Inhibition of Protein Kinase C Delta Attenuates Allergic Airway Inflammation through Suppression of PI3K/Akt/mTOR/HIF-1 Alpha/VEGF Pathway

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-1 alpha). 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-1 alpha-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1 alpha-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 delta) in various cell types. Consistent with these, our results have revealed that suppression of PKC d by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1a-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC d is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1a activity and VEGF expression. In conclusion, PKC d may represent a valuable target for innovative therapeutic treatment of allergic airway disease.