Cytokines and Growth Factors in Autoimmune Diseases

自身免疫性疾病中的细胞因子和生长因子

• 批准号: 6104673
• 负责人: Ashok B. KULKARNI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 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/6104673
• 关键词: autoimmune disorder; cell cycle; cytokine; genetically modified animals; hematopoiesis; histocompatibility antigens; inflammation; laboratory mouse; macrophage; migration inhibition factor; pituitary hormones; transforming growth factors

Cytokines and growth factors play critical roles in normal homeostasis of immune functions. TGF-'1 is the dominant negative regulator of inflammatory responses. We have earlier generated TGF-'1 null mice that exhibit multifocal inflammation associated with increased adhesion of leukocytes to endothelium, aberrant expression of MHC class-I and -II antigens, and autoimmune manifestations similar to Sjogren syndrome. Moreover, depletion of CD8 cells ameliorated health status of TGF-'1 null mice. To delineate role of TGF-'1 in aberrant MHC expression, TGF-'1 null mice were generated in the MHC-I and MHC-II deficient backgrounds. TGF-'1 X MHC-I null mice exhibit increased longevity associated with reduced inflammation, diminished autoimmune manifestations and significantly elevated myelopoiesis. Although the TGF-'1 X MHC-II mice exhibited lack of inflammation and autoimmune response, they showed neonatal mortality associated with increased myelopoiesis and metaplasia. These results indicate a dominant role of TGF-'1 in leukocyte maturation and function. Macrophage migration inhibitory factor (MIF) is a major protein constituent of the anterior pituitary gland released into the bloodstream during endotoxemia. For many years, MIF had been thought to be a T cell product associated with delayed-type hypersensitivity reactions. The identification of MIF as a pituitary "stress" hormone provides an important link in the regulation of systemic inflammatory responses by CNS. Additionally, there is a compelling evidence that suggests a strong link between MIF and cell cycle suggesting MIF as an inhibitor in G0 phase. In order to delineate the precise role of MIF in vivo, we have initiated targeted recombination for the generation of MIF null mice. During the process of generating ES cell clones that have disrupted MIF gene we found abnormally recombined clones. Detailed analysis of these clones revealed specific sequence motifs that can affect the homologous recombination process. These motifs include short regions of homologous sequence identity that have been shown to promote DNA alignment, a preponderance of tetramers (5'-AAGG/TTCC 3'), topoisomerase I consensus sites, and AT-rich sequences that can promote DNA cleavage and recombination. A retrovirus-like sequence, intracisternal-A particle, is identified 2 kb upstream of the murine MIF gene. One of the recombinations occurred near the long terminal repeat of this IAP sequence. These sequence motifs may affect planned disruption of this genetic locus and their characterization will help to delineate the mechanism of recombination.

细胞因子和生长因子在 免疫功能的正常稳态。 TGF-'1 占主导地位 炎症反应的负调节因子。我们早先有 生成表现出多灶性炎症的 TGF-'1 缺失小鼠 与白细胞与内皮细胞的粘附增加有关， MHC I 类和 II 类抗原的异常表达，以及 自身免疫表现类似于干燥综合征。而且， CD8 细胞的耗竭改善了 TGF-'1 的健康状况 null 老鼠。为了描述 TGF-'1 在异常 MHC 表达中的作用， 在 MHC-I 和 MHC-II 中生成 TGF-'1 缺失小鼠 背景不足。 TGF-'1 X MHC-I 缺失小鼠表现出 与减少炎症相关的寿命延长， 自身免疫表现减弱并显着升高 骨髓生成。尽管 TGF-'1 X MHC-II 小鼠表现出缺乏 炎症和自身免疫反应的影响，他们显示新生儿 死亡率与骨髓生成和化生增加有关。 这些结果表明 TGF-'1 在白细胞中起主导作用 成熟和功能。巨噬细胞迁移抑制因子 (MIF) 是垂体前叶的主要蛋白质成分 内毒素血症期间释放到血液中。多年， MIF 曾被认为是与以下因素相关的 T 细胞产物： 迟发型超敏反应。 MIF 的识别为 垂体“应激”激素在 中枢神经系统对全身炎症反应的调节。 此外，有令人信服的证据表明， MIF 和细胞周期之间的联系表明 MIF 作为抑制剂 G0阶段。为了描述 MIF 在体内的精确作用，我们 已启动靶向重组以生成 MIF null 老鼠。在产生 ES 细胞克隆的过程中， 当MIF基因被破坏时，我们发现了异常重组的克隆。 对这些克隆的详细分析揭示了特定的序列基序 可以影响同源重组过程。这些 基序包括同源序列同一性的短区域 已被证明可以促进 DNA 排列，其中大部分 四聚体（5'-AAGG/TTCC 3'），拓扑异构酶 I 共有位点， 和富含 AT 的序列，可以促进 DNA 切割和 重组。逆转录病毒样序列，脑池内 A 颗粒， 被鉴定为鼠 MIF 基因上游 2 kb。中的一个 重组发生在该 IAP 的长末端重复附近 顺序。这些序列基序可能会影响计划的破坏 该遗传位点及其特征将有助于描绘 重组机制。