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CFLIP expression is altered in severe corticosteroid-resistant asthma.

ABSTRACT: Dysregulation of alternative splicing of mRNA precursors is known to contribute to numerous human diseases. In this study we carried out the first systematic search for asthma-associated changes in alternative splicing events, using a model of Aspergillus fumigatus (A. fumigatus)-sensitized mice and an exon junction microarray to detect potential changes in alternative splicing. One of the sensitization-associated changes identified in the search was a shift in alternative splicing of the mRNA encoding cFLIP, a modulator of the caspase-mediated extrinsic apoptosis pathway. Expanding these studies to human asthma patients, we discovered a significant decrease in the expression of both cFLIP isoforms in severe corticosteroid-resistant asthmatics. Although it is unclear whether these changes were due solely to differences in alternative splicing, these findings provide evidence that dysregulation of the extrinsic apoptosis pathway is part of the underlying immunopathogenesis of severe refractory asthma.

SUBMITTER: Lazarev D

PROVIDER: S-EPMC4535947 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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cFLIP expression is altered in severe corticosteroid-resistant asthma.

Lazarev Dennis D Miller Rachel L RL Dimango Emily E Fu Xian-Dong XD Li Hai-Ri HR Logan Charlotte J CJ Manley James L JL

Genomics data 20140523

Dysregulation of alternative splicing of mRNA precursors is known to contribute to numerous human diseases. In this study we carried out the first systematic search for asthma-associated changes in alternative splicing events, using a model of Aspergillus fumigatus (A. fumigatus)-sensitized mice and an exon junction microarray to detect potential changes in alternative splicing. One of the sensitization-associated changes identified in the search was a shift in alternative splicing of the mRNA e ...[more]

PMID: 26484081

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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.

Dataset Information

CFLIP expression is altered in severe corticosteroid-resistant asthma.

Publications

cFLIP expression is altered in severe corticosteroid-resistant asthma.

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