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.