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

Journal of Leukocyte Biology

Elena Goleva¹  Donald Y. M. Leung²  Clifton F. Hall¹  Ling-bo Li¹ 

[1] Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and;Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Pediatrics, University of Colorado Health Sciences Center, Denver Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Pediatrics, University of Colorado Health Sciences Center, Denver Department of Pediatrics, University of Colorado Health Sciences Center, Denver Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Pediatrics, University of Colorado Health Sciences Center, Denver

关键词: steroid resistance;    MKP-1;    dexamethasone;   

DOI  :  10.1189/jlb.0805466

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 β (GCRβ) 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 GCRβ 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 GCRβ than T cells. Furthermore, GCRβ was found in the cytoplasm and nucleus of monocytes, and GCRβ was localized to the nucleus of T cells. This raised the possibility that GCRβ 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 GCRβ in human monocytes resulted in enhanced steroid-induced GCRα transactivation and transrepression. Our data suggest that GCRβ contributes to variation in the GC responses of monocytes versus T cells.

【 授权许可】

Unknown