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Role for Lipids in the Maintenance of Chemokine and T-Cell Receptor Signaling

脂质在维持趋化因子和 T 细胞受体信号传导中的作用

基本信息

批准号：
7732321
负责人：
DENNIS D. TAUB
金额：
$ 8.5万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
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/7732321
关键词：
Actins Affinity Anti-Inflammatory Agents Anti-inflammatory Antibodies Attention Binding Biology CCL4 gene CCR5 gene CXCL12 gene CXCR4 Receptors CXCR4 gene Cell Surface Proteins Cell Surface Receptors Cell membrane Cell surface Cells Cellular biology Chemotactic Factors Cholesterol Chronic Class Classification Collection Data Dexamethasone Disease Epitopes Event Family G-Protein-Coupled Receptors GPI Membrane Anchors Giant Cells Glucocorticoid Receptor Glucocorticoids Growth Factor Receptors HIV Hormones Human Hypersensitivity Immigration Immune Immunosuppressive Agents Inflammatory Ligand Binding Ligands Ligation Lipids Lymphocyte Activation Maintenance Mediating Mediator of activation protein Membrane Microdomains Molecular Conformation Natural regeneration Neurons Numbers PTPRC gene Phosphorylation Play Population Proteins RNA Interference Receptor Signaling Recruitment Activity Reporting Rest Role Signal Transduction Signaling Molecule Sphingolipids Stream T Cell Receptor Signaling Pathway T-Cell Receptor T-Lymphocyte Technology Time Today Virus age related beta-Cyclodextrins betadex cell motility cell type chemokine chemokine receptor cytokine flotillin insight macrophage member non-genomic oxidation polymerization receptor response trafficking virus tropism

项目摘要

Lipid rafts play an important role in signal integration and cellular activation of a number of cytokine and growth factor receptors. Flotillin proteins have recently been shown to be recruited to lipid raft microdomains upon cellular activation and have been implicated in neural cell regeneration, receptor signaling and lymphocyte activation. However, little is known about the relevance of the flotillin proteins in T cell responses to chemoattractant stimulation. To this end, cytoplasmic and lipid raft fractions from human T cells were analyzed for flotillin protein redistribution prior to and after CXCL12 stimulation. Flotillin-1 but not flotillin-2 redistributes to lipid rafts upon CXCR4 ligation. Moreover, in CXCL12-treated T cells, flotillin-1 also associates with several raft proteins including LAT, Lck, CD48 and CD11a. In addition, an increase in CXCR4 association with flotillin-1 in lipid rafts was observed after chemokine treatment. RNAi technology was also utilized to inhibit the expression of flotillin-1 resulting in an inhibition of CXCL12-mediated signaling, function and CXCR4 recruitment into lipid rafts. Together, these data suggest that the association of flotillin-1 with lipid raft during chemokine exposure may play an important role in chemokine receptor recruitment to and signaling in lipid rafts and possibly in leading edge formation. Overall, we believe that a greater understanding of the various signaling and cell surface proteins associated with lipid rafts may provide insight into age-related alterations in cell signaling and trafficking. Additional studies have also revealed that dexamethasone (DM)-treated T cells demonstrate enhanced migration in response to the chemokine CXCL12, possibly through altering the cell membranes and rafts or through direct interaction with the chemokine and T-cell receptor signaling pathways. DM is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly utilized to treat chronic inflammatory disorders, severe allergies and other disease states. While glucocorticoids are known to mediate well-defined transcriptional effects via GC receptors, there is increasing evidence that GCs also initiate rapid non-genomic signaling events in a variety of cell types. Here, we report that dexamethasone appears to induce the phosphorylation of Lck and the activation of other down stream mediators including p59Fyn, Zap70, Rac1 and Vav in resting but not activated human T cells. DM treatment also appears to augment CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4 resulting in the enhanced actin polymerization and cell migration upon ligand exposure. Lck was found to be a critical intermediate in these DM-induced signaling activities. Moreover, DM-mediated Lck phosphorylation in T cells was dependent on the presence of both the glucocorticoid receptor and the CD45 molecule. Overall, these results elucidate additional non-genomic effects of DM on resting human T cells, inducing Lck activation and augmenting chemokine signaling and function.

脂筏在多种细胞因子和生长因子受体的信号整合和细胞激活中发挥重要作用。最近发现，Flotillin蛋白在细胞激活时被招募到脂筏微域，并与神经细胞再生、受体信号转导和淋巴细胞激活有关。然而，关于Flotillin蛋白在T细胞对化学诱导剂刺激的反应中的相关性，人们知之甚少。为此，我们分析了CXCL12刺激前后人T细胞胞浆和脂筏部分的Flotillin蛋白再分布情况。当CXCR4结扎时，Flotillin-1而不是Flotillin-2重新分布到脂筏上。此外，在CXCL12处理的T细胞中，Flotillin-1还与LAT、Lck、CD48和CD11a等多种RAFT蛋白结合。此外，经趋化因子治疗后，脂筏中CXCR4与Flotillin-1的相关性增加。RNAi技术也被用来抑制Flotillin-1的表达，从而抑制CXCL12介导的信号、功能和CXCR4在脂筏中的募集。综上所述，这些数据表明，在趋化因子暴露期间，fltillin-1与脂筏的联系可能在趋化因子受体在脂筏中的募集和信号传递中发挥重要作用，并可能在前沿的形成中发挥重要作用。总体而言，我们认为，更好地了解与脂筏相关的各种信号和细胞表面蛋白可能有助于洞察细胞信号和运输中与年龄相关的变化。其他研究也表明，地塞米松(DM)处理的T细胞对趋化因子CXCL12的反应表现出增强的迁移，可能是通过改变细胞膜和筏子，或者通过与趋化因子和T细胞受体信号通路的直接相互作用。糖尿病是糖皮质激素(GC)类激素的合成成员，具有抗炎和免疫抑制活性，通常用于治疗慢性炎症性疾病、严重过敏和其他疾病状态。虽然已知糖皮质激素通过GC受体介导明确的转录效应，但越来越多的证据表明，GC也在各种类型的细胞中启动快速的非基因组信号事件。在这里，我们报告地塞米松似乎诱导静息但不激活的人T细胞中Lck的磷酸化和其他下游介质的激活，包括p59Fyn，ZAP70，rac1和Vav。DM治疗似乎还通过其细胞表面受体CXCR4增强CXCL12介导的静息T细胞信号传递，从而在配体暴露时促进肌动蛋白聚合和细胞迁移。在DM诱导的这些信号活动中，LCK被发现是一个关键的中间体。此外，DM介导的T细胞Lck磷酸化依赖于糖皮质激素受体和CD45分子的存在。总体而言，这些结果阐明了DM对静息的人类T细胞、诱导LCK激活和增强趋化因子信号和功能的额外非基因组效应。