The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Md Mostafizur Rahman, Laura Prünte, Leonard F Lebender, Brijeshkumar S Patel, Ingrid Gelissen, Philip M Hansbro, Jonathan C Morris, Nicole M Verrills, Alaina J Ammit

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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 PGE2 secretion 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.

Original languageEnglish
Pages (from-to)37297
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 16 Nov 2016
Externally publishedYes

Keywords

  • A549 Cells
  • Cyclooxygenase 2/genetics
  • Dinoprostone/metabolism
  • Enzyme Activation/drug effects
  • Epithelial Cells/drug effects
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Inflammation/genetics
  • Interleukin-6/genetics
  • Interleukin-8/genetics
  • Lung/pathology
  • Lysophospholipids/pharmacology
  • Organophosphates/pharmacology
  • Protein Phosphatase 2/metabolism
  • Sphingosine/analogs & derivatives
  • Tumor Necrosis Factor-alpha/pharmacology

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