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PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma.

ABSTRACT: BACKGROUND:Glucocorticoid (GC) insensitivity is an important feature of severe and fatal asthma. Oxidative stress can induce phosphoinositide-3-kinase (PI3K) activation, contributing to the development of GC insensitivity in chronic airway diseases. However, the underlying molecular mechanism of PI3K in the pathogenesis of severe asthma remains unknown. METHODS:We isolated peripheral blood mononuclear cells (PBMCs) from 34 participants (12 patients with mild/moderate asthma, 10 patients with severe asthma, and 12 control subjects). H2O2 was used to stimulate the human macrophage line U937 to mimic the oxidative stress status in severe asthma. The ability of candidate compounds, namely, azithromycin, PI3K inhibitors (BEZ235 and LY294002) and a p38 MAPK inhibitor (BIRB796), to ameliorate GC insensitivity in severe asthma was evaluated. RESULTS:PBMCs from patients with severe asthma exhibited dose-dependent and time-dependent GC insensitivity, which correlated with reduced activity of histone deacetylase 2 (HDAC2) (p?

SUBMITTER: Bi J

PROVIDER: S-EPMC7048898 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma.

Bi Jing J Min Zhihui Z Yuan Honglei H Jiang Zhilong Z Mao Ruolin R Zhu Tao T Liu Chunfang C Zeng Yuzhen Y Song Juan J Du Chunling C Chen Zhihong Z

Clinical and translational medicine 20200228 1

<h4>Background</h4>Glucocorticoid (GC) insensitivity is an important feature of severe and fatal asthma. Oxidative stress can induce phosphoinositide-3-kinase (PI3K) activation, contributing to the development of GC insensitivity in chronic airway diseases. However, the underlying molecular mechanism of PI3K in the pathogenesis of severe asthma remains unknown.<h4>Methods</h4>We isolated peripheral blood mononuclear cells (PBMCs) from 34 participants (12 patients with mild/moderate asthma, 10 pa ...[more]

PMID: 32112175

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Project description:BACKGROUND: Corticosteroid insensitivity is a major barrier of treatment for some chronic inflammatory diseases, such as severe asthma, but the molecular mechanism of the insensitivity has not been fully elucidated. The object of this study is to investigate the role of protein phosphate 2A (PP2A), a serine/threonine phosphatase, on corticosteroid sensitivity in severe asthma. METHODOLOGY/PRINCIPAL FINDINGS: Corticosteroid sensitivity was determined by the dexamethasone ability to inhibit TNF?-induced IL-8 or LPS-induced TNF? production. PP2A expression, glucocorticoid receptor (GR) nuclear translocation defined as the nuclear/cytoplasmic GR ratio and phosphorylation of GR-Ser²²?, c-Jun N-terminal kinase 1 (JNK1) and PP2A were analysed by Western-blotting. Phosphatase activity was measured by fluorescence-based assay. Okadaic acid (OA), a PP2A inhibitor, reduced corticosteroid sensitivity with reduced GR nuclear translocation and increased GR phosphorylation in U937 monocytic cells. PP2A knockdown by RNA interference showed similar effects. IL-2/IL-4 treatment to U937 reduced corticosteroid sensitivity, and PP2A expression/activity. In peripheral blood mononuclear cells (PBMCs) from severe asthma, the PP2A expression and activity were significantly reduced with concomitant enhancement of PP2A(C)-Tyr³?? phosphorylation compared with those in healthy volunteers. As the results, GR-Ser²²? and JNK1 phosphorylation were increased. The expression and activity of PP2A were negatively correlated with phosphorylation levels of GR-Ser²²?. Furthermore, co-immunoprecipitation assay in U937 cells revealed that PP2A associated with GR and JNK1 and IL-2/IL-4 exposure caused dissociation of each molecule. Lastly, PP2A overexpression increased corticosteroid sensitivity in U937 cells. CONCLUSIONS/SIGNIFICANCE: PP2A regulates GR nuclear translocation and corticosteroid sensitivity possibly by dephosphorylation of GR-Ser²²? via dephosphorylation of upstream JNK1. This novel mechanism will provide new insight for the development of new therapy for severe asthma.

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PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma.

Publications

PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma.

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