REGULATION OF IL-1BETA & IL-1 INHIBITOR GENE EXPRESSION

我的实验室的长期目标是研究可能的作用 单核细胞和巨噬细胞在人类炎症性疾病中的作用 类风湿关节炎。这种可能性存在于炎症性疾病中 白介素1(IL-1)可能介导组织破坏的疾病，局部 巨噬细胞产生的IL-1可能过多。这种不受监管的IL-1 生产可能主要是由于差异化或 作用于组织巨噬细胞的激活剂。 在这些拟议的研究中要检验的假设是单核细胞 暴露在可溶性分化剂中，或在特定条件下培养 底物，将进化成巨噬细胞，表现出更高水平的 IL-1的产生对触发刺激的反应。这些研究将 检测人单核细胞、体外来源的巨噬细胞产生IL-1， 肺泡和滑膜巨噬细胞及不同生理因素的影响 细胞在类风湿中可能遇到的试剂或条件 联合。 拟议的研究将在三个具体目标下进行： 1.探讨白介素1β产生的调节机制 人单核细胞和体外来源的巨噬细胞对 与脂多糖不同的触发剂，如PMA、二氧化硅颗粒、 肿瘤坏死因子α和特异性IL-1诱导的淋巴因子。 2.探讨影响人IL-1β产生的机制 单核细胞在干扰素-1等分化剂中的培养 γ、1，25(OH)2-维生素D3、GM-CSF或IL-4，以及在不同条件下的培养 底物。 3.检测IL-1β在肺泡和滑膜中的产生规律 巨噬细胞和类风湿滑膜来源的克隆细胞系。 单核细胞和巨噬细胞在各种细胞存在的情况下培养 将检查区分和引发剂对 调节IL-1的产生。需要研究的监管水平 包括转录、翻译以及蛋白质加工和分泌。 这些研究与炎症的病理生理学有直接关系。 关节疾病，如类风湿性关节炎，IL-1可能在其中发挥作用 在关节早期变化中的重要作用以及 在组织破坏的调解中。更好地理解 对细胞因子产生的调节可能会导致更多的 治疗这些疾病的特定治疗剂。

The long-term objective of my laboratory is to examine the possible role of monocytes and macrophages in human inflammatory diseases such as rheumatoid arthritis. The possibility exists that in inflammatory diseases where interleukin 1 (IL 1) may mediate tissue destruction, local IL 1 production by macrophages may be excessive. This unregulated IL 1 production may result primarily from the effects of differentiating or activating agents acting on tissue macrophages. The hypothesis to be examined in these proposed studies is that monocytes exposed to soluble differentiating agents, or cultured on particular substrates, will evolve into macrophages that exhibit increased levels of IL 1 production in response to triggering stimuli. These studies will examine IL 1 production in human monocytes, in vitro-derived macrophages, alveolar and synovial macrophages, and the effects of various physiologic agents or conditions that the cells might encounter in the rheumatoid joint. The proposed studies will be pursued under three specific aims: 1. To examine the mechanisms of regulation of IL-1beta production by human monocytes and in in vitro-derived macrophages in response to different triggering agents than LPS, such as PMA, silica particles, TNFalpha and a specific IL 1-inducing lymphokine. 2. To examine the mechanisms of effects on IL-1beta production by human monocytes of culture in differentiating agents such as IFN- gamma,1,25(OH)2-vitamin D3, GM-CSF or IL 4, and of culture on different substrates. 3. To examine regulation of IL-1beta production in alveolar and synovial macrophages and in cloned cell line derived from rheumatoid synovium. Monocytes and macrophages cultured in the presence of the various differentiating and triggering agents will be examined for effects on regulation of IL 1 production. The levels of regulation to be studied include transcription, translation and protein processing and secretion. These studies have direct relevance to the pathophysiology of inflammatory joint diseases such as rheumatoid arthritis where IL 1 may play an important role in the initiation of early changes in the joint as well as in mediation of tissue destruction. A greater understanding of the regulation of cytokine production may permit the development of more specific therapeutic agents in these disease.