REGULATION OF INTERLEUKIN-6 (IL-6)

白介素6是一种具有多种功能的炎性细胞因子 包括体液和细胞免疫反应的调节，以及 诱导血栓生成。这种细胞因子既有治疗作用，又有 病理效应取决于体内发现的水平；异常高的 IL-6水平是有害的，有助于疾病的发展，而 适当的免疫功能需要生理水平的IL-6 和血栓生成。我们工作的目标是阐明这些机制 从而在体内控制IL-6水平。我们已经培育出一只小鼠 用于这一目的的临床前模型。该实验系统包括 伴随着长时间的炎症反应的诱导 高水平的IL-6。我们的数据显示，为了达到炎症的目的 化合物要诱导PGE2介导的IL-6合成，必须诱导表达 环氧合酶-2，这是一种可诱导的前列腺素合成酶同工酶。 目前，IL-6正在开发用于三种临床用途：(A)IL-6是 作为刺激血小板的治疗剂使用 化疗后的生产；(B)设计用于 降低IL-6的活性正被开发为一种阻断其 作为肿瘤促进剂的作用；及(C)IL-6可作为临床诊断 多发性骨髓瘤和类风湿性关节炎等疾病的标志物。 我们的研究旨在阐明 控制IL-6的合成和周转。这些研究涉及验证 检测体液中IL-6水平的方法。我们研究的关键 是临床前模型的使用，它允许我们测量控制 IL-6在体内的水平及其致瘤机制。我们的 研究计划有助于CBER科学家的监管能力 IL-6作为一种治疗剂，因为它探索了两种体外方法 检测体液和临床前模型中的IL-6有助于预测 IL-6在体内的调节作用。

Interleukin-6 (IL-6) is an inflammatory cytokine with diverse functions including regulation of the humoral and cellular immune response and induction of thrombopoiesis. This cytokine can have both therapeutic and pathologic effects depending on the levels found in vivo; abnormally high levels of IL-6 are deleterious and contribute to disease development while physiological levels of IL-6 are required for appropriate immune function and thrombopoiesis. The goal of our work is to elucidate the mechanisms whereby IL-6 levels are controlled in vivo. We have developed a murine pre-clinical model for this purpose. The experimental system involves induction of an inflammatory response that is accompanied by prolonged high levels of IL-6. Our data show that in order for an inflammatory compound to induce PGE2-mediated IL-6 synthesis, it must induce expression of cyclooxygenase-2, which is an inducible prostaglandin synthase isozyme. Currently, IL-6 is under development for three clinical uses: (a) IL-6 is being administered as a therapeutic agent for stimulation of platelet production following chemotherapy; (b) Clinical protocols designed to diminish the activity of IL-6 are being developed as a means to block its action as a tumor promoter; and (c) IL-6 serves as a clinical diagnostic marker for diseases such as multiple myeloma and rheumatoid arthritis. Our research is designed to elucidate the biological mechanisms that control IL-6 synthesis and turnover. These studies involve validation of assays to measure IL-6 levels in biological fluids. Key to our research is the use of a pre-clinical model which allows us to measure control of IL-6 levels and mechanisms of IL-6-induced tumorigenicity in vivo. Our research program contributes to the ability of CBER scientists to regulate IL-6 as a therapeutic agent in that it explores both in vitro methods for testing IL-6 in body fluids and pre-clinical models that help to predict IL-6 regulation in vivo.