Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck

Abstract

Dexamethasone (DM) is a synthetic member of the glucocorticoid (GC) class of hormones that possesses antiinflammatory and immunosuppressant activity and is commonly used to treat chronic inflammatory disorders, severe allergies, and other disease states. Although GCs are known to mediate welldefined transcriptional effects via GC receptors (GCR), there is increasing evidence that GCs also initiate rapid nongenomic signaling events in a variety of cell types. Here, we report that DM induces the phosphorylation of Lck IntroductionGlucocorticoids (GCs) are used to treat diseases with an inflammatory or immune-mediated component, including autoimmune diseases, graft rejection, and leukemia. GCs act via the T-cell intracellular GC receptor (GCR) and may negatively regulate the expression of numerous genes associated with proinflammatory cytokine signaling. 1,2 This inhibition of gene transcription appears to result from the ability of the GC/GCR complex to interfere with the activity of numerous transcription factors, either by binding to negative regulatory elements in the promoter region or through protein/protein interactions, impeding the ability of these factors to positively direct gene transcription. 3 In addition to these genomic effects, several studies have also described nongenomic, rapid effects of GCs on immune cells. [4][5][6][7] Dexamethasone (DM) can attenuate the early events of the T-cell receptor (TCR)-induced signaling cascade, including the activation of Src kinases via the GCR. GCRdeficient Jurkat cells and human T cells treated with the GCR blocker, Ru486, during cell activation failed to demonstrate any inhibition in kinase activation in response to DM. Interestingly, many of the inhibitory effects of GC have been observed in activated human or rodent T cells and immune cell subpopulations; however, the effects of DM on resting T cells are unclear.CXCR4, a chemokine receptor specific for the chemokine ligand, CXCL12, is expressed on leukocytes and is involved in the recirculation of naive lymphocytes into lymphoid tissue. 8 This receptor also plays a role in the retention of stem cells, differentiating B cells and neutrophils within bone marrow 9 and controls B-cell positioning within lymph nodes, where its expression is regulated by interleukin-4. 10 CXCR4 has been found to play a critical role in thymocyte chemotaxis and apoptosis 11 as well as thymic development. 12 CXCL12 was found to counteract the effects of DM on the apoptosis of CD4 ϩ CD8 ϩ T cells. Interestingly, several reports have also demonstrated that exposure of T-cell lines to GC can up-regulate cell surface CXCR4 expression. 13,14 Signals delivered through CXCR4-CXCL12 interactions result in potent chemotactic and pro-adhesive signals facilitating T-and B-lymphocyte migration. [15][16][17] Several reports have suggested that the activation of the Src kinase, Lck, on treatment of T cells with CXCL12 may be involved in orchestrating the downstream signals necessary for chemotaxis. 18,19 CXCR4 physically associates with the TC...

Glucocorticoids Suppress CCR9-Mediated Chemotaxis, Calcium Flux, and Adhesion to MAdCAM-1 in Human T Cells

“…2C). These results are in accord with reports that DEX increases CXCR4 surface expression and CXCL12-mediated chemotaxis through activation of the GC receptor (22,23).…”

“…As a control, we compared the effects of GCs on CXCR4, which is coexpressed on CCR9 + T cells. CXCR4 is stimulated by a single ligand, CXCL12, and consistent with previous reports, GCs increase CXCR4 expression and enhance CXCL12-mediated functions (22,23). These results identify novel effects of GCs on the function of primary human T cells that are likely to be physiologically and clinically relevant in intestinal inflammation.…”

“…The effects of DEX on CXCR4 surface expression and cell migration have been previously described in other cell types; however, to our knowledge, these are the first reports of suppressive effects on CCR9-and CXCR3-mediated cell migration (22,28). Although the effects of DEX on CXCR3 were novel, our main interest was intestinal-specific homing, and therefore we continued to study CCR9 using CXCR4 as a positive control.…”

“…In human T cells and eosinophils, DEX-enhanced migration through CXCR4 is dose-dependent at concentrations .10 nM (22,29). To determine whether differences in CCR9 and CXCR4 functions were due to the effect of GC concentrations, two lower doses of DEX were tested in our system.…”

Mechanism of Salt-Sensitive Hypertension

“…37 T-cell signaling is induced by chemokines and other stimulants and mediated by the activation of Rhoguanine triphosphate hydroxylases, such as Rac1. 38,39 Tregulatory lymphocytes prevent AII-and aldosterone-induced hypertension and vascular injury, 40 and crosstalk occurs between aldosterone and angiotensin signaling. 41 MR activation in macrophages contributes to BP elevation and vascular damages in AII/Nv-nitro-L-arginine methyl ester hypertension and deoxycorticosterone acetate (DOCA) salt hypertension.…”