Vascular endothelial growth factor (VEGF) is supposed to contribute to the 
pathogenesis of allergic airway disease. VEGF expression is regulated by a 
variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible 
factor-1 alpha (HIF-1α). Recently, inhibition of the mammalian target of 
rapamycin (mTOR) has been shown to alleviate cardinal asthmatic features, 
including airway hyperresponsiveness, eosinophilic inflammation, and increased 
vascular permeability in asthma models. Based on these observations, we have 
investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in 
allergic asthma. In studies with the mTOR inhibitor rapamycin, we have 
elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. 
Next, the mechanisms by which mTOR is activated to modulate this response have 
been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase 
(PI3K)/Akt or protein kinase C-delta (PKC δ) in various cell types. Consistent 
with these, our results have revealed that suppression of PKC δ by rottlerin 
leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a 
mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a 
murine model. Thus, the present data indicate that PKC δ is necessary for the 
modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight 
regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may 
represent a valuable target for innovative therapeutic treatment of allergic 
airway disease.