Cytokine Production In Phagocytosis of Apoptotic Cells

凋亡细胞吞噬作用中细胞因子的产生

• 批准号: 6818993
• 负责人: XIAOJING MA
• 金额: $ 33.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818993
• 关键词: DNA footprinting; RNA interference; apoptosis; biological signal transduction; cell line; cell surface receptors; chemical stability; chromatin immunoprecipitation; clinical research; enzyme activity; gene expression; genetic regulation; genetic translation; human subject; immunoregulation; interleukin 10; interleukin 12; laboratory mouse; macrophage; microarray technology; mitogen activated protein kinase; phagocytosis; phosphatidylserines; phosphorylation; posttranslational modifications; protein biosynthesis; transcription factor

DESCRIPTION (provided by applicant): Apoptosis and the rapid clearance of apoptotic cells by professional phagocytes are normal and coordinated processes that ensure controlled cell growth with non-pathological outcomes. Defects in clearance of apoptotic cells have serious consequences by engendering persistent self-antigens and triggering the production of proinflammatory cytokines, resulting in the generation of autoreactive lymphocytes that drive autoimmune disorders. Phosphatidylserine (PS) exposed on dying cells and its interaction with certain phagocytic receptors are essential for the uptake of apoptotic cells by phagocytes. Interleukin-12 (IL-12) is a proinflammatory cytokine produced by phagocytic cells and plays a critical role in the activation and function of antigen-presenting cells and effector lymphocytes during microbial infection. Interleukin-10 (IL-10) is a pivotal homeostatic regulator of immune reactivity. Both IL-12 and IL-10 have been strongly implicated as effector cytokines in the pathogenesis of autoimmune disorders. The production of IL-12 and IL-10 by phagocytic and antigen-presenting cells is regulated in opposite manners following the ingestion of apoptotic cells. How apoptotic cell-derived signals regulate IL-12 and IL-10 production is not understood. Recent evidence generated by our group indicates that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression through a novel zinc finger transcriptional repressor, GC-BP, and in the activation of IL-10 expression at the transcriptional level while it inhibits IL-12 p40 post-transcriptionally. We propose to elucidate the molecular mechanisms that control the cytokine responses during phagocyte-mediated clearance of apoptotic cells. I. To investigate how apoptotic cell-derived signals regulate the synthesis of IL-12 p40 at post- transcriptional levels. II. To investigate the expression, activation and function of the transcription repressor GC-BP during phagocytosis of apoptotic cells. III. To investigate the transcriptional mechanisms whereby IL-10 gene expression is regulated during phagocytosis of apoptotic cells. The long-term goal of this project is to understand the regulation of cytokine production in normal and pathological processes of dead cell removal. The knowledge gained will be beneficial to efforts to control dysregulated host responses in infection, autoimmunity, graft-versus-host disease, and cancer.

描述（由申请人提供）：专业吞噬细胞对凋亡细胞的凋亡和快速清除率是正常的和协调的过程，可确保通过非病理结果受控的细胞生长。清除凋亡细胞的缺陷通过产生持续的自我抗原并触发促炎性细胞因子的产生，从而产生严重的后果，从而导致自动反应性淋巴细胞的产生，从而驱动自身免疫性疾病。暴露于垂死细胞上的磷脂酰丝氨酸（PS）及其与某些吞噬受体的相互作用对于吞噬细胞摄取凋亡细胞至关重要。白介素12（IL-12）是吞噬细胞产生的促炎细胞因子，在微生物感染过程中在抗原呈递细胞的激活和功能和效应淋巴细胞中起关键作用。白介素10（IL-10）是免疫反应性的关键稳态调节剂。 IL-12和IL-10都在自身免疫性疾病的发病机理中均已强烈地作为效应细胞因子。吞噬凋亡细胞后，通过吞噬细胞和抗原呈递细胞的产生IL-12和IL-10。凋亡细胞衍生的信号如何调节IL-12和IL-10的产生。我们小组产生的最新证据表明，通过活化的巨噬细胞对凋亡细胞的吞噬作用会通过一种新型的锌指转录抑制剂GC-BP，以及在转录水平激活IL-10表达，导致IL-12的新型锌指转录器GC-BP对IL-12 p35基因表达的强烈抑制。 我们建议阐明吞噬细胞介导的凋亡细胞清除期间控制细胞因子反应的分子机制。 I.研究凋亡细胞衍生的信号如何在转录后水平调节IL-12 p40的合成。 ii。研究凋亡细胞吞噬过程中转录阻遏物GC-BP的表达，激活和功能。 iii。为了研究凋亡细胞吞噬过程中IL-10基因表达的转录机制。 该项目的长期目标是了解在去除死细胞的正常和病理过程中细胞因子产生的调节。获得的知识将有助于控制失调的宿主反应，自身免疫性，移植物抗宿主病和癌症。