REGULATION OF INTERLEUKIN-6 (IL-6)

白细胞介素-6（IL-6）是一种多功能细胞因子。 它刺激 B和T淋巴细胞的活化和分化，诱导 血小板生成和发热，调节急性期反应， 炎症，并且是一些肿瘤的生长因子。 失调 IL-6的产生或周转导致IL-6的异常水平， 细胞因子，并具有病理后果，如在 多发性骨髓瘤和类风湿性关节炎患者。 在大多数情况下， 体内异常IL-6水平的原因尚不清楚。 的目标 这项工作是为了确定白细胞介素-6调节异常的机制， 在慢性炎症中。 我们建立了一个实验模型 包括注入矿物油姥鲛烷（2，6，10，14- 四甲基十五烷）注入近交系小鼠的腹膜腔。 该治疗诱导慢性腹膜炎， 腹膜内IL-6水平显著升高，持续 注入石油后的几个月。 这种情况与 在某些品系的小鼠中发生浆细胞肿瘤。 两 正在采取各种方法来阐明 IL-6的升高。 第一个是继续我们先前的观察 IL-6的增加可以通过联合施用 环氧合酶抑制剂吲哚美辛对降植烷处理的小鼠的作用。 这 结果表明，三尖杉酯碱可能负责刺激 炎症反应过程中IL-6的产生。 体外实验 其中腹膜巨噬细胞被分离并用 前列腺素E2现在支持这一假设，其机制似乎是 由腺苷酸环化酶介导。 几种不同类型的代理 升高细胞内cAMP都被测试， IL-6分泌。 结果表明，吲哚美辛降低IL-6水平 在降植烷处理后通过抑制环氧合酶活性， cAMP作为巨噬细胞IL-6产生的第二信使。 未来 研究将致力于建立一个直接的联系， 体内前列腺素和IL-6产生异常。 我们的第二种方法 确定负责IL-6失调的途径是 确定调节巨噬细胞IL-6产生的基因是否可以 鉴定 第一步是治疗不同的近交系小鼠 并测量腹膜内IL-6的水平， 开发. 已观察到显著的遗传差异。 最 值得注意的是，BALB/c小鼠产生最高的IL-6水平（约350 pg/ml， 平均值），而C3H小鼠（HeJ和HeN）仅发生边缘水平的 诱导低于或接近15 pg/ml的测定下限。 这两个品系小鼠第一代杂交的后代 仅显示低水平的IL-6响应降植烷。 实验 以确定该性状是否存在于单个基因中。 在 此外，环氧合酶基因的表达正在进行比较， 来自BALB/c和C3H小鼠的炎性巨噬细胞。

Interleukin-6 (IL-6) is a multifunctional cytokine. It stimulates activation and differentiation of B and T lymphocytes, induces thrombopoiesis and fever, regulates the acute phase response of inflammation, and is a growth factor for some tumors. Dysregulation of the production or turnover of IL-6 leads to abnormal levels of the cytokine and has pathologic consequences such as those observed in patients with multiple myeloma and rheumatoid arthritis. In most cases, the causes for abnormal IL-6 levels in vivo are not known. The goal of this work is to identify mechanisms of dysregulation of interleukin-6 during chronic inflammation. We have established an experimental model that involves injection of the mineral oil pristane (2,6,10,14- tetramethyl- pentadecane) into the peritoneal cavities of inbred mice. The treatment induces a chronic peritonitis that is accompanied by dramatically elevated levels of intraperitoneal IL-6 that persist for months after injection of the oil. This condition is associated with development of plasma cell tumors in some strains of mice. Two approaches are being followed to elucidate the mechanisms responsible for the elevation of IL-6. The first is to pursue our earlier observation that the increase in IL-6 can be inhibited by co-administration of the cyclooxygenase inhibitor indomethacin to pristane-treated mice. This result suggested that prostaglandins might be responsible for stimulating IL-6 production during the inflammatory response. In vitro experiments in which peritoneal macrophages were isolated and treated with prostaglandin E2 now support this hypothesis, and the mechanism appears to be mediated by adenylate cyclase. Several different types of agents that elevate intracellular cAMP were tested and all acted to stimulate IL-6 secretion. The results suggest that indomethacin lowers IL-6 levels after pristane treatment by inhibiting cyclooxygenase activity and that cAMP serves as a second messenger for macrophage IL-6 production. Future studies will be directed toward establishing a direct link between abnormal prostaglandin and IL-6 production in vivo. Our second approach to identifying the pathways responsible for dysregulation of IL-6 is to determine whether genes that regulate macrophage IL-6 production can be identified. The first step has been to treat different inbred mouse strains with pristane and measure the levels of intraperitoneal IL-6 that develop. Significant heritable differences have been observed. Most notably, BALB/c mice develop the highest IL-6 levels (~ 350 pg/ml on average) while C3H mice (HeJ and HeN) incur only marginal levels of induction that are below or near the lower assay limit of 15 pg/ml. Progeny of the first generation cross between these two strains of mice show only low levels of IL-6 in response to pristane. Experiments are underway to determine whether the trait resides in a single gene. In addition, expression of the cyclooxygenase genes is being compared in inflammatory macrophages from BALB/c and C3H mice.