KLF2 monocyte activation and vascular inflammation

KLF2单核细胞活化与血管炎症

• 批准号: 7621025
• 负责人: MUKESH Kumar JAIN
• 金额: $ 38.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7621025
• 关键词: Acute; Adhesions; Animals; Arterial Fatty Streak; Atherosclerosis; Biology; CCAAT-Enhancer-Binding Proteins; Carotid Endarterectomy; Carrageenan; Cell Line; Cells; Cellular biology; Characteristics; Chronic; Complex; Coronary Arteriosclerosis; Development; Disease; Edema; Endothelial Cells; Enzymes; Foundations; Gene Expression; Histone Acetylation; Human; Immunodeficient Mouse; In Vitro; Infiltration; Inflammation; Inflammatory; Investigation; Lesion; Lipids; Lipopolysaccharides; Macrophage Activation; Mediating; Modeling; Molecular; Mus; NF-kappa B; PCAF gene; Pathway interactions; Patients; Phase; Phosphorylation; Research Personnel; Role; Small Interfering RNA; Stimulus; T-Cell Activation; T-Lymphocyte; Techniques; Therapeutic; Tissues; Transcription Factor AP-1; Viral; Zinc Fingers; base; chemokine; chromatin immunoprecipitation; cytokine; in vivo; insight; interest; macrophage; migration; monocyte; novel strategies; overexpression; programs; reconstitution; serial analysis of gene expression; transcription factor; uptake; vascular inflammation

DESCRIPTION (provided by applicant): The infiltration and accumulation of monocytes/macrophages is a characteristic feature seen in a number of chronic inflammatory disease states such as atherosclerosis. With respect to latter, activated macrophages have been identified in every phase of the atherosclerotic lesions development-from earliest lesion termed the fatty streak to the mature and obstructive plaque. Therefore, identification of the molecular mechanisms regulating macrophage activation is of considerable scientific and therapeutic interest. The Kruppel-like Factor 2 (KLF2) is a zinc-finger transcription factor implicated in endothelial cell pro-inflammatory activation and T cell quiescence. Studies comparing the in vivo transcriptomes of monocytes purified from patients undergoing carotid endarterectomy and normal subjects by using the serial analysis of gene expression technique revealed that (1) KLF2 is expressed in human monocytes and (2) that expression is reduced in patients with coronary artery disease. Consistent with this observation, in vitro studies confirm that KLF2 expression in primary human monocytes and monocytic cell lines is reduced with activation. Adenoviral overexpression of KLF2 inhibits the lipopolysaccharide (LPS)-mediated induction of pro- inflammatory factors, cytokines, and chemokines. Conversely, siRNA mediated knockdown of KLF2 enhances pro-inflammatory gene expression. Finally, reconstitution of immunodeficient mice with KLF2 overexpressing monocytes significantly reduced carrageenan-induced acute paw inflammation and edema. Mechanistically, our studies indicate that KLF2 inhibits the key pro-inflammatory regulator NF-kB. On the basis of these observations, we hypothesize that KLF2 may serve as a negative regulator of monocyte/macrophage activation. The studies outlined in this proposal will (1) examine the effect of KLF2 overexpression and deficiency on monocyte/macrophage functions in vitro, (2) explore the molecular basis for KLF2's ability to inhibit key pro-inflammatory pathways, and (3) explore the effect of KLF2 overexpression on acute and chronic models of inflammation. The results of these investigations will provide considerable insight regarding the role of KLF2 as a regulator of macrophage activation. Furthermore, these results may provide a foundation for novel strategies to limit macrophage activation and inflammation.

描述（由申请人提供）：单核细胞/巨噬细胞的浸润和积累是在许多慢性炎性疾病状态（如动脉粥样硬化状态）中看到的一个特征。关于后者，在最早的病变中，在动脉粥样硬化病变的每个阶段都发现了活化的巨噬细胞，该病变将脂肪条纹称为成熟和阻塞性斑块。因此，鉴定调节巨噬细胞激活的分子机制具有相当大的科学和治疗兴趣。 Kruppel样因子2（KLF2）是一种锌指转录因子，与内皮细胞促炎性激活和T细胞静止有关。通过使用基因表达技术的串行分析，比较了接受颈动脉内膜切除术和正常受试者的单核细胞体内转录组的研究，表明（1）KLF2在人类单核细胞中表达，（2）冠状动脉疾病患者的表达降低。与这一观察结果一致，体外研究证实，原代人单核细胞和单核细胞系中的KLF2表达会随着激活而降低。 KLF2的腺病毒过表达抑制了脂多糖（LPS）介导的炎性因子，细胞因子和趋化因子的诱导。相反，siRNA介导的KLF2敲低增强了促炎基因表达。最后，用KLF2过表达的单核细胞重建免疫缺陷的小鼠可显着降低角叉菜胶诱导的急性PAW炎症和水肿。从机械上讲，我们的研究表明KLF2抑制了关键的促炎调节剂NF-KB。根据这些观察结果，我们假设KLF2可以作为单核细胞/巨噬细胞激活的负调节剂。该提案中概述的研究将（1）研究KLF2过表达和缺乏对单核细胞/巨噬细胞功能的影响，（2）探索KLF2抑制关键关键促炎途径的能力的分子基础，以及（3）探索KLF2过表达对急性和循环模型的影响。这些研究的结果将为KLF2作为巨噬细胞激活的调节剂的作用提供大量见解。此外，这些结果可能为限制巨噬细胞激活和炎症的新策略提供了基础。