Pretreatment with glucocorticoids enhances T-cell effector function: Possible implication for immune rebound accompanying glucocorticoid withdrawal

Glucocorticoids (GCs) exert their immunosuppressive/antiproliferative effec ts largely through inhibition of cytokine expression, and paradoxically upr egulate the expression of (proinflammatory) cytokine receptors on select no nlymphoid cells. Clinically, withdrawal of GCs was frequently associated wi th worsening of the outcome of heightened immunity disorders, thereby impli cating enhanced cytokine and cytokine receptor expression as a possible con sequence of acute/short-term GCs withdrawal. In view of the significance of this complication of GC therapy, we addressed the effect of GC withdrawal on cytokine receptor expression and subsequent T-cell effector function, us ing the proliferation of human T cells as biological readout. To mimic GC w ithdrawal, T cells were created with GCs or controls, stimulated, and incub ated for 16-20 h at 37 degrees C, washed, and reactivated for a further 4-4 8 h. Surface marker expression was assessed by FAGS analysis, and prolifera tion was determined by measuring the cellular uptake of tritiated thymidine . Dexa methasone (DEX) and prednisolone (PRED), in a concentration-dependen t manner. inhibited T-cell proliferation induced by anti-CD28 Ab + PMA. How ever, pretreatment of T cells activated with mitogens, crosslinking antibod ies, or PMA + ionomycin ("CD3-bypass" stimulation regimen), but not resting T cells, with DEX or PRED resulted in a marked increase in IL-1R, IL-2R al pha, and IL-6R expression, which was accompanied by a significant enhanceme nt in T-cell proliferation. This effect of GCs was neither stimulus specifi c nor did it result from alteration in cell viability, and was paralleled b y augmentation in cytokine (rIL-2) effects on DEX-pretreated and preactivat ed T cells. Taken together, our results underline the dual effects of GCs i n regulating T-cell activation and cytokine expression. In essence, GCs dir ectly inhibited T-cell proliferation by suppressing cytokine production, an d, by enhancing cytokine receptor expression: pretreatment with GCs augment ed T-cell proliferation.