Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells

Rahman, MM; Rumzhum, NN; Hansbro, PM; Morris, JC; Clark, AR; Verrills, NM; Ammit, AJ

Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells

Rahman, MM Rumzhum, NN Hansbro, PM

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

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Publication Type:: Journal Article
Citation:: Cellular Signalling, 2016, 28 (4), pp. 325 - 334
Issue Date:: 2016-04-01

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Field	Value	Language
dc.contributor.author	Rahman, MM	en_US
dc.contributor.author	Rumzhum, NN	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	2016-01-23	en_US
dc.date.issued	2016-04-01	en_US
dc.identifier.citation	Cellular Signalling, 2016, 28 (4), pp. 325 - 334	en_US
dc.identifier.issn	0898-6568	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128760
dc.description.abstract	© 2016. Chronic respiratory diseases are driven by inflammation, but some clinical conditions (severe asthma, COPD) are refractory to conventional anti-inflammatory therapies. Thus, novel anti-inflammatory strategies are necessary. The mRNA destabilizing protein, tristetraprolin (TTP), is an anti-inflammatory molecule that functions to induce mRNA decay of cytokines that drive pathogenesis of respiratory disorders. TTP is regulated by phosphorylation and protein phosphatase 2A (PP2A) is responsible for dephosphorylating (and hence activating) TTP, amongst other targets. PP2A is activated by small molecules, FTY720 and AAL(S), and in this study we examine whether these compounds repress cytokine production in a cellular model of airway inflammation using A549 lung epithelial cells stimulated with tumor necrosis factor α (TNFα) in vitro. PP2A activators significantly increase TNFα-induced PP2A activity and inhibit mRNA expression and protein secretion of interleukin 8 (IL-8) and IL-6; two key pro-inflammatory cytokines implicated in respiratory disease and TTP targets. The effect of PP2A activators is not via an increase in TNFα-induced TTP mRNA expression; instead we demonstrate a link between PP2A activation and TTP anti-inflammatory function by showing that specific knockdown of TTP with siRNA reversed the repression of TNFα-induced IL-8 and IL-6 mRNA expression and protein secretion by FTY720. Therefore we propose that PP2A activators affect the dynamic equilibrium regulating TTP; shifting the equilibrium from phosphorylated (inactive) towards unphosphorylated (active) but unstable TTP. PP2A activators boost the anti-inflammatory function of TTP and have implications for future pharmacotherapeutic strategies to combat inflammation in respiratory disease.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/
dc.relation.ispartof	Cellular Signalling	en_US
dc.relation.isbasedon	10.1016/j.cellsig.2016.01.009	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Respiratory Mucosa	en_US
dc.subject.mesh	Cell Line	en_US
dc.subject.mesh	Epithelial Cells	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Enzyme Activation	en_US
dc.subject.mesh	Tristetraprolin	en_US
dc.subject.mesh	Protein Phosphatase 2	en_US
dc.subject.mesh	Fingolimod Hydrochloride	en_US
dc.title	Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	28	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1116 Medical Physiology	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.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	28	en_US

Abstract:

© 2016. Chronic respiratory diseases are driven by inflammation, but some clinical conditions (severe asthma, COPD) are refractory to conventional anti-inflammatory therapies. Thus, novel anti-inflammatory strategies are necessary. The mRNA destabilizing protein, tristetraprolin (TTP), is an anti-inflammatory molecule that functions to induce mRNA decay of cytokines that drive pathogenesis of respiratory disorders. TTP is regulated by phosphorylation and protein phosphatase 2A (PP2A) is responsible for dephosphorylating (and hence activating) TTP, amongst other targets. PP2A is activated by small molecules, FTY720 and AAL(S), and in this study we examine whether these compounds repress cytokine production in a cellular model of airway inflammation using A549 lung epithelial cells stimulated with tumor necrosis factor α (TNFα) in vitro. PP2A activators significantly increase TNFα-induced PP2A activity and inhibit mRNA expression and protein secretion of interleukin 8 (IL-8) and IL-6; two key pro-inflammatory cytokines implicated in respiratory disease and TTP targets. The effect of PP2A activators is not via an increase in TNFα-induced TTP mRNA expression; instead we demonstrate a link between PP2A activation and TTP anti-inflammatory function by showing that specific knockdown of TTP with siRNA reversed the repression of TNFα-induced IL-8 and IL-6 mRNA expression and protein secretion by FTY720. Therefore we propose that PP2A activators affect the dynamic equilibrium regulating TTP; shifting the equilibrium from phosphorylated (inactive) towards unphosphorylated (active) but unstable TTP. PP2A activators boost the anti-inflammatory function of TTP and have implications for future pharmacotherapeutic strategies to combat inflammation in respiratory disease.

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http://hdl.handle.net/10453/128760