Glucocorticoid-Inducible Genes That Regulate T-Cell Function

Abstract

Upon antigenic challenge, the immune system must detect and respond to subtle perturbations in local microenvironments. While many important transactions entail cell-to-cell contact, coordination between multiple cells and cell types is carried out through antigen-nonspecific soluble mediators, broadly classified as cytokines and hormones. Messages delivered by the cytokines are for the most part pro-inflammatory and/or immune activating, whereas those delivered by the glucocorticoid hormones are thought to be largely inhibitory. One of the major inhibitory effects of glucocorticoids is the suppression of the synthesis of a large number of cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, GM-CSF, TNF-α, and IFN-γ, Kunicka et al. 1993). When viewed individually, however, a number of effects of glucocorticoids appear to break this “rule,” with glucocorticoids acting in pro-inflammatory or immunostimulatory ways. For example, glucocorticoids can increase the expression of receptors for some of the pro-inflammatory cytokines that it suppresses (IL-1, IL-6, GM-CSF, and IFN-γ; Almawi et al. 1996). A more complicated example is the effect of glucocorticoids on lymphocyte viability. Whereas thymocytes, and to a lesser extent mature lymphocytes, are induced to undergo apoptosis in response to glucocorticoid receptor (GR) occupancy (immunosuppressive), glucocorticoids inhibit apoptosis elicited by T-cell receptor (TCR)-mediated activation (immunostimulatory). This phenomenon is due to the inhibition of activation-induced Fas ligand (FasL) upregulation (Yang et al. 1995), which in normal circumstances binds Fas and elicits a death response. This chapter deals with new information about two glucocorticoid-regulated genes that appear to have negative and positive effects on immune function: GILZ and the receptor for interleukin (IL)-7 (IL-7Rα).