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

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. Func-tional studies revealed that dexamethasone (DEX) inhibited phorbol 12-myristate 13-acetate/ionomy-cin-induced tumor necrosis factor and interleu-kin-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-in-duced mitogen-activated protein kinase phospha-tase-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 (GCR) is a splicing variant of the classic GCR, GCR, which functions as a domi-nant-negative inhibitor of GCR in humans, not mice (as mice do not express GCR 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 GCR than T cells. Furthermore, GCR was found in the cytoplasm and nucleus of monocytes, and GCR was localized to the nucleus of T cells. This raised the possibility that GCR in the cytoplasm could affect GCR cellular shuttling in response to DEX. Indeed, we found that DEX-induced nuclear translocation of GCR was decreased in monocytes as compared with T cells. Specific RNA silencing of GCR in human monocytes resulted in enhanced steroid-induced GCR transactivation and transrepres-sion. Our data suggest that GCR contributes to variation in the GC responses of monocytes versu