CHEMOATTRACTANT INDUCED GENE EXPRESSION IN LEUKOCYTES

白细胞趋化因子长期以来被认为是一组 促炎因子，触发特定的细胞功能， 趋化性、脱粒、超氧阴离子的产生和活化 整合素 最近的研究结果表明， 还可诱导促炎细胞因子的合成和分泌 包括趋化因子，一种可能对启动 和局部细胞因子网络的调节，和/或 白细胞聚集到炎症部位。 我们研究的初步结果表明， 趋化因子诱导的NF-κ B活化是 白细胞中的细胞因子基因表达。 也有人认为， 导致趋化因子诱导的NF（kappa）B的信号通路 活化不同于其他NF（κ）B活化所利用的 药物如TNF（α）和PMA。 目前的项目旨在测试 这些假设，并包含2个具体目标。 (1)表征 趋化因子刺激的信号传导事件导致转录 activation. 这是应用程序的核心。 我们的主要兴趣 是识别化学引诱物的独特机制 (PAF，FMLP）刺激的NF-（κ）B活化。 一种重构系统， 基于质粒DNA的瞬时共转染，将用于 鉴定另外髓样分化相关因子 FMLP-（以及C5 a和IL-8）诱导的NF-（κ）B所需 activation. (2)调查经济、社会和文化权利 单核细胞中的趋化因子刺激的基因表达， 多形核粒细胞（PMN）。 在这一点上，我们将研究 单核细胞和中性粒细胞是否采用相同的基因机制 表达对化学引诱物刺激的响应。 我们还将测试 IL-8可以通过结合 IL-8受体和NF-（kappa）B活化。 实现这些 目标将扩展我们目前对生理学的理解， 化学引诱物的功能，是我们长期的一个组成部分， 研究目的与白细胞的分子机制有关 activation.

Leukocyte chemoattractants have long been regarded as a group of proinflammatory factors that trigger specific cellular function such as chemotaxis, degranulation, generation of superoxide anions and activation of integrins. Results from recent studies indicate that chemoattractants can also induce the synthesis and secretion of proinflammatory cytokines including chemokines, a functions that may be crucial for the initiation and regulation of a local cytokine network and or the continued recruitment of leukocytes to site of inflammation. Preliminary results derived from our studies suggest the hypothesis that chemoattractant-induced NF-kappa B- activation is a primary mechanism for cytokine gene expression in leukocytes. It is also postulated that the signaling pathways leading to chemoattractant-induced NF(kappa)B activation differ from that utilized by other NF(kappa)B-activating agents such as TNF(alpha) and PMA. The current project aims to test these hypothesis, and contains 2 specific aims. (1) Characterization of chemoattractant-stimulated signaling events leading to transcription activation. This is the core of the application. Our primary interest is in the identification of mechanisms that unique to chemoattractant (PAF, FMLP)-stimulated NF-(kappa) B activation. A reconstitution system, based on transient co-transfection of plasmid DNA, will be employed to identify an additional myeloid differentiation-association factor required for FMLP-( and also C5a and IL-8) induced NF-(kappa)B activation. (2) Investigation of the extent and variability of chemoattractant-stimulated gene expression in monocytes and polymorphonulear neutrophils (PMN). IN this specific we will examine whether monocytes and neutrophils employ the same mechanism for gene expression in response to chemoattractant stimulation. We will also test the notion IL-8 can regulate its own gene expression through binding of the IL-8 receptors and activation of NF-(kappa) B. Achievement of these goals will extend our current understanding of the physiological functions of chemoattractants, and is an integral part of our long term research objective relating to the molecular mechanisms of leukocyte activation.