Mechanism of glucocorticoid resistance

Abstract

Many patients have a form of glucocorticoid resistance, yet the mechanism of this serious medical problem has not been established. Previous studies have shown that glucocorticoid resistance is associated with impairment of transcriptional factors, such as activator protein 1 (AP-1), but an integrated view that allows for significant variability in individual patient responses has been unclear. In the current study, the investigators examined murine and human T cells for their responsiveness to glucocorticoids in vitro, aiming to determine whether the degree of signaling during T cell activation, affected responsiveness. Notably, dexamethasone (Dex) did not promote substantial T-cell apoptosis. Rather, Dex suppressed T-cell receptor (TCR)–induced proliferation of naive CD4+ T cells through a mechanism involving downregulation of c-Fos expression and inhibition of AP-1, nuclear factor of activated T cells (NF-AT), and NF-kB transcriptional activity. Importantly, enhancement of TCR signaling by CD28- or IL-2–mediated costimulation blocked the suppressive effect of Dex on c-Fos expression and AP-1 function and restored cellular proliferation. In contrast, NF-kB remained inhibited by Dex. Using specific signaling inhibitors, the investigators demonstrated that costimulatory signaling via MAPK kinase (MEK) and extracellular signal–regulated kinase (ERK) was essential for the development of T-cell resistance to Dex. Selective blockade of MEK/ERK signal transduction abolished the costimulation-induced resistance. Thus, the amount of signaling through the MAPK pathway was critical in determining the effect of Dex on T-cell activation. These results imply that the degree of local costimulation through MEK/ERK, affected by variable processes (including antigenic exposure in individual patients), can modify the effect of glucocorticoids on T cells. These findings raise hope that MAPK inhibitors might have therapeutic utility for glucocorticoid resistance.