ROLE OF ENDOGENOUS LEUKOTRIENE PRODUCTION IN LYMPHOCYTE

本建议的目的是确定以下方面的作用： 花生四烯酸的白三烯和其它脂氧合酶代谢物 酸在人T细胞活化和增殖中的作用 大部分 这项工作包括精确定义花生四烯酸 代谢物由T细胞产生。 我和我的同事最近 发现外源花生四烯酸在很大程度上 有些病例完全抑制白三烯B4（LTB 4）的产生， 有丝分裂原刺激的T细胞。 由于所有先前发表的研究 对T细胞花生四烯酸代谢的影响包括加入 外源花生四烯酸的培养基，这就要求 在普遍接受的概念中，T细胞不 主要代谢花生四烯酸。我们的初步 结果表明，LTB 4是花生四烯酸的主要代谢产物 的T细胞。 在这项研究中，我将试图描述所有 人T细胞和T细胞系的花生四烯酸代谢 使用高效液相色谱法（HPLC）， 放射免疫测定（RIA）。 T细胞会受到各种刺激 包括有丝分裂原，抗原，钙离子载体， 白细胞介素1（IL-1）和IL-2。 单核细胞衍生因子的作用 还将评估LTB 4在T细胞中的产生。 我还将继续初步研究 内源性LTB 4在T细胞增殖中的作用。 初步结果 在提案中描述的强烈建议，内源性LTB 4 产生是T细胞增殖的必要组成部分， 对有丝分裂原的反应。 LTB 4是植物血凝素所必需的 (PHA)诱导IL-2的产生，但它也可能在 活化的T细胞对IL-2的反应。 未来的研究将探讨 LTB 4产生、IL-2产生 和T细胞增殖响应于不同的刺激，包括 所谓的IL-2非依赖性有丝分裂原。 两种人类外周 血液T细胞和多种人和鼠T细胞系将 用于这些实验。

The purpose of this proposal is to determine the role of leukotrienes and other lipoxygenase metabolites of arachidonc acid in human T cell activation and proliferation. Most of the work involves defining precisely what arachidonic acid metabolites are produced by T cells. I and my coworkers recently discovered that exogenous arachidonic acid substantially and in some cases totally inhibits leukotriene B4 (LTB4) production by mitogenstimulated T cells. Since all previously published studies on arachidonic acid metabolism of T cells included the addition of exogenous arachidonic acid to the culture media, this calls into question in generally accepted concept that T cells do not metabolize arachidonic acid in a major way. Our preliminary results show that LTB4 is the major arachidonic acid metabolize of T cells. In this study, I will attempt to characterize all arachidonic acid metabolities of human T cells and T cell lines using high performance liquid chromatography (HPLC) and radioimmunoassays (RIAs). T cells will be stimulated by a variety of compounds including mitogens, antigens, calcium ionophores, interleukin 1 (IL-1) and IL-2. The role of moncyte derived factors in T cell production of LTB4 will also be assessed. I will also continue my preliminary studies on the precise role of endogenous LTB4 in T cell proliferation. Preliminary results described in the proposal strongly suggest that endogenous LTB4 production is a necessary component of T cell proliferation in response to mitogens. LTB4 is necessary for phytohemagglutinin (PHA) induced IL-2 production, but it may also have a role in the response of activated T cells to IL-2. Future studies will examine the precise relationship between LTB4 production, IL-2 production and T cell proliferation in response to different stimuli, including so-called IL-2 independent mitogens. Both human peripheral blood T cells and a variety of human and murine T cell lines will be used in these experiments.