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 alpha-induced IL-8 or LPS-induced TNF alpha production. PP2A expression, glucocorticoid receptor (GR) nuclear translocation defined as the nuclear/cytoplasmic GR ratio and phosphorylation of GR-Ser(226), 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)-Tyr(307) phosphorylation compared with those in healthy volunteers. As the results, GR-Ser(226) and JNK1 phosphorylation were increased. The expression and activity of PP2A were negatively correlated with phosphorylation levels of GR-Ser(226). 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-Ser(226) via dephosphorylation of upstream JNK1. This novel mechanism will provide new insight for the development of new therapy for severe asthma.
机构:NYU, Sch Med, Dept Urol, New York, NY 10016 USA
Chen, Weiwei
;
Dang, Thoa
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机构:
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Dang, Thoa
;
Blind, Raymond D.
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机构:NYU, Sch Med, Dept Urol, New York, NY 10016 USA
Blind, Raymond D.
;
Wang, Zhen
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Wang, Zhen
;
Cavasotto, Claudio N.
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机构:
Molesoft, La Jolla, CA 92037 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Cavasotto, Claudio N.
;
Hittelman, Adam B.
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Hittelman, Adam B.
;
Rogatsky, Inez
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h-index: 0
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Hosp Special Surg, New York, NY 10021 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Rogatsky, Inez
;
Logan, Susan K.
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Urol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Logan, Susan K.
;
Garabedian, Michael J.
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h-index: 0
机构:
NYU, Sch Med, Dept Urol, New York, NY 10016 USA
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
机构:NYU, Sch Med, Dept Urol, New York, NY 10016 USA
Chen, Weiwei
;
Dang, Thoa
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Dang, Thoa
;
Blind, Raymond D.
论文数: 0引用数: 0
h-index: 0
机构:NYU, Sch Med, Dept Urol, New York, NY 10016 USA
Blind, Raymond D.
;
Wang, Zhen
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Wang, Zhen
;
Cavasotto, Claudio N.
论文数: 0引用数: 0
h-index: 0
机构:
Molesoft, La Jolla, CA 92037 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Cavasotto, Claudio N.
;
Hittelman, Adam B.
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Hittelman, Adam B.
;
Rogatsky, Inez
论文数: 0引用数: 0
h-index: 0
机构:
Hosp Special Surg, New York, NY 10021 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Rogatsky, Inez
;
Logan, Susan K.
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Urol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA
Logan, Susan K.
;
Garabedian, Michael J.
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Urol, New York, NY 10016 USA
NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA
NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USANYU, Sch Med, Dept Urol, New York, NY 10016 USA