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PI3K delta contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD-RIG-I-NF-kappa B axis

Title
PI3K delta contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD-RIG-I-NF-kappa B axis
Authors
Kim, Hyun-KyoungLee, Geum-HwaBhattarai, Kashi RajJunjappa, Raghu PatilLee, Hwa-YoungHandigund, MallikarjunMarahatta, AnuBhandary, BidurBaek, In-HwanPyo, Jae SungKim, Hye-KyungChai, Ok HeeKim, Hyung-RyongLee, Yong-ChulChae, Han-Jung
DGIST Authors
Kim, Hyung-Ryong
Issue Date
2018-02
Citation
Experimental and Molecular Medicine, 50(2), e444-12
Type
Article
Article Type
Article
Keywords
OXIDATIVE STRESSACTIVATIONMICEPATHOGENESISRESPONSESPATHWAYENDOPLASMIC-RETICULUM STRESSALLERGIC AIRWAY INFLAMMATIONPROTEIN DISULFIDE-ISOMERASEPHOSPHOINOSITIDE 3-KINASE
ISSN
1226-3613
Abstract
Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3K delta inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-kappa B (NF-kappa B) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1 alpha (IRE1 alpha)-dependent degradation (RIDD) of IRE1 alpha was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3K delta may induce severe airway inflammation and hyperresponsiveness by activating NF-kappa B signaling through ER-associated ROS and RIDD-RIG-I activation. The PI3K delta inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.
URI
http://hdl.handle.net/20.500.11750/6218
DOI
10.1038/emm.2017.270
Publisher
NLM (Medline)
Files:
Collection:
ETC1. Journal Articles


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