title: Divergent expression and function of glucocorticoid receptor beta 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. 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 (GCRbeta) is a splicing variant of the classic GCR, GCRalpha, which functions as a dominant-negative inhibitor of GCRalpha in humans, not mice (as mice do not express GCRbeta 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 GCRbeta than T cells. Furthermore, GCRbeta was found in the cytoplasm and nucleus of monocytes, and GCRbeta was localized to the nucleus of T cells. This raised the possibility that GCRbeta in the cytoplasm could affect GCRalpha cellular shuttling in response to DEX. Indeed, we found that DEX-induced nuclear translocation of GCRalpha was decreased in monocytes as compared with T cells. Specific RNA silencing of GCRbeta in human monocytes resulted in enhanced steroid-induced GCRalpha transactivation and transrepression. Our data suggest that GCRbeta contributes to variation in the GC responses of monocytes versus T cells.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Room K926i, Denver, CO 80206, USA.
authors.forename: Ling-Bo
authors.initials: LB
authors.lastname: Li
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
authors.forename: Clifton F
authors.initials: CF
authors.lastname: Hall
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000187:drug effects; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000276:immunology*; D013045:Species Specificity; D013256:Steroids / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; C121943:glucocorticoid receptor beta; D003907:Dexamethasone; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases