Phosphoinositide 3-kinase δ inhibitor suppresses interleukin-17 expression in a murine asthma model.
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 PI3Kδ in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma. After ovalbumin inhalation, administration of a selective p110δ 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)-κB activity. In addition, a NF-κB 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 p110δ signalling pathway suppresses IL-17 expression through regulation of NF-κB activity and, thus, has therapeutic potential in asthma.
Park
S J
SJ
Dept of Internal Medicine, Chonbuk National University Medical School, Deokjin-gu, Jeonju, Jeonbuk 561-180, South Korea.
Lee
K S
KS
Kim
S R
SR
Min
K H
KH
Moon
H
H
Lee
M H
MH
Chung
C R
CR
Han
H J
HJ
Puri
K D
KD
Lee
Y C
YC
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002630:Chemotactic Factors / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D020381:Interleukin-17 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000201:enzymology; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000008:administration & dosage*; D013450:Sulfones / Q000494:pharmacology
C416282:BAY 11-7085; D002630:Chemotactic Factors; C477872:IC 87114; D020381:Interleukin-17; D015848:Interleukin-5; D016328:NF-kappa B; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D013450:Sulfones; D015847:Interleukin-4; D000225:Adenine