MULTIPLICITY OF GLUCOCORTICOID ACTION IN INHIBITING ALLOGRAFT-REJECTION

Glucocorticoids (GCs) are used as immunosuppressive and antiinflammato ry agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders. GCs were shown to exert their antiprolife rative effects directly through blockade of certain elements of an ear ly membrane-associated signal transduction pathway, modulation of the expression of select adhesion molecules, and by suppression of cytokin e synthesis and action. GCs may act indirectly by inducing lipocortin synthesis, which in turn, inhibits arachidonic acid release from membr ane-bound stores, and also by inducing transforming growth factor (TGF )-beta expression that subsequently blocks cytokine synthesis and T ce ll activation. Furthermore, by preferentially inhibiting the productio n of Th1 cytokines, GCs may enhance Th2 cell activity and, hence, prec ipitate a long-lasting state of tolerance through a preferential promo tion of a Th2 cytokine-secreting profile. In exerting their antiprolif erative effects, GCs influence both transcriptional and posttranscript ional events by binding their cytosolic receptor (GR), which subsequen tly binds the promoter region of cytokine genes on select DNA sites co mpatible with the GCs responsible elements (GRE) motif. In addition to direct DNA binding, GCs may also directly bind to, and hence antagoni ze, nuclear factors required for efficient gene expression, thereby ma rkedly reducing transcriptional rate. The pleiotrophy of the GCs actio n, coupled with the diverse experimental conditions employed in assess ing the GCs effects, indicate that GCs may utilize more than one mecha nism in inhibiting T cell activation, and warrant careful scrutiny in assigning a mechanism by which GCs exert their antiproliferative effec ts. (C) 1998 Elsevier Science Inc.