EARLY EVENTS IN ACCESSORY CELL ACTIVATION

单核细胞和巨噬细胞功能研究的一个中心挑战是， 免疫系统是了解早期事件， activation. 这些辅助细胞在抗原加工中起主要作用 和呈递，分泌几种有效的多肽因子， 支持T淋巴细胞增殖和活化。 若干第二 信使系统可以传递多种刺激信号， 产生适当的细胞反应，例如产生 特定的早期激活基因产物。 本提案的目的是 为了进一步了解单核细胞/巨噬细胞的激活， 抑制刺激信号的核调节蛋白的研究 并控制早期激活基因的表达。 实验将 关注单核因子白细胞介素1 α（IL-1 α）的表达， 白细胞介素1 β（IL-1 β作为研究早期事件的模型系统 单核细胞活化。 这些重要的免疫调节多肽是 研究早期事件的候选人，因为他们是迅速和 在单核细胞/巨噬细胞刺激后协同表达。 的 这些研究的长期目标是（1）鉴定和纯化 调节IL-1表达的核调节蛋白，（2）评估 这些蛋白质的功能作用，（3）以确定如何巨噬细胞 激活因子如γ干扰素和集落刺激因子 可以通过对这些核蛋白的作用增加IL-1的表达， (4)来研究它们的活动是如何被第二信使信号所调节的 和/或特异性细胞内抑制剂。 这些研究将导致 更好地理解各种刺激信号 被巨噬细胞/单核细胞利用以产生特异性DNA-蛋白质 相互作用，并导致特定的早期事件的启动， activation. 这一信息对于理解 几种自身免疫性和炎症性疾病的病因，可能涉及 单核因子的异常表达 此外，激活 HIV感染的巨噬细胞可导致两种病毒基因的共表达 产品和IL-1，从而了解早期事件，调节 IL-1表达可能揭示HIV感染者的病理变化， 巨噬细胞

A central challenge in the study of monocyte and macrophage function in the immune system is understanding the early events which regulate their activation. These accessory cells play a major role in antigen processing and presentation, the secretion of several potent polypeptide factors, and the support T lymphocyte proliferation and activation. Several second messenger systems may transmit a variety of stimulatory signals in order to generate an appropriate cellular response, such as the production of specific early-activation gene products. The objective of this proposal is to further the understanding of monocyte/macrophage activation through the study of nuclear regulatory proteins which transduce stimulatory signals and control the expression of early-activation genes. Experiments will focus on the expression of the monokines interleukin 1alpha (IL-1alpha) and interleukin 1beta (IL-1beta as a model system for the study of early events in monocyte activation. These important immunoregulatory polypeptides are candidates for the study of early events since they are rapidly and coordinately expressed following monocyte/macrophage stimulation. The long-range goals of these studies are (1) to identify and purify the nuclear regulatory proteins which modulate IL-1 expression, (2) to evaluate the functional role of these proteins, (3) to determine how macrophage activating factors such as gamma interferon and colony stimulating factors can augment IL-1 expression through effects on these nuclear proteins, and (4) to examine how their activity is regulated by second messenger signals and/or specific intracellular inhibitors. These studies should lead to a greater understanding of the mechanism by which various stimulatory signals are utilized by the macrophage/monocyte to generate specific DNA-protein interactions and lead to the initiation of specific early events during activation. This information has particular value in understanding the etiology of several autoimmune and inflammatory diseases which may involve the aberrant expression of monokines. Furthermore, the activation of HIV-infected macrophages can lead to the co-expression of both viral gene products and IL-1, thus an understanding of the early events which regulate IL-1 expression may shed light on the pathology of HIV-infected macrophages.