REGULATION OF CYTOKINE PRODUCTION BY IL-10 IN ENDOTOXIN-STIMULATED MONOCYTES

当暴露在细菌内毒素、脂多糖(LPS)下时，人类 单核细胞被激活以协调表达多种细胞因子。多数 其中有一些是早期反应基因，它们的产物进而激活 其他基因在组织部位的表达通常远离 单核细胞初始激活的焦点。白介素10(IL-10)也是 由内毒素诱导，但与其他内毒素诱导的细胞因子不同，它反馈 通过下调多种细胞因子的表达抑制单核细胞的激活 细胞因子。在这个项目中，我们正在研究调节 人单核细胞内源性IL-10的合成及其机制 通过IL-10抑制各种内毒素诱导基因的表达， 尤其是人类单核细胞中的肿瘤坏死因子(TNF)。 IL-10如何抑制血管内皮细胞炎性细胞因子的表达 人类单核细胞是我们理解其发病机制的关键。 这种细胞因子的作用。此信息在评估时可能有用 在未来的临床试验中观察到的任何治疗活动。 白介素10(IL-10)是最近发现的一种细胞因子， 抑制许多促炎细胞因子的产生，包括肿瘤坏死因子， 人单核细胞中的IL-1和IL-6。人们对此知之甚少 这种细胞因子的作用机制或控制其的因素 在激活的单核细胞中表达。IL-10目前正在作为一种 潜在的抗炎药用于治疗一些 炎症性疾病。白介素10的调节因素分析 在人单核细胞中的表达可能提供有关 该细胞因子在抑制促炎细胞因子中的作用 体内合成。它还可以帮助CBER工作人员更关键地 评估IL-10未来的临床试验。此外，还分析了 IL-10对细胞因子表达的影响可能有助于识别 IL-10活性的替代标记物可能有助于监测 重组IL-10在人类受体中的效力。

When exposed to the bacterial endotoxin, lipopolysaccharide (LPS), human monocytes are activated to coordinately express multiple cytokines. Most of these are early response genes whose products in turn activate expression of other genes at tissue sites often far removed from the focus of initial monocyte activation. Interleukin-10 (IL-10) is also induced by LPS, but unlike other LPS-inducible cytokines, it feedback inhibits monocyte activation by down-regulating expression of many cytokines. In this project, we are examining the factors that regulate endogenous IL-10 synthesis in human monocytes, as well as the mechanism by which IL-10 suppresses expression of various LPS-inducible genes, particularly tumor necrosis factor (TNF), in human monocytes. Determining how IL-10 inhibits proinflammatory cytokine expression in human monocytes is critical to our understanding of the mechanism of action of this cytokine. This information may be useful when evaluating any therapeutic activity observed in future clinical trials. Interleukin-10 (IL-10) is a relatively recently discovered cytokine that inhibits production of many proinflammatory cytokines, including TNF, IL-1 and IL-6, in human monocytes. Relatively little is known about mechanism of action of this cytokine or the factors that control its expression in activated monocytes. IL-10 is currently being tested as a potential antiinflammatory agent for the treatment of a number of inflammatory diseases. Analysis of the factors that regulate IL-10 expression in human monocytes may provide important information regarding the role of this cytokine in suppressing proinflammatory cytokine synthesis in vivo. It may also help CBER staff to more critically evaluate future clinical trials of IL-10. Furthermore, analysis of the effects of IL-10 on cytokine expression in vitro may help to identify surrogate markers of IL-10 activity that may be useful in monitoring the potency of recombinant IL-10 in human recipients.