Divergent expression and function of glucocorticoid receptor β in human monocytes and T cells

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 alpha 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 beta (GCR beta) is a splicing variant of the classic GCR, GCR alpha, which functions as a dominant-negative inhibitor of GCR alpha in humans, not mice (as mice do not express GCRP 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 GCRP than T cells. Furthermore, GCRP was found in the cytoplasm and nucleus of monocytes, and GCRP was localized to the nucleus of T cells. This raised the possibility that GCRP in the cytoplasm could affect GCR alpha cellular shuttling in response to DEX. Indeed, we found that DEX-induced nuclear translocatioD of GCR alpha was decreased in monocytes as compared with T cells. Specific RNA silencing of GCR beta in human monocytes resulted in enhanced steroid-induced GCR alpha transactivation and transrepression. Our data suggest that GCR beta contributes to variation in the GC responses of monocytes versus T cells.