Chemokines Induce Wnt-Frizzled Gene Expression in Human T Cells

趋化因子诱导人类 T 细胞中 Wnt 卷曲基因表达

• 批准号: 8335923
• 负责人: DENNIS D. TAUB
• 金额: $ 34.5万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335923
• 关键词: Activated B-Lymphocyte; Adhesions; Adrenal Glands; Binding; Biology; Bone Marrow; CCL19 gene; CXCL12 gene; CXCR4 gene; Cells; Cellular biology; Chemotactic Factors; Chemotaxis; Data; Development; Event; Family member; GTP-Binding Proteins; Gene Expression; Gene Family; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV-1; Human; Immigration; Immune; In Vitro; Inflammation; Inflammatory; Leukocytes; Ligands; Ligation; Liver; Lung; Maintenance; Manuscripts; Mediating; Membrane Microdomains; Microarray Analysis; Organogenesis; Pathway interactions; Play; Protein Family; Protein Kinase C; Receptor Activation; Receptor Signaling; Recombinants; Reporting; Rest; Rodent; Role; Signal Pathway; Signal Transduction; Stream; Structure; Surface; System; T-Lymphocyte; Thymus Gland; Time; Tissues; Virus; Wnt proteins; Work; beta catenin; blastomere structure; cell motility; cell type; chemokine; chemokine receptor; in vivo; lymph nodes; member; migration; novel; receptor; receptor expression; response; seven-transmembrane G-protein-coupled receptor; trafficking

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.

趋化因子在体外和体内均可诱导和指导人类和啮齿动物白细胞的粘附、趋化、激活和脱颗粒。CXCL12和CCL19是两个重要的趋化因子，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告，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家族蛋白在CXCL12处理期间显著上调。在CXCL12研究中，我们发现在配体刺激T细胞时，Wnt5A和其他非典型Wnt通路成员的表达被特异性上调，而β -catenin和典型Wnt家族成员的表达被选择性下调。发现Wnt5A通过激活蛋白激酶C （PKC）增强CXCL12-CXCR4轴的信号传导。此外，我们的数据显示，Wnt5A表达是介导t细胞定向迁移以响应CXCL12的必要条件，并且重组Wnt5A处理人t细胞使t细胞对CXCL12诱导的迁移敏感。此外，Wnt5A的表达也是CXCR4在转录和翻译上持续表达所必需的。有趣的是，在ccl19处理的T细胞中，我们发现Wnt10A而不是Wnt5A在ccl19介导的趋化和维持CCR7在T细胞上的表达中起作用。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多种趋化因子和Wnt受体及配体之间的新型合作信号网络，可能控制细胞极化和定向迁移。此外，内源性Wnt通路调节因子Klotho的功能作用也正在研究中。