GLUCOCORTICOID-MEDIATED INHIBITION OF INTERLEUKIN-2 RECEPTOR-ALPHA AND RECEPTOR-BETA SUBUNIT EXPRESSION BY HUMAN T-CELLS

To determine the mechanism of glucocorticoid (GC)-mediated inhibition of T cell functions, the effect of dexamethasone (DM) on T cell prolif eration and interleukin-2 receptor (IL-2R) generation were studied. De xamethasone inhibited IL-2-induced T cell proliferation by 30%-88%, re lative to its concentration within the cultures. The effect of DM on e xpression of IL-2R alpha (Tac, p55, CD25) and beta (p75) genes in acti vated T cells was examined next. In T cells stimulated with purified p hytohemagglutinin (PHA-p) and 4 beta-phorbol 12-myristate 13-acetate ( PMA) addition of DM to the cultures resulted in a 60% reduction in IL- 2R alpha and a 30% reduction in IL-2R beta membrane expression compare d to T cells cultured in the absence of DM (p<0.01). Inhibition of mem brane IL-2R alpha and IL-2R beta expression by 10(-6)M DM was partiall y reversible by recombinant human IL-2 (rhIL-2). By Northern blot anal ysis, DM caused a comparable decrease in IL-2R alpha and in IL-2R beta mRNA levels to membrane receptor expression in mitogen-stimulated T c ells. By in vitro transcription assays, DM regulated IL-2R alpha gene expression at a transcriptional level while transcription of IL-2R bet a gene was unaffected by DM. The mechanism of action of DM on IL-2R al pha transcription was examined by determining the mRNA levels of the p 50 subunit of nuclear factor kappa B (NF-kappa B), a transcription fac tor that stimulates IL-2R alpha gene expression. The data indicate tha t 10(-6)M DM increased T cell p50 NF-kappa B mRNA levels by four-fold compared to the levels obtained in the absence of DM. Further, the lev el of nuclear proteins capable of binding to the NF-kappa B sites in a ctivated T cells increased in response to DM. In sum, DM regulates T c ell membrane expression of IL-2R by more than one molecular mechanism.