HUMAN COMPLEMENT C5A--INFLAMMATION AND IMMUNOMODULATION

人类补体 C5A——炎症和免疫调节

• 批准号: 2067403
• 负责人: EDWARD L. MORGAN
• 金额: $ 18.23万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2067403
• 关键词: RNase protection assay; T lymphocyte; antireceptor antibody; cell population study; complement; complement receptor; cytokine; enzyme linked immunosorbent assay; human tissue; immunoregulation; inflammation; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; mixed lymphocyte reaction test; monocyte; northern blottings; protein biosynthesis; receptor expression; tissue /cell culture; transfection

Human, porcine, and murine complement (C') fragment C5a has been shown to be both a potent inflammatory agent and more recently, a modifier of in vitro and in vivo immune responses. Besides the well characterized proinflammatory potential of C5a, this C' component enhance both in vitro humoral and cell-mediated immune (CMI) responses. Human C5a has been reported to induce the synthesis of important cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor- alpha (TNF-alpha), which are known to play key roles as mediators of immune reactivity. In addition, the recent cloning of PMN chemotactic factor (interleukin-8; IL-8) and its demonstrated importance in the inflammatory process makes IL-8 along with IL-1, IL-6, and TNF-alpha likely candidates for involvement in C5a-mediated biological activity. The induction of cytokine synthesis by C5a is a controversial point. It has been suggested that a synergy between low levels of endotoxin (ET) and C5a is responsible for the observed effects. This initial cell "priming" event may be necessary for the expression of C5a receptors (C5aR) on the appropriate cell population(s) prior to C5a exerting its modulatory effects. the possibility of a synergy between ET and C5a in vivo, although unproven, is appealing since this may represent a positive feed back mechanism that could result in an amplification of the immune response to invading pathogens. The major hypothesis in this proposal is that the proinflammatory and immunoregulatory activities associated with human C5a are due in part to the synthesis and action of multiple cytokines. the importance of C5a as a mediator of inflammation and its potential role in normal and aberrant immune function necessitates the elucidation of the complete mechanism of action of this C' fragment. In this proposal we will address the mechanism(s) of C5a-mediated immunoregulation and inflammation on the cellular and molecular levels. Specific questions asked include: 1) Which cell populations are stimulated by C5a to secrete cytokines and what is the cytokine profile produced by these cell populations?; 2) Is the expression of the C5a receptor on monocytes and lymphocytes a constitutive or inducible event?; 3) Are cytokines involved in C5a-mediated enhancement of T cell activation?; 4) What is the role of cell "priming" in the C5a-mediated immunoenhancement?; and 6) Will modulation of C5a receptor expression suppress C5a-mediated immunoenhancement and inflammation?

已经显示了人，猪和鼠补体（C'）片段C5a 既是一种有效的炎症剂，又是最近， 体外和体内免疫反应。 除了良好的特征 C5a的促炎潜力，该C'成分在体外增强了 体液和细胞介导的免疫（CMI）反应。 人C5a一直 据报道诱导重要的细胞因子（例如 白介素1（IL-1），白介素6（IL-6）和肿瘤坏死因子 - alpha（TNF-alpha），众所周知，它是作为介体的关键角色 免疫反应性。 另外，PMN趋化的最近克隆 因子（白介素8; IL-8）及其在 炎症过程与IL-1，IL-6和TNF-alpha一起制造IL-8 可能参与C5A介导的生物学活性的候选者。 C5A诱导细胞因子合成是一个有争议的点。 它 已经提出，低水平的内毒素（ET）之间的协同作用 C5a负责观察到的效果。 这个初始单元 “启动”事件对于表达C5a受体可能是必需的 （C5AR）在适当的细胞群体上施加C5A之前 调节作用。 ET和C5A之间的协同作用的可能性 体内虽然未经证实，但很有吸引力，因为这可能代表了积极的 反馈机制，可能导致免疫扩增 对入侵病原体的反应。 该提议中的主要假设是促炎和 与人C5A相关的免疫调节活动部分是由于 多种细胞因子的合成和作用。 C5A的重要性 作为炎症的调解人及其在正常和 异常免疫功能需要阐明完整 该C片段的作用机理。 在此提案中，我们将解决C5A介导的机制 细胞和分子水平上的免疫调节和炎症。 提出的具体问题包括：1）哪些细胞种群是 由C5A刺激以分泌细胞因子，什么是细胞因子谱 这些细胞群体产生？ 2）是C5a的表达 单核细胞和淋巴细胞上的受体或可诱导的受体 事件？; 3）参与C5A介导的T细胞增强的细胞因子 激活？; 4）细胞在C5a介导的“启动”的作用是什么 免疫原？ 6）将调节C5a受体表达 抑制C5A介导的免疫原质和炎症？