Glucocorticoid-mediated transrepression is regulated by histone acetylation and DNA methylation

Glucocorticoids are highly effective in controlling chronic inflammatory di seases by inhibiting the expression of cytokines and chemokines. Glucocorti coids act through binding of their receptor resulting to inhibition of tran scription factors such as nuclear factor kappaB (NF-kappaB). This may occur via the transcription integrator protein, CREB binding protein (CBP), whic h has intrinsic histone acetylase (HAT) activity. Interleukin (IL)-1 beta c aused a significant increase in NF-kappaB-mediated granulocyte/macrophage c olony stimulating factor (GM-CSF) release, which was inhibited by the gluco corticoid mometasone furoate (MF) (EC50 = 2 X 10(-11) M). This effect was i nhibited by CBP over-expression. The role of histone acetylation and DNA me thylation in the transcription of GM-CSF was indicated by trichostatin A (T SA), an inhibitor of histone deacetylases, and 5-azacytidine (5-aza), a DNA methylase inhibitor, to increase GM-CSF expression partially blocking gluc ocorticoid inhibition of IL-lp-stimulated GM-CSF release. These data sugges t that the mechanism of glueocorticoid action in suppressing interleukin-lp -stimulated GM-CSF release in A549 cells may involve modulation of CBP-medi ated histone-acetylase activity and DNA methylation. (C) 2001 Elsevier Scie nce B.V. All rights reserved.