Transcriptional and post‐transcriptional mechanisms of glucocorticoid antiproliferative effects

Mar 29, 2002Hematological oncology

How glucocorticoids slow cell growth through gene activity and other processes

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Abstract

Glucocorticoids (GCs) inhibit cytokine production through multiple mechanisms.

GCs suppress cytokine expression at both transcriptional and post-transcriptional levels.
Binding of GCs to their receptor facilitates nuclear translocation and regulation of cytokine gene expression.
GCs can upregulate high-affinity cytokine receptors on target cells despite decreased cytokine stimulation.
GCs favor the development of anti-inflammatory Th2 cells while suppressing pro-inflammatory Th1 cells.
Expression of the immunosuppressive cytokine transforming growth factor (TGF)-beta is stimulated by GCs.

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Glucocorticoids (GCs) are used as immunosuppressive and anti-inflammatory agents in treating organ transplantation rejection, autoimmune diseases, (hematological) cancers, and inflammatory disorders. GCs exert their effects through a multitude of mechanisms, the most significant of which is inhibition of cytokine production, and for some cytokines their effects on target cells. Paradoxically, GCs also upregulate the expression of (pro-inflammatory) high-affinity cytokine receptors on target cells in the face of lost ligand (cytokine) stimulation. GC inhibition of cytokine expression occurs at both transcriptional and post-transcriptional levels. GCs acted transcriptionally by binding their cytosolic receptor (GR), thereby facilitating its nuclear translocation and subsequent binding to the promoter region of cytokine genes on sites compatible with GC response element (GRE) motifs, which in turn directly or indirectly regulated gene expression. In addition to direct DNA binding, GCs acted post-transcriptionally by: (1) antagonism of nuclear factors required for efficient gene expression either directly or through induction of the expression of specific transcription factor antagonists, (2) altered Th lineage development by favouring the generation of (anti-inflammatory) Th2 cells and suppressing the induction or the activity of established (pro-inflammatory) Th1 cells, and (3) stimulating the expression of transforming growth factor (TGF)-beta, an immunosuppressive cytokine which inhibited cytokine production. However, these mechanisms are not mutually exclusive, since GCs may utilize more than one mechanism in exerting their anti-proliferative effect.

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Transcriptional and post‐transcriptional mechanisms of glucocorticoid antiproliferative effects

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