Glucocorticoid-mediated transrepression is regulated by histone acetylation and DNA methylation.
Glucocorticoids are highly effective in controlling chronic inflammatory diseases by inhibiting the expression of cytokines and chemokines. Glucocorticoids act through binding of their receptor resulting to inhibition of transcription factors such as nuclear factor kappa B (NF-kappa B). This may occur via the transcription integrator protein, CREB binding protein (CBP), which has intrinsic histone acetylase (HAT) activity. Interleukin (IL)-1 beta caused a significant increase in NF-kappa B-mediated granulocyte/macrophage colony stimulating factor (GM-CSF) release, which was inhibited by the glucocorticoid mometasone furoate (MF) (EC(50)=2 x 10(-11) M). This effect was inhibited by CBP over-expression. The role of histone acetylation and DNA methylation in the transcription of GM-CSF was indicated by trichostatin A (TSA), an inhibitor of histone deacetylases, and 5-azacytidine (5-aza), a DNA methylase inhibitor, to increase GM-CSF expression partially blocking glucocorticoid inhibition of IL-1 beta-stimulated GM-CSF release. These data suggest that the mechanism of glucocorticoid action in suppressing interleukin-1 beta-stimulated GM-CSF release in A549 cells may involve modulation of CBP-mediated histone-acetylase activity and DNA methylation.
Kagoshima
M
M
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK.
Wilcke
T
T
Ito
K
K
Tsaprouni
L
L
Barnes
P J
PJ
Punchard
N
N
Adcock
I M
IM
D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology; D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D000068656:Mometasone Furoate; D011244:Pregnadienediols / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D006657:Histones; D007375:Interleukin-1; D011244:Pregnadienediols; D029701:Saccharomyces cerevisiae Proteins; D000068656:Mometasone Furoate; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000123:Acetyltransferases; D051548:Histone Acetyltransferases