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肿瘤的发生发展中起着关键作用。 免疫功能的正常稳态。TGF-β 1是主要的 炎症反应的负调节因子。我们早些时候 产生的TGF-β 1缺失小鼠表现出多灶性炎症， 与白细胞对内皮细胞的粘附增加有关， MHC I类和II类抗原的异常表达，和 类似于干燥综合征的自身免疫表现。此外，委员会认为， 去除CD 8细胞改善TGF-β 1缺失的健康状况 小鼠为了阐明TGF-β 1在异常MHC表达中的作用， 在MHC-I和MHC-II中产生TGF-β 1敲除小鼠 缺乏背景。TGF-β 1 X MHC-I无效小鼠表现出 与减少炎症相关的寿命增加， 减少自身免疫性表现和显著升高 骨髓生成虽然TGF-β 1 × MHC-II小鼠表现出缺乏 炎症和自身免疫反应，他们显示新生儿 与骨髓生成和化生增加相关的死亡率。 这些结果表明，TGF-β 1在白细胞中起主导作用， 成熟和功能。巨噬细胞移动抑制因子 (MIF)是脑垂体前叶的主要蛋白质成分 内毒素血症时释放到血液中多年来， MIF一直被认为是一种T细胞产物， 迟发型超敏反应。将MIF鉴定为 脑垂体“应激”激素提供了 中枢神经系统调节全身炎症反应。 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， G 0阶段。为了阐明MIF在体内的确切作用，我们 启动了靶向重组，以产生MIF空 小鼠在产生ES细胞克隆的过程中， 破坏MIF基因，我们发现异常重组克隆。 对这些克隆的详细分析揭示了特定的序列基序 会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对齐， 四聚体（5 ′-AAGG/TTCC 3 ′），拓扑异构酶I共有位点， 和富含AT的序列，其可以促进DNA切割， 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2kb。之一 重组发生在该IAP的长末端重复序列附近 顺序这些序列基序可能会影响有计划的破坏， 这个遗传位点及其特征将有助于描绘 重组机制。