title: In human T cells mifepristone antagonizes glucocorticoid non-genomic rapid responses in terms of Na(+)/H(+)-exchange 1 activity, but not ezrin/radixin/moesin phosphorylation.
abstract: Glucocorticoids (GCs) and progesterone have been employed as immunosuppressive agents during pregnancy for many years. Intracellular acidification by GCs is due to a rapid non-genomic inhibition of membrane Na(+)/H(+)-exchange 1 (NHE1) activity and is followed by immunosuppression of PHA-stimulated proliferation. NHE1 is tethered to the cortical actin cytoskeleton through ezrin/radixin/moesin (ERM) proteins within lipid rafts; these regulate cell shape, migration and resistance to apoptosis. We explored whether mifepristone (RU486), an antagonist of GCs in T cells, is able to completely block rapid non-genomic responses, namely NHE1 activity and the phosphorylation C-terminal residues of ERM proteins at threonine (cp-ERM). GCs stimulate a rapid non-genomic cp-ERM response in cells within 5min. RU486 antagonized the GC-induced rapid decrease in NHE1 activity, and arrested PHA-stimulated T cells at G0/G1 phase but had no effect on the rapid increase in cp-ERM, which persisted for 24h. However, the cp-ERM response was blocked by staurosporine in both resting and GC stimulated cells. The results of RU486 antagonized the GC induced rapid decrease in NHE1 ion transport activity, but not the increase cp-ERM. This suggests that RU486 in T cells exerts its antagonistic effects at NHE1 containing plasma membrane sites and not where cp-ERM links lipid rafts to cortical cytoskeletons.
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC; Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan, ROC; Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 40402, Taiwan, ROC. Electronic address: eileen@ym.edu.tw.
authors.forename: Eileen Jea
authors.initials: EJ
authors.lastname: Chien
authors.affiliation: Division of Allergy-Immunology-Rheumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC.
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Vincent Han-Jhih
authors.initials: VH
authors.lastname: Chang
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Enoch Pin-Yi
authors.initials: EP
authors.lastname: Lin
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Trista Pin-Tsun
authors.initials: TP
authors.lastname: Kuo
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Chau-Heng
authors.initials: CH
authors.lastname: Chien
authors.affiliation: Department of Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC; Division of Allergy-Immunology-Rheumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC. Electronic address: hylin@vghtpe.gov.tw.
authors.forename: Hsiao-Yi
authors.initials: HY
authors.lastname: Lin
mesh_terms: D000328:Adult; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D055815:Young Adult; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D005938:Glucocorticoids; D008565:Membrane Proteins; D008840:Microfilament Proteins; D015735:Mifepristone; D017923:Sodium-Hydrogen Exchangers; D000099149:Ezrin; C071058:moesin; C071776:radixin
keywords: Ezrin/radixin/moesin; Glucocorticoids; Mifepristone; Na(+)/H(+)-exchange 1; Phosphorylation; T cells