Divergent expression and function of glucocorticoid receptor ß in human monocytes and T cells.
J Leukoc Biol
; 79(4): 818-827, 2006 Apr.
Article
em En
| MEDLINE
| ID: mdl-29350843
ABSTRACT
Glucocorticoid (GC) insensitivity is a significant problem in the treatment of immune-mediated diseases. The current study examined whether T cells and monocytes differed in their response to GC and the potential molecular basis for their variation in response to steroids. Functional studies revealed that dexamethasone (DEX) inhibited phorbol 12-myristate 13-acetate/ionomycin-induced tumor necrosis factor α and interleukin-6 production to a significantly lesser extent in monocytes than T cells. In parallel, a significantly longer period of time was required for DEX to induce the steroid-responsive gene, mitogen-activated protein kinase phosphatase-1 (MKP-1), in human monocytes as compared with T cells. It is interesting that such differences were not observed between murine T cells and monocytes. GC receptor ß (GCRß) is a splicing variant of the classic GCR, GCRα, which functions as a dominant-negative inhibitor of GCRα in humans, not mice (as mice do not express GCRß mRNA as a result of a difference in the murine GCR 9b exon sequence). It was found that human monocytes had a significantly higher level of GCRß than T cells. Furthermore, GCRß was found in the cytoplasm and nucleus of monocytes, and GCRß was localized to the nucleus of T cells. This raised the possibility that GCRß in the cytoplasm could affect GCRα cellular shuttling in response to DEX. Indeed, we found that DEX-induced nuclear translocation of GCRα was decreased in monocytes as compared with T cells. Specific RNA silencing of GCRß in human monocytes resulted in enhanced steroid-induced GCRα transactivation and transrepression. Our data suggest that GCRß contributes to variation in the GC responses of monocytes versus T cells.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Leukoc Biol
Ano de publicação:
2006
Tipo de documento:
Article