IL-10 Receptor Function in Lung Inflammation

描述(由申请人提供)： 对肺部炎症的有效调节不仅对 允许在感染期间快速动员炎症细胞，但也 以防止肺部暴露于无害物质时的炎症。 肺部正常的动态平衡状态通常被认为是 免疫抑制，部分原因是肺泡巨噬细胞(AM)可以释放 一氧化氮、前列腺素、转化生长等抑制因子 因子和白介素10(IL-10)。IL-10与AM上IL-10受体的结合 显著抑制促炎细胞因子IL-1、IL-6的产生， IL-8和肿瘤坏死因子α。然而，我们已经表明，在炎症条件下， AM在合成肿瘤坏死因子α和IL-6过程中对IL-10反应减弱 不能被IL-10有效抑制。支气管肺泡上皮细胞 (EPC)也被证明能结构性地释放IL-10，但会松动 在炎症条件下的能力。我们假设在正常情况下 在肺部的条件下，抑制环是活跃的，在这个环中 EPC产生的IL-10作用于AM以防止不适当的合成 促炎细胞因子。在接触到传染性微生物后， EPC产生IL-10的动态平衡和/或IL-10的应答 AM上的受体通过信号传递模式迅速减少 EPC和AM上的识别受体促炎症细胞因子的诱生作用 因此，微生物比非微生物更能有效地诱导肺部 物质。利用活体小鼠模型和细胞培养模型，我们 将评估以下内容：1.)在合成过程中引起了哪些变化 IL-10在肺泡上皮细胞中的作用及在IL-10受体中的作用 肺泡巨噬细胞受微生物和非微生物刺激？)是 IL-10诱导肺泡巨噬细胞低反应性的实验研究 模式识别受体，包括Toll样受体和吞噬细胞 受体？3.)IL-10受体低反应性是直接通过 抑制信号转导通路或间接通过合成 抑制性分子，如“细胞因子信号转导抑制因子”(SOCS)？ 抑制Toll样能改善体内IL-10的低反应性吗 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?