Control of innate immune reactions by bronchial epithelial cells

器官特异性免疫受局部微环境控制。在呼吸道内，上皮细胞在调节专业免疫细胞方面的作用迄今被低估。在以前的工作中，我们可以证明，在动态平衡条件下，支气管上皮细胞分泌前列腺素E2并重新激活糖皮质激素，从而调节树突状细胞的活性。这导致在上皮细胞条件树突状细胞中诱导了一种以抑制促炎症反应为特征的交替激活的表型。通过基因表达分析，在原代呼吸道树突状细胞中观察到相同的表型。此外，我们还分析了细胞因子信号转导抑制因子-1(SOCS1)蛋白的功能。令人惊讶的是，我们观察到SOCS1移位到细胞核，在哮喘患者的上皮细胞中可以观察到它的表达增加。为了进一步研究核功能，我们培育了一只表达非核SOCS1突变体的BAC转基因小鼠。在这项提案中，我们想要解决的主要问题是，当呼吸道上皮细胞受到感染或抗原攻击时，这些体内平衡调节机制如何改变。具体地说，我想分析(I)前列腺素E_2和糖皮质激素在人体呼吸道内介导的调节作用的重要性。(Ii)此外，我们将研究在体外、体内和人类呼吸道炎症性疾病中，当感染或抗原攻击时，上皮细胞和树突状细胞之间的抑制性相互作用是如何变化的。(Iii)我们打算分析内质网应激在刺激时上皮细胞内从抑制到激活的转换中所起的作用。(Iv)最后，我们将使用新开发的小鼠模型以及对炎症条件下的人类呼吸道进行分析，研究核SOCS1对呼吸道上皮细胞生物学的作用。这些结果将提高我们对呼吸道内上皮细胞介导的微环境调节的理解。

Organ specific immunity is controlled by the local microenvironment. Within the airways epithelial cells serve a so far underestimated role in modulating professional immune cells. In previous work we could show that bronchial epithelial cells under homeostatic conditions secrete prostaglandin E2 and reactivate glucocorticoids thereby modulating dendritic cell activity. This resulted in the induction of a phenotype of alternative activation in epithelial cell conditioned dendritic cells that was characterized by inhibition of proinflammatory reactivity. The same phenotype was observed in primary respiratory dendritic cells as examined by gene expression analysis. Moreover, we have analyzed the function of inhibitory Suppressor of Cytokine Signaling-1 (SOCS1) protein. Surprisingly, we observed that SOCS1 translocates to the nucleus where it can be observed at increased expression in epithelial cells from asthma patients. To further study the nuclear function we generated a BAC-transgenic mouse expressing a non-nuclear SOCS1 mutant. In this proposal we want to address the overarching question how those homeostatic regulatory mechanisms change when airway epithelial cells are challenged by infection or antigen encounter. Specifically, want to analyze (i) the importance of PGE2 and glucocorticoid mediated modulatory effects within human airways. (ii) Moreover, we will study how the suppressive interactions between epithelial cells and dendritic cells change upon infection or antigenic challenge in vitro as well as in vivo and in human airway inflammatory diseases. (iii) We intend to analyze the role of endoplasmic reticulum stress for the switch from inhibition to activation within epithelial cells upon stimulation. (iv) Finally, we will examine the function of nuclear SOCS1 for the cell biology of airway epithelial cells using the newly developed mouse model as well as analysis of human airways with inflammatory conditions. The results will improve our understanding of epithelial cell mediated microenvironment regulation within the airways.