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

我实验室的长期目标是研究 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 在炎症中存在的可能性 白细胞介素1（IL 1）可能介导组织破坏、局部 巨噬细胞产生的IL-1可能过多。 这种不受调节的IL 1 生产可能主要是由于分化或 激活剂作用于组织巨噬细胞。 在这些拟议的研究中要检验的假设是， 暴露于可溶性分化剂，或在特定的 基质，将演变成巨噬细胞，表现出增加的水平， IL 1的产生是对触发刺激的响应。 这些研究将 检测人单核细胞，体外衍生的巨噬细胞， 肺泡和滑膜巨噬细胞，以及各种生理 细胞在类风湿性关节炎中可能遇到的试剂或条件 关节 拟议的研究将在三个具体目标下进行： 1. 为了研究IL-1 β产生的调节机制， 人单核细胞和体外衍生的巨噬细胞对 与LPS不同的触发剂，例如PMA，二氧化硅颗粒， TNF α和特异性IL 1诱导淋巴因子。 2. 目的：探讨人白细胞介素1 β（IL-1 β）产生的影响机制。 单核细胞培养物中的分化剂，如IFN- γ，1，25（OH）2-维生素D3，GM-CSF或IL 4，以及在不同 印刷受体. 3. 检测肺泡和滑膜中IL-1 β产生的调节， 巨噬细胞和来源于类风湿性滑膜的克隆细胞系中。 单核细胞和巨噬细胞培养在存在的各种 分化和触发剂将被检查的影响， 调节IL 1的产生。 拟研究的规管水平 包括转录、翻译和蛋白质加工和分泌。 这些研究与炎症的病理生理学直接相关， 关节疾病，如类风湿性关节炎，其中IL 1可能发挥作用， 在关节的早期变化中起重要作用， 在组织破坏的调解。 更好地了解 调节细胞因子的产生可能会导致更多的细胞因子的产生。 在这些疾病中的特异性治疗剂。

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.