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。它目前正在作为一种 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)，临床方案旨在调节合成 或IL-6的活性也在调查中。当前的目标是 工作是阐明IL-6水平调节的机制。 活着。为此，我们开发了一种小鼠临床前模型。 实验系统包括注射矿物油Pristane 进入BALB/c小鼠的腹膜腔。这种治疗导致了一种 伴有水平显著升高的慢性腹膜炎 用生物测定法和酶联免疫吸附试验测定IL-6的含量。上一首 研究表明，IL-6的升高可以被 环氧合酶抑制剂吲哚美辛联合给药 老鼠。我们发现，Pristane诱导的IL-6增加是 与内源性前列腺素E_2水平升高有关。这个 结果表明，炎症巨噬细胞分泌的前列腺素 可能负责刺激同一细胞中IL-6的产生 通过一个正反馈循环。类似的机制可能有助于 前列腺素和IL-6共同参与的人类疾病的发病机制 慢性升高(如类风湿性关节炎、克罗恩病)。 我们最近的数据表明，PGE2的来源可能在 确定是否打开了IL-6合成。也就是说，当 通过刺激腹膜巨噬细胞合成前列腺素E_2 前列腺素合成酶-1，它是结构性表达的，很少或 未观察到IL-6的合成。然而，当同样的巨噬细胞 前列腺素诱导产生前列腺素E_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。

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.