EP <inf>2</inf> and EP <inf>4</inf> receptor antagonists: Impact on cytokine production and β <inf>2</inf> -adrenergic receptor desensitization in human airway smooth muscle

Bradbury, P; Rumzhum, NN; Ammit, AJ

EP <inf>2</inf> and EP <inf>4</inf> receptor antagonists: Impact on cytokine production and β <inf>2</inf> -adrenergic receptor desensitization in human airway smooth muscle

Bradbury, P

Rumzhum, NN Ammit, AJ

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Publication Type:: Journal Article
Citation:: Journal of Cellular Physiology, 2019, 234 (7), pp. 11070 - 11077
Issue Date:: 2019-07-01

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Field	Value	Language
dc.contributor.author	Bradbury, P https://orcid.org/0000-0001-6360-9591	en_US
dc.contributor.author	Rumzhum, NN	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.available	2020-05-25T19:27:33Z
dc.date.issued	2019-07-01	en_US
dc.identifier.citation	Journal of Cellular Physiology, 2019, 234 (7), pp. 11070 - 11077	en_US
dc.identifier.issn	0021-9541	en_US
dc.identifier.uri	http://hdl.handle.net/10453/129046
dc.description.abstract	© 2018 Wiley Periodicals, Inc. Prostaglandin E 2 (PGE 2 ) is a key prostanoid known to have both proinflammatory and anti-inflammatory impact in the context of chronic respiratory diseases. We hypothesize that these opposing effects may be the result of different prostanoid E (EP) receptor-mediated signaling pathways. In this study, we focus on two of the four EP receptors, EP 2 and EP 4 , as they are known to induce cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. Using primary human airway smooth muscle (ASM) cells, we first focussed on the PGE 2 -induced production of two cAMP-dependent proinflammatory mediators: interleukin 6 (IL-6) and cyclo-oxygenase 2 production. We show that PGE 2 -induced IL-6 protein secretion occurs via an EP 2 -mediated pathway, in a manner independent of receptor-mediated effects on messenger RNA (mRNA) expression and temporal activation kinetics of the transcription factor cAMP response element binding. Moreover, stimulation of ASM with PGE 2 did not establish a positive, receptor-mediated, feedback loop, as mRNA expression for EP 2 and EP 4 receptors were not upregulated and receptor antagonists were without effect. Our studies revealed that the EP 2 , but not the EP 4 , receptor is responsible for β 2 -adrenergic desensitization induced by PGE 2 . We demonstrate that PGE 2 -induced heterologous receptor desensitization responsible for tachyphylaxis to short- (salbutamol) or long- (formoterol) β 2 -agonists (measured by cAMP release) can be reversed by the EP 2 receptor antagonist PF-04418948. Importantly, this study highlights that inhibiting the EP 2 receptor restores β 2 -adrenergic receptor function in vitro and offers an attractive novel therapeutic target for treating infectious exacerbations in people suffering from chronic respiratory diseases in the future.	en_US
dc.relation.ispartof	Journal of Cellular Physiology	en_US
dc.relation.isbasedon	10.1002/jcp.27938	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.title	EP <inf>2</inf> and EP <inf>4</inf> receptor antagonists: Impact on cytokine production and β <inf>2</inf> -adrenergic receptor desensitization in human airway smooth muscle	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	234	en_US
utslib.for	1116 Medical Physiology	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 Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	234	en_US

Abstract:

© 2018 Wiley Periodicals, Inc. Prostaglandin E 2 (PGE 2 ) is a key prostanoid known to have both proinflammatory and anti-inflammatory impact in the context of chronic respiratory diseases. We hypothesize that these opposing effects may be the result of different prostanoid E (EP) receptor-mediated signaling pathways. In this study, we focus on two of the four EP receptors, EP 2 and EP 4 , as they are known to induce cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. Using primary human airway smooth muscle (ASM) cells, we first focussed on the PGE 2 -induced production of two cAMP-dependent proinflammatory mediators: interleukin 6 (IL-6) and cyclo-oxygenase 2 production. We show that PGE 2 -induced IL-6 protein secretion occurs via an EP 2 -mediated pathway, in a manner independent of receptor-mediated effects on messenger RNA (mRNA) expression and temporal activation kinetics of the transcription factor cAMP response element binding. Moreover, stimulation of ASM with PGE 2 did not establish a positive, receptor-mediated, feedback loop, as mRNA expression for EP 2 and EP 4 receptors were not upregulated and receptor antagonists were without effect. Our studies revealed that the EP 2 , but not the EP 4 , receptor is responsible for β 2 -adrenergic desensitization induced by PGE 2 . We demonstrate that PGE 2 -induced heterologous receptor desensitization responsible for tachyphylaxis to short- (salbutamol) or long- (formoterol) β 2 -agonists (measured by cAMP release) can be reversed by the EP 2 receptor antagonist PF-04418948. Importantly, this study highlights that inhibiting the EP 2 receptor restores β 2 -adrenergic receptor function in vitro and offers an attractive novel therapeutic target for treating infectious exacerbations in people suffering from chronic respiratory diseases in the future.

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http://hdl.handle.net/10453/129046