REGULATION OF IL 12 PRODUCTION BY BETA 2 INTEGRINS

Beta 2 整合素对 IL 12 产生的调节

• 批准号: 6288991
• 负责人: BRIAN KELSALL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/6288991
• 关键词: cellular immunity; clinical research; complement receptor; human subject; integrins; interferon gamma; interleukin 12; laboratory mouse; microorganism immunology; monocyte; neutrophil; protein biosynthesis; tissue /cell culture

The broad purpose of this work is to further understand how microorganisms through their interaction with antigen presenting cells, such as macrophages and dendritic cells, affect the generation of T cell mediated immune responses via their ability to regulate the production of critical cytokines, such as IL-12 and IL-10. We initially studied the role of complement receptor 3 (CR3, CD11b/CD18) in regulation of IL-12 production from human monocytes. We determined that signaling via CR3, which serves as a receptor for a number of infectious organisms and endogenous molecules, such as the complement fragment opsonin iC3b, suppresses the ability of human monocytes to make IL-12 in response to known IL-12 stimuli. These studies established a novel role for CR3 in regulating cell mediated immune responses via its ability to regulate the production of IL-12, and suggest that organisms that bind to CR3 in either a complement- dependent or independent fashion have evolved to take advantage of this pathway to avoid the induction of IL-12 dependent T helper 1 (Th1) immune responses that are important for host defenses. Since these initial findings, we have focused our work on understanding the mechanism and relevance of CR3-mediated suppression of IL-12 production, and on how these findings relate to other newly defined signals for the regulation of IL-12 production in humans. These studies involve defining the relevant CR3-mediated intracellular signals and their effects on transcription factors that regulate IL-12 gene transcription, determining IL-12 production from cells of patients with a genetic defect in beta2-integrin expression (leukocyte adhesion deficiency), and examining the role of CR3 activation on IL-12 production in vitro. A second aspect of this project involves the ability of molecules that signal via G-protein coupled receptors to affect the production of IL-12 from human cells. The purpose of these studies is to define endogenous factors that regulate IL-12 production during normal and abnormal immune responses in vivo, and to determine whether novel therapeutic agents for autoimmune or infectious diseases can be developed based on this information. We initially determined that cholera toxin, which activates Gs-mediated signaling can suppress IL-12 production from monocytes and dendritic cells. We now have defined a series of chemokines that can also suppress IL-12 production via a mechanism that involves the activation of Gi-mediated signaling. - Integrin, IL-12, chemokine, G-protein, cholera toxin, complement, Th1, Th2, autoimmunity, CD18 - Human Subjects

这项工作的广泛目的是进一步了解微生物如何通过它们与抗原呈递细胞（如巨噬细胞和树突细胞）的相互作用，通过它们调节关键细胞因子（如IL-12和IL-10）的产生的能力影响T细胞介导的免疫应答的产生。我们首先研究了补体受体3（CR 3，CD 11b/CD 18）在调节人单核细胞产生IL-12中的作用。我们确定了通过CR 3的信号传导，CR 3作为许多感染性生物体和内源性分子的受体，如补体片段调理素iC 3b，抑制人单核细胞响应已知IL-12刺激产生IL-12的能力。这些研究确立了CR 3通过其调节IL-12产生的能力来调节细胞介导的免疫反应的新作用，并表明以补体依赖性或独立方式结合CR 3的生物体已经进化到利用这一途径来避免诱导IL-12依赖性T辅助细胞1（Th 1）免疫反应，这对于宿主防御很重要。自从这些初步发现以来，我们的工作重点是了解CR 3介导的IL-12产生抑制的机制和相关性，以及这些发现如何与其他新定义的调节人类IL-12产生的信号相关。这些研究涉及定义相关的CR 3介导的细胞内信号及其对调节IL-12基因转录的转录因子的影响，确定β 2-整联蛋白表达遗传缺陷（白细胞粘附缺陷）患者细胞的IL-12产生，并检查CR 3激活对IL-12体外产生的作用。该项目的第二个方面涉及通过G蛋白偶联受体发出信号的分子影响人类细胞产生IL-12的能力。这些研究的目的是确定在体内正常和异常免疫应答期间调节IL-12产生的内源性因子，并确定是否可以基于此信息开发用于自身免疫性疾病或感染性疾病的新型治疗剂。我们最初确定，激活GS介导的信号转导的霍乱毒素可以抑制单核细胞和树突状细胞产生IL-12。我们现在已经定义了一系列趋化因子，它们也可以通过涉及Gi介导的信号转导的激活的机制来抑制IL-12的产生。- 整合素，IL-12，趋化因子，G蛋白，霍乱毒素，补体，Th 1，Th 2，自身免疫，CD 18-人类受试者