Glucocorticoids Augment CXCR4-Mediated Signaling and Function Via the Activation of the Src Kinase, Lck (94.10)

Abstract

Abstract Dexamethasone is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly utilized to treat chronic inflammatory disorders, severe allergies and other disease states. While glucocorticoids are known to mediate well-defined transcriptional effects via GC receptors, there is increasing evidence that GCs also initiate rapid non-genomic signaling events in a variety of cell types. Here, we report that dexamethasone appears to induce the phosphorylation of Lck and the activation of other down stream mediators in resting human T cells including p59Fyn, Zap70, Rac1, Cdc42 and Vav1. DM treatment also appeared to augment CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4, resulting in the enhanced actin polymerization and cell migration upon 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 glucocorticoid receptor and the CD45 molecule. Overall, these results elucidate additional non-genomic effects of DM on resting human T cells, inducing Lck activation and augmenting chemokine signaling and function.