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

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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 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.
Funding Information
  • NIH (AR41256, 5R21AR051634)
  • NIH
  • NIAID (N01 AI40029, N01 AI40030)
  • General Clinical Research Center (MO1 RR00051)
  • Division of Research Resources
  • Edelstein Family Chair in Pediatric Allergy and Immunology
  • University of Colorado Cancer Center