Controversies Surrounding the Potential Use of Histone Deacetylase Inhibitors for the Treatment of Asthma

Figure 4

Corticosteroids diffuse into the cell where they bind to the glucocorticoid receptor. Activated receptors bind to glucocorticoid response elements in promoters and alter the transcription of glucocorticoid-responsive genes. Corticosteroids attenuate inflammatory gene transcription which, is mediated by the proinflammatory transcription factor NF-κB, by inhibiting HAT activity and by recruiting HDAC2 repressor complexes. Theophylline reverses oxidative stress-induced decreases in the expression of HDACs which are mediated by activation of PI3K-δ. This mechanism may account, at least in part, for the therapeutic benefits seen by combinations of low-dose theophylline and corticosteroids.