化因子受体的连接可能提供一种手段来解剖这些化学引诱剂诱导细胞迁移和激活的途径，以及任何主机的转录信号在HIV的进入和复制的重要。

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.