Fig. 8

Possible mechanism by which PI3K inhibitors ameliorate GC insensitivity in severe asthma. GC bind with GC receptors (GR) in the cytoplasm,then the GC-bound GR complex diffuse across the nuclear membrane where it binds to the glucocorticoid response element (GRE). The GRE is responsible for transcribing anti-inflammatory proteins. Additionally, binding of GC to GR results in recruitment of histone deacetylase 2 (HDAC2), which is responsible for deacetylating GR, permitting its binding to nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1). Upon binding, these transcription factors are deactivated, thereby inhibiting the transcription of pro-inflammatory proteins. Additionally, HDAC2 deacetylates the histone permitting transcription of anti-inflammatory genes by GR. In severe asthma, oxidative stress can activate phosphoinositide 3-kinase (PI3K) pathway. PI3K phosphorylation reduce HDAC2 activity, affect the balance between pro-inflammatory and anti-inflammatory gene transcription and finally decrease corticosteroid sensitivity. Selective PI3K inhibitor (BEZ235 et al.) can restore HDAC-2 activity, and nonselective PI3K inhibitor (LY294002 et al.) can directly inhibit phosphorylation of nuclear signal transcription factors and finally improve glucocorticoid insensitivity