REGULATION OF INTERLEUKIN-6 (IL-6)

白细胞介素 6 (IL-6) 的调节

• 批准号: 2569002
• 负责人: E B SHACTER
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2569002
• 关键词: alkanes; bioassay; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; fatty acid biosynthesis; immunoregulation; indomethacin; inflammation; interleukin 6; laboratory mouse; macrophage; model design /development; peritonitis; plasma cell neoplasm; prostaglandin E; prostaglandin endoperoxide synthase

Interleukin-6 (IL-6) is an inflammatory cytokine with diverse functions including regulation of the humoral and cellular immune response and induction of thrombopoiesis. It is presently under development as a therapeutic agent for induction of platelets following chemotherapy. Because IL-6 is a growth factor for some hematopoietic tumors (e.g., multiple myeloma), clinical protocols designed to regulate the synthesis or activity of IL-6 are also being investigated. The goal of the present work is to elucidate the mechanisms whereby IL-6 levels are regulated in vivo. We have developed a murine pre-clinical model for this purpose. The experimental system involves injection of the mineral oil pristane into the peritoneal cavities of BALB/c mice. This treatment induces a chronic peritonitis that is accompanied by dramatically elevated levels of intraperitoneal IL-6 as determined by bioassay and ELISA. Previous studies showed that the elevation in IL-6 can be inhibited by co-administration of the cyclooxygenase inhibitor indomethacin to the mice. We have found that the pristane-induced increase in IL-6 is associated with an elevation in endogenous prostaglandin E2 levels. The results suggest that prostaglandins secreted by inflammatory macrophages might be responsible for stimulating IL-6 production in the same cells through a positive feedback loop. A similar mechanism may contribute to the pathogenesis of human diseases in which both prostaglandins and IL-6 are chronically elevated (e.g., rheumatoid arthritis, Crohn's disease). Our recent data indicate that the source of the PGE2 may be critical in determining whether IL-6 synthesis is turned on or not. That is, when peritoneal macrophages are stimulated to synthesize PGE2 through prostaglandin synthase-1, which is expressed constitutively, little or no IL-6 synthesis is observed. However, when the same macrophages are stimulated to generate PGE2 through induction of prostaglandin synthase-2, IL-6 synthesis is turned on. Current studies are aimed at understanding the cellular mechanisms underlying this phenomenon.

白细胞介素-6（IL-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应答的调节， 诱导血小板生成。 目前正在开发中， 化疗后诱导血小板的治疗剂。 因为IL-6是一些造血肿瘤的生长因子（例如， 多发性骨髓瘤），设计用于调节合成的临床方案 或IL-6的活性也在研究中。 目前的目标是 我们的工作是阐明IL-6水平调节的机制， vivo. 为此，我们开发了一种小鼠临床前模型。 实验系统包括注入矿物油降植烷 注入BALB/c小鼠的腹腔。 这种治疗会导致 慢性腹膜炎伴随着显著升高的水平 通过生物测定和ELISA测定腹腔内IL-6。 先前 研究表明，IL-6的升高可以被抑制， 将环加氧酶抑制剂吲哚美辛共同给药至 小鼠 我们已经发现降植烷诱导的IL-6的增加， 与内源性前列腺素E2水平升高相关。 的 结果表明，炎症巨噬细胞分泌的洋地黄素 可能负责刺激IL-6的产生在相同的细胞 通过一个积极的反馈循环。 类似的机制可能有助于 在人类疾病的发病机制中， 是慢性升高的（例如，类风湿性关节炎、克罗恩病）。 我们最近的数据表明，PGE 2的来源可能是关键， 确定IL-6合成是否开启。 即当 刺激腹腔巨噬细胞合成PGE 2， 前列腺素合酶-1，其组成性表达，很少或 没有观察到IL-6合成。 然而，当相同的巨噬细胞 通过诱导前列腺素而刺激产生PGE 2 合成酶-2，IL-6的合成被打开。目前的研究旨在 了解这种现象背后的细胞机制。