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Although the inhibitory effects of therapeutic glucocorticoids (GCs) on dendritic cells (DCs) are well established, the roles of endogenous GCs in DC homeostasis are less clear. A critical element regulating endogenous GC concentrations involves local conversion of inactive substrates to active 11-hydroxyglucocorticoids, a reduction reaction catalyzed within the endoplasmic reticulum by an enzyme complex containing 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase (H6PDH). In this study, we found that this GC amplification pathway operates both constitutively and maximally in steady state murine DC populations and is unaffected by additional inflammatory stimuli. Under physiologic conditions, 11βHSD1-H6PDH increases the sensitivity of plasmacytoid DCs (pDCs) to GC-induced apoptosis and restricts the survival of this population through a cell-intrinsic mechanism. Upon CpG activation, the effects of enzyme activity are overridden, with pDCs becoming resistant to GCs and fully competent to release type I interferon. CD8α(+) DCs are also highly proficient in amplifying GC levels, leading to impaired maturation following toll-like receptor-mediated signaling. Indeed, pharmacologic inhibition of 11βHSD1 synergized with CpG to enhance specific T-cell responses following vaccination targeted to CD8α(+) DCs. In conclusion, amplification of endogenous GCs is a critical cell-autonomous mechanism for regulating the survival and functions of DCs in vivo.

Original publication

DOI

10.1182/blood-2013-03-489138

Type

Journal article

Journal

Blood

Publication Date

07/11/2013

Volume

122

Pages

3288 - 3297

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Animals, Apoptosis, Bone Marrow Transplantation, CD8 Antigens, Carbohydrate Dehydrogenases, Cells, Cultured, Corticosterone, Cyclopropanes, Dendritic Cells, Female, Gene Expression Regulation, Guanosine, Interferon Type I, Mice, Mice, Knockout, Receptors, Glucocorticoid, Signal Transduction, T-Lymphocytes, Toll-Like Receptors, Whole-Body Irradiation