Phosphoinositide 3-kinase δ inhibitor suppresses interleukin-17 expression in a murine asthma model

Abstract

Phosphoinositide 3-kinases (PI3Ks) contribute to the pathogenesis of asthma by regulating the activation of inflammatory mediators, inflammatory cell recruitment and immune cell function. Recent findings have indicated that PI3Ks also regulate the expression of interleukin (IL)-17, which has been recognised as an important cytokine involved in airway inflammation.In the present study, we investigated a role of PI3Kd in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma.After ovalbumin inhalation, administration of a selective p110d inhibitor, IC87114, significantly attenuated airway infiltration of total cells, lymphocytes, neutrophils and eosinophils, as well as airway hyperresponsiveness, and attenuated the increase in IL-17 protein and mRNA expression. Moreover, IC87114 reduced levels of IL-4, -5 and -13, expression of keratinocyte chemoattractant protein and mRNA, and nuclear factor (NF)-kB activity. In addition, a NF-kB inhibitor, BAY 11-7085 substantially reduced the increase in IL-17 protein levels. Our results also showed that inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness.These findings suggest that inhibition of the p110d signalling pathway suppresses IL-17 expression through regulation of NF-kB activity and, thus, has therapeutic potential in asthma.

The Receptor For Advanced Glycation End-Products Is A Central Mediator Of Asthma Pathogenesis

“…Moreover, it may account for the subtle differences in airway responsiveness to methacholine challenge between naive saline-treated WT and RAGE KO mice (RAGE KO mice treated with saline showed an elevated Rn parameter compared with WT mice thus treated), as a number of studies have indicated a role for IL-17 in promoting airway hyperresponsiveness. [47][48][49][50] As an asthmatic response is not initiated in the RAGE KO mice treated with HDM extract (as evidenced by pulmonary function parameters, histology, and cytokine profiling), it is not particularly surprising that in this strain there was no consequent up-regulation in IL-17 from baseline in response to allergen.…”

The role of cytokines and chemokines in severe respiratory syncytial virus infection and subsequent asthma

“…Recent studies have suggested that IL-17 was involved in the pathogenesis of allergic asthma. Expression of IL-17 increases in sputum, bronchoalveolar lavage (BAL) fluids, bronchial biopsies, plasma, and activated PMBCs from asthmatic patients and mouse models [91][92][93][94]. Inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness [95].…”

Special Consideration in Treating Patients of Overlap Between Asthma and COPD

“…PI3K is important for chemotactic responses, and selective inhibitors are in development, whereas PI3K activation results in reduced steroid responsiveness through reducing histone deacetylase (HDAC)2 activity, thus PI3K inhibitors could potentially reverse corticosteroid resistance in severe asthma . In addition, selective inhibition of the PI3K signaling pathway suppresses IL-17 expression through regulation of NF-B activity in asthma (Park et al, 2010). These findings suggest that PI3K/ targeting agent can be a promising therapeutic tool for the treatment and prevention of severe asthma having COPD natures and acute exacerbation.…”