Control of innate immune reactions by bronchial epithelial cells

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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.