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Transcriptional and post‐transcriptional mechanisms of glucocorticoid antiproliferative effects
Author(s) -
Almawi Wassim Y.,
Abou Jaoude Maroun M.,
Li Xian C.
Publication year - 2002
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.684
Subject(s) - cytokine , biology , transcription factor , microbiology and biotechnology , glucocorticoid receptor , downregulation and upregulation , glucocorticoid , gene expression , receptor , cancer research , immunology , gene , genetics
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)‐β, 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. Copyright © 2001 John Wiley & Sons, Ltd.