title: Bronchial epithelial cells induce alternatively activated dendritic cells dependent on glucocorticoid receptor signaling.
abstract: Airway epithelial cells mount a tolerogenic microenvironment that reduces the proinflammatory potential of respiratory dendritic cells (DCs). We recently demonstrated that tracheal epithelial cells continuously secrete soluble mediators that affect the reactivity of local innate immune cells. Using transcriptional profiling, we now observed that conditioning of DCs by tracheal epithelial cells regulated 98 genes under homeostatic conditions. Among the most upregulated genes were Ms4a8a and Ym1, marker genes of alternatively activated myeloid cells. Ex vivo analysis of respiratory DCs from nonchallenged mice confirmed a phenotype of alternative activation. Bioinformatic analysis showed an overrepresentation of hormone-nuclear receptors within the regulated genes, among which was the glucocorticoid receptor. In line with a role for glucocorticoids, pharmacological blockade as well as genetic manipulation of the glucocorticoid receptor within DCs inhibited Ms4a8a and Ym1 expression as well as MHC class II and CD86 regulation upon epithelial cell conditioning. Within epithelial cell-conditioned medium, low amounts of glucocorticoids were present. Further analysis showed that airway epithelial cells did not produce glucocorticoids de novo, yet were able to reactivate inactive dehydrocorticosterone enzymatically. The results show that airway epithelial cells regulate local immune responses, and this modulation involves local production of glucocorticoids and induction of an alternative activation phenotype in DCs.
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany;
authors: Michael
authors: M
authors: Weitnauer
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
authors: Lotte
authors: L
authors: Schmidt
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany;
authors: Nathalie
authors: N
authors: Ng Kuet Leong
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany;
authors: Stephanie
authors: S
authors: Muenchau
authors: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
authors: Felix
authors: F
authors: Lasitschka
authors: Department of Medicine V, University Hospital Heidelberg, 69120 Heidelberg, Germany; and.
authors: Volker
authors: V
authors: Eckstein
authors: Institute of General Zoology and Endocrinology, University of Ulm, 89081 Ulm, Germany.
authors: Sabine
authors: S
authors: Hübner
authors: Institute of General Zoology and Endocrinology, University of Ulm, 89081 Ulm, Germany.
authors: Jan
authors: J
authors: Tuckermann
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany; alexander.dalpke@med.uni-heidelberg.de.
authors: Alexander H
authors: AH
authors: Dalpke
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D060833:Cellular Microenvironment / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D011897:Random Allocation; D020239:Receptor Cross-Talk / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D011965:Receptors, Glucocorticoid; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse