title: Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans.
abstract: Although glucocorticoids are a profoundly important class of anti-inflammatory and immunosuppressive agents, their actions in dendritic cells (DCs) are not well understood. We found that dexamethasone, a potent glucocorticoid, selectively induced apoptosis in mature, but not in immature, DCs in healthy mice, in mice with experimental airway inflammation, and in vitro in bone marrow–derived DCs. Distinct glucocorticoid receptor (GR) translational isoforms expressed in immature and mature DCs probably contribute to the DC maturational stage-specific glucocorticoid sensitivity. The GR-D isoforms were the predominant isoforms in immature DCs, whereas the proapoptotic GR-A isoform was the main isoform in mature DCs. Ectopic expression of the GR-A isoform in immature DCs increased glucocorticoid sensitivity and RU486, a selective GR antagonist, inhibited the glucocorticoid sensitivity of mature DCs. Furthermore, the distinct expression pattern of GR isoforms in immature and mature murine DCs was also observed in human monocyte–derived DCs. These studies suggest that glucocorticoids may spare immature DCs and suppress mature DCs and inflammation via differential expression of GR translational isoforms.
authors.affiliation: Division of Allergy-Immunology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cao
authors.forename: Ingrid K
authors.initials: IK
authors.lastname: Bender
authors.forename: Athanasios K
authors.initials: AK
authors.lastname: Konstantinidis
authors.forename: Soon Cheon
authors.initials: SC
authors.lastname: Shin
authors.forename: Christine M
authors.initials: CM
authors.lastname: Jewell
authors.forename: John A
authors.initials: JA
authors.lastname: Cidlowski
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schleimer
authors.forename: Nick Z
authors.initials: NZ
authors.lastname: Lu
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity / Q000187:drug effects / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D053148:Caspase 3