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

Rahman, MM; Prünte, L; Lebender, LF; Patel, BS; Gelissen, I; Hansbro, PM; Morris, JC; Clark, AR; Verrills, NM; Ammit, AJ

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

Rahman, MM Prünte, L Lebender, LF Patel, BS Gelissen, I Hansbro, PM

Morris, JC Clark, AR Verrills, NM Ammit, AJ

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Publication Type:: Journal Article
Citation:: Scientific Reports, 2016, 6
Issue Date:: 2016-11-16

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Field	Value	Language
dc.contributor.author	Rahman, MM	en_US
dc.contributor.author	Prünte, L	en_US
dc.contributor.author	Lebender, LF	en_US
dc.contributor.author	Patel, BS	en_US
dc.contributor.author	Gelissen, I	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Morris, JC	en_US
dc.contributor.author	Clark, AR	en_US
dc.contributor.author	Verrills, NM	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.available	2016-10-27	en_US
dc.date.issued	2016-11-16	en_US
dc.identifier.citation	Scientific Reports, 2016, 6	en_US
dc.identifier.uri	http://hdl.handle.net/10453/116818
dc.description.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.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1079187
dc.relation.ispartof	Scientific Reports	en_US
dc.relation.isbasedon	10.1038/srep37297	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Epithelial Cells	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Inflammation	en_US
dc.subject.mesh	Sphingosine	en_US
dc.subject.mesh	Dinoprostone	en_US
dc.subject.mesh	Lysophospholipids	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Interleukin-8	en_US
dc.subject.mesh	Interleukin-6	en_US
dc.subject.mesh	Gene Expression Regulation, Neoplastic	en_US
dc.subject.mesh	Enzyme Activation	en_US
dc.subject.mesh	Cyclooxygenase 2	en_US
dc.subject.mesh	Protein Phosphatase 2	en_US
dc.subject.mesh	Organophosphates	en_US
dc.subject.mesh	A549 Cells	en_US
dc.title	The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells	en_US
dc.type	Journal Article
utslib.citation.volume	6	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.publication-status	Published	en_US
pubs.volume	6	en_US

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.

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http://hdl.handle.net/10453/116818