Multiplicity of glucocorticoid action in inhibiting allograft rejection.
Glucocorticoids (GCs) are used as immunosuppressive and antiinflammatory agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders. GCs were shown to exert their antiproliferative effects directly through blockade of certain elements of an early membrane-associated signal transduction pathway, modulation of the expression of select adhesion molecules, and by suppression of cytokine synthesis and action. GCs may act indirectly by inducing lipocortin synthesis, which in turn, inhibits arachidonic acid release from membrane-bound stores, and also by inducing transforming growth factor (TGF)-beta expression that subsequently blocks cytokine synthesis and T cell activation. Furthermore, by preferentially inhibiting the production of Th1 cytokines, GCs may enhance Th2 cell activity and, hence, precipitate a long-lasting state of tolerance through a preferential promotion of a Th2 cytokine-secreting profile. In exerting their antiproliferative effects, GCs influence both transcriptional and posttranscriptional events by binding their cytosolic receptor (GR), which subsequently binds the promoter region of cytokine genes on select DNA sites compatible with the GCs responsible elements (GRE) motif. In addition to direct DNA binding, GCs may also directly bind to, and hence antagonize, nuclear factors required for efficient gene expression, thereby markedly reducing transcriptional rate. The pleiotrophy of the GCs action, coupled with the diverse experimental conditions employed in assessing the GCs effects, indicate that GCs may utilize more than one mechanism in inhibiting T cell activation, and warrant careful scrutiny in assigning a mechanism by which GCs exert their antiproliferative effects.
Almawi
W Y
WY
Medical Sciences Unit, Lebanese National Council for Scientific Research, Beirut.
Hess
D A
DA
Rieder
M J
MJ
D000818:Animals; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D016377:Organ Transplantation; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D005938:Glucocorticoids