Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid.

Soulier, Annelise; Blois, Sandra M; Sivakumaran, Shivajanani; Fallah-Arani, Farnaz; Henderson, Stephen; Flutter, Barry; Rabbitt, Elizabeth H; Stewart, Paul M; Lavery, Gareth G; Bennett, Clare; Curnow, S John; Chakraverty, Ronjon

Soulier, Annelise; Blois, Sandra M; Sivakumaran, Shivajanani; Fallah-Arani, Farnaz; Henderson, Stephen; Flutter, Barry; Rabbitt, Elizabeth H; Stewart, Paul M; Lavery, Gareth G; Bennett, Clare; Curnow, S John; Chakraverty, Ronjon.

Afiliación

Soulier A; School of Immunity and Infection, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;

Blood ; 122(19): 3288-97, 2013 Nov 07.

Article en En | MEDLINE | ID: mdl-24081658

RESUMEN

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 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) 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, 11ßHSD1-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 11ßHSD1 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.

Asunto(s)

11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/inmunología; Deshidrogenasas de Carbohidratos/inmunología; Corticosterona/análogos & derivados; Células Dendríticas/inmunología; Receptores de Glucocorticoides/inmunología; 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética; Animales; Apoptosis/efectos de los fármacos; Trasplante de Médula Ósea; Antígenos CD8/genética; Antígenos CD8/inmunología; Deshidrogenasas de Carbohidratos/genética; Células Cultivadas; Corticosterona/metabolismo; Corticosterona/farmacología; Ciclopropanos/farmacología; Células Dendríticas/citología; Células Dendríticas/efectos de los fármacos; Femenino; Regulación de la Expresión Génica; Guanosina/análogos & derivados; Guanosina/farmacología; Interferón Tipo I/biosíntesis; Interferón Tipo I/inmunología; Ratones; Ratones Noqueados; Receptores de Glucocorticoides/genética; Transducción de Señal; Linfocitos T/citología; Linfocitos T/efectos de los fármacos; Linfocitos T/inmunología; Receptores Toll-Like/genética; Receptores Toll-Like/inmunología; Irradiación Corporal Total

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Dendríticas / Corticosterona / Deshidrogenasas de Carbohidratos / Receptores de Glucocorticoides / 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 Límite: Animals Idioma: En Revista: Blood Año: 2013 Tipo del documento: Article Pais de publicación: Estados Unidos

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