title: The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells.
abstract: Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2(PGE2)production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.
authors.affiliation: Faculty of Pharmacy, University of Sydney, NSW, 2006, Australia.
authors.forename: Md Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Faculty of Pharmacy, University of Sydney, NSW, 2006, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Prünte
authors.affiliation: Faculty of Pharmacy, University of Sydney, NSW, 2006, Australia.
authors.forename: Leonard F
authors.initials: LF
authors.lastname: Lebender
authors.affiliation: Faculty of Pharmacy, University of Sydney, NSW, 2006, Australia.
authors.forename: Brijeshkumar S
authors.initials: BS
authors.lastname: Patel
authors.affiliation: Faculty of Pharmacy, University of Sydney, NSW, 2006, Australia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Gelissen
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and the University of Newcastle, NSW, 2308, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: School of Chemistry, University of NSW, NSW, 2052, Australia.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, NSW, 2308, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Verrills
authors.affiliation: Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, NSW, Australia.|School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000072283:A549 Cells; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology; D010755:Organophosphates / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C525008:FTY 720P; D015850:Interleukin-6; D016209:Interleukin-8; D008246:Lysophospholipids; D010755:Organophosphates; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D051546:Cyclooxygenase 2; D054648:Protein Phosphatase 2; D015232:Dinoprostone; D013110:Sphingosine