Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck.
Dexamethasone (DM) is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly used to treat chronic inflammatory disorders, severe allergies, and other disease states. Although GCs are known to mediate well-defined 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 and the activation of other downstream mediators, including p59Fyn, Zap70, Rac1, and Vav in resting but not activated human T cells. DM treatment also augments CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4 resulting in the enhanced actin polymerization, Rac activation, and cell migration on ligand exposure. Lck was found to be a critical intermediate in these DM-induced signaling activities. Moreover, DM-mediated Lck phosphorylation in T cells was dependent on the presence of both the GCR and the CD45 molecule. Overall, these results elucidate additional nongenomic effects of DM and the GCR on resting human T cells, inducing Lck and downstream kinase activation and augmenting chemokine signaling and function.
Laboratory of Immunology, Intramural Research Program, National Institute of Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
Manik C
MC
Ghosh
Dolgor
D
Baatar
Gary
G
Collins
Arnell
A
Carter
Fred
F
Indig
Arya
A
Biragyn
Dennis D
DD
Taub
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D003907:Dexamethasone; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)