Published online before print February 3, 2006

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(Journal of Leukocyte Biology. 2006;79:818-827.)
© 2006 by Society for Leukocyte Biology

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

Ling-bo Li^*, Donald Y. M. Leung^*,,1, Clifton F. Hall^* and Elena Goleva^*

^* Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and
Department of Pediatrics, University of Colorado Health Sciences Center, Denver

¹Correspondence: National Jewish Medical and Research Center, 1400 Jackson Street, Room K926i, Denver, CO 80206. E-mail: leungd{at}njc.org

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 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, GCR, which functions as a dominant-negative inhibitor of GCR 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 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 GCRß in human monocytes resulted in enhanced steroid-induced GCR transactivation and transrepression. Our data suggest that GCRß contributes to variation in the GC responses of monocytes versus T cells.

Key Words: steroid resistance • MKP-1 • dexamethasone

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