IL-10 Receptor Function in Lung Inflammation

描述（由申请人提供）： 肺中炎症的有效调节不仅是至关重要的 允许在感染期间迅速动员炎性细胞，而且 以防止肺部暴露于无害物质时发生炎症。 肺中正常的稳态条件通常被认为是 免疫抑制，部分原因是肺泡巨噬细胞（AM）可以释放 抑制因子，包括一氧化氮、洋地黄素、转化生长 因子和白细胞介素-10（IL-10）。IL-10与AM上的IL-10受体的结合 显著抑制促炎细胞因子IL-1，IL-6， IL-8和TNF α。然而，我们已经表明，在炎症条件下， AM在TNF α和IL-6合成中对IL-10变得低应答 不能被IL-10有效抑制。肺泡上皮细胞 (EpC)也显示出组成性释放IL-10，但释放出IL-10， 在炎症条件下的能力。我们假设在正常情况下 在肺中的条件下，抑制回路是活跃的，其中组成性地 由EpC产生的IL-10作用于AM以防止 促炎细胞因子在接触感染性微生物后， 通过EpC的IL-10的稳态产生和/或IL-10的应答 AM上的受体通过以下模式的信号传导迅速减少 EpC和AM上的识别受体。促炎性细胞因子的诱导 因此，肺由微生物而不是非微生物更有效地诱导， 物质.使用体内小鼠模型和细胞培养模型，我们 将评估以下内容：1.）在合成过程中诱导了哪些变化 IL-10受体功能的影响 肺泡巨噬细胞的微生物和非微生物刺激？2.）是 介导肺泡巨噬细胞IL-10低反应性 模式识别受体，包括Toll样受体和吞噬细胞 受体？3.）第三章IL-10受体低反应性是否通过 抑制信号转导途径或间接通过合成 抑制分子，如“细胞因子信号转导抑制因子”（SOCS）？4.） 抑制Toll样因子能改善体内IL-10低反应性吗 受体信号？

DESCRIPTION (provided by applicant): Efficient regulation of inflammation in the lungs is essential not only to allow for rapid mobilization of inflammatory cells during infection, but also to prevent inflammation during exposure of the lungs to innocuous substances. Normal homeostatic conditions in the lungs are generally thought to be immunosuppressive, due in part to alveolar macrophages (AM) which can release inhibitory factors including nitric oxide, prostaglandins, transforming growth factor and interleukin-10 (IL-10). Binding of IL-10 to IL-10 receptors on AM dramatically inhibits the production of proinflammatory cytokines, IL-1, IL-6, IL-8 and TNFalpha. However, we have shown that under inflammatory conditions, AM become hyporesponsive to IL-10 in that synthesis of TNFalpha and IL-6 cannot be effectively inhibited by IL-10. Bronchoalveolar epithelial cells (EpC) also have been shown to constitutively release IL-10, but to loose that capacity during inflammatory conditions. We hypothesize that under normal conditions in the lung, an inhibitory loop is active in which constitutively produced IL-10 by EpC acts on AM to prevent inappropriate synthesis of proinflammatory cytokines. Following exposure to infectious microorganisms, the homeostatic production of IL-10 by EpC and/or the response of the IL-10 receptors on AM are rapidly diminished via signaling through pattern recognition receptors on EpC and AM. Induction of proinflammatory cytokines in the lungs is thus more efficiently induced by microbial rather than by non-microbial substances. Using in vivo murine models and cell culture models, we will evaluate the following: 1.) What changes are induced in the synthesis of IL-10 by alveolar epithelial cells and in IL-10 receptor function on alveolar macrophages by microbial and non-microbial stimuli? 2.) Is induction of IL-10 hyporesponsiveness in alveolar macrophages mediated via pattern recognition receptors, including Toll-like receptors and phagocytic receptors? 3.) Is IL-10 receptor hyporesponsiveness mediated directly via inhibition of signal transduction pathways or indirectly via synthesis of inhibitory molecules such as "suppressors of cytokine signaling" (SOCS)? 4.) Can IL-10 hyporesponsiveness in vivo be ameliorated by inhibition of Toll-like receptor signaling?