PI3Kδ contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD–RIG-I–NF-κB axis
| Autor: | Anu Marahatta, Hyung Ryong Kim, Hye Kyung Kim, Jae Sung Pyo, Yong Chul Lee, Kashi Raj Bhattarai, Ok Hee Chai, Bidur Bhandary, Mallikarjun Handigund, Hyun Kyoung Kim, Han-Jung Chae, In-hwan Baek, Geum Hwa Lee, Hwa-Young Lee, Raghu Patil Junjappa |
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| Rok vydání: | 2018 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Ovalbumin Clinical Biochemistry Nerve Tissue Proteins Receptors Cell Surface Biochemistry Proinflammatory cytokine Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors chemistry.chemical_classification Reactive oxygen species biology Adenine Endoplasmic reticulum NF-kappa B Membrane Proteins NF-κB Endoplasmic Reticulum Stress Asthma Cell biology Disease Models Animal Oxidative Stress 030104 developmental biology chemistry Quinazolines biology.protein Unfolded protein response Molecular Medicine Original Article Lipid Peroxidation Reactive Oxygen Species Oxidation-Reduction 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Experimental & Molecular Medicine |
| ISSN: | 2092-6413 1226-3613 |
| DOI: | 10.1038/emm.2017.270 |
| Popis: | 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 PI3Kδ 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-κB (NF-κB) 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-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD-RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma. |
| Databáze: | OpenAIRE |
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