The glucocorticoid receptor 1A3 promoter correlates with high sensitivity to glucocorticoid‐induced apoptosis in human lymphocytes

Abstract

Glucocorticoids (GCs) are powerful inhibitors of inflammation and immunity. Although glucocorticoid-induced cell death (GICD) is an important part of GCs actions, the cell types and molecular mechanisms involved are not well understood. Untranslated exon 1A3 of the human glucocorticoid receptor (GR) gene is a major determinant of GICD in GICD-sensitive human cancer cell lines, operating to dynamically upregulate GR levels in response to GCs. We measured the GICD sensitivity of freshly isolated peripheral blood mononuclear cells and thymocytes to dexamethasone in vitro, relating this to GR exon 1A3 expression. A clear GICD sensitivity hierarchy was detected: B cells4thymocytes/natural killer (NK) cells4peripheral T cells. Within thymocyte populations, GICD sensitivity decreased with maturation. Interestingly, NK cell subsets were differentially sensitive to GICD, with CD16 þ CD56 int (cytotoxic) NK cells being highly resistant to GICD, whereas CD16 À CD56 hi (cytokine producing) NK cells were highly sensitive (similar to B cells). B-cell GICD was rescued by co-culture with interleukin-4. Strikingly, although no significant increases in GR protein were observed during 48 h of culture of GICD-sensitive and -resistant cells alike, GR 1A3 expression was increased over pre-culture levels in a manner directly proportional to the GICD sensitivity of each cell type. Accordingly, this is the first evidence that the GR exon 1A3 promoter is differentially regulated during thymic development and maturation of human T cells. Furthermore, human peripheral blood B cells are exquisitely GICD-sensitive in vitro, giving new insight into how GCs may downregulate immunity. Collectively, these data show that GR 1A3 expression is tied with GICD sensitivity in human lymphocytes, underscoring the potential for GR 1A3 expression to be used as a biomarker for sensitivity to GICD.

Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

“…113,114 Anti-inflammatory effects of GCs are related to their actions on innate immune cells and adaptive cells. [115][116][117] The induction of GC-induced leucine zipper (GILZ) expression in MQs during inflammation has been reported to be an essential cell-type-specific anti-inflammatory action of GCs. 118 Moreover, GCs have been reported to impact on the developing immune system interfering with TNF-a and granulocyte-macrophage colony-stimulating factor production in pregnant animal model.…”

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion

“…17,18 Corticosteroids are a potent antiinflammatory agent with broad immunosuppressive effects on a number of cell types, such as T cells, because they can block several inflammatory pathways and induce apoptosis. [19][20][21] Meanwhile, vitamin D3 analogues possess a more specific immunomodulatory profile characterized by the capacity to induce a tolerogenic state in DCs 22,23 and T cells, enhancing the immunosuppressive capacity of regulatory T cells 24,25 and driving T cells toward a T H 2 profile while inhibiting T H 1/ T H 17 cells. 26 It is assumed that a corticosteroid and a vitamin D3 analogue synergistically improve psoriasis when their combination is applied to the plaque lesion.…”

Hypothalamus-pituitary-adrenal axis involves in anti-viral ability through regulation of immune response in piglets infected by highly pathogenic porcine reproductive and respiratory syndrome virus

“…Interestingly, most of the infected piglets displayed severe thymus atrophy and lymphocyte apoptosis from 3 to 10 days after the virus infection [7,10,[16][17][18]. These symptoms may develop under NEI deficient conditions, which suggests that some neuroendocrine hormones released by the HPA axis failed to modulate the anti-viral innate immune response during the viral infection [19][20][21]. Thus, we hypothesized that the HPA axis was affected by the HP-PRRSV infection, which then failed to sustain homeostasis in the infected piglets.…”