REGULATION OF INTERLEUKIN-6 (IL-6)

白细胞介素 6 (IL-6) 的调节

• 批准号: 3748229
• 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/3748229
• 关键词: adenylate cyclase; alkanes; disease /disorder model; enzyme activity; fatty acid biosynthesis; genetic strain; immunoregulation; indomethacin; inflammation; interleukin 6; laboratory mouse; macrophage; peritoneum; peritonitis; plasma cell neoplasm; prostaglandins

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.

白介素6(IL-6)是一种多功能细胞因子。它刺激了 B和T淋巴细胞的激活和分化，诱导 促血小板生成和发热，调节急性时相反应 炎症，是一些肿瘤的生长因子。失调症 IL-6的产生或周转导致血浆中IL-6水平异常 细胞因子，具有病理后果，如观察到的 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IL-6水平异常的原因尚不清楚。的目标是 这项工作是为了确定白细胞介素6的失调机制。 在慢性炎症期间。我们已经建立了一个实验模型 这涉及到注射矿物油Pristane(2，6，10，14- 四甲基十五烷)进入近交系小鼠的腹膜腔。 这种治疗会导致慢性腹膜炎，并伴有 腹膜腔内IL-6水平显著升高，并持续 在注入石油几个月后。此情况与 某些品系小鼠的浆细胞肿瘤的发生。二 目前正在采用各种方法来阐明导致以下问题的机制 IL-6的升高。第一个是继续我们先前的观察 白介素6的增加可以通过联合给药来抑制 环氧合酶抑制剂吲哚美辛对普里斯坦处理的小鼠。这 结果提示前列腺素可能负责刺激 炎症反应过程中产生IL-6。体外实验 在其中分离腹膜巨噬细胞并用 前列腺素E2现在支持这一假说，其机制出现了 由腺苷环化酶介导。几种不同类型的代理 对升高细胞内cAMP的细胞进行了测试，所有这些都是为了刺激 IL-6的分泌。结果表明，吲哚美辛可降低IL-6水平 Pristane治疗后抑制环氧合酶活性及 CAMP是巨噬细胞产生IL-6的第二信使。未来 研究将致力于建立两国之间的直接联系 体内前列腺素和IL-6产生异常。我们的第二种方法 找出导致IL-6调节失调的途径是 确定调节巨噬细胞IL-6产生的基因是否可以 确认身份。第一步是处理不同的近交系小鼠 并检测腹水中IL-6的水平。 发展。观察到了显著的可遗传差异。多数 值得注意的是，BALB/c小鼠产生的IL-6水平最高(~350pg/ml 平均)，而C3H小鼠(HEJ和HEN)仅产生边缘水平的 诱导浓度低于或接近15pg/ml的检测下限。 这两个品系小鼠的第一代杂交后代 仅显示低水平的IL-6对Pristane的反应。实验是 目前正在确定该特征是否存在于单个基因中。在……里面 此外，环氧合酶基因的表达正在进行比较 BALB/c和C3H小鼠的炎性巨噬细胞。