IL-17A increases TNF-α-induced COX-2 protein stability and augments PGE<inf>2</inf> secretion from airway smooth muscle cells: Impact on β<inf>2</inf>-adrenergic receptor desensitization

Rumzhum, NN; Patel, BS; Prabhala, P; Gelissen, IC; Oliver, BG; Ammit, AJ

IL-17A increases TNF-α-induced COX-2 protein stability and augments PGE<inf>2</inf> secretion from airway smooth muscle cells: Impact on β<inf>2</inf>-adrenergic receptor desensitization

Rumzhum, NN Patel, BS Prabhala, P Gelissen, IC Oliver, BG

Ammit, AJ

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Publication Type:: Journal Article
Citation:: Allergy: European Journal of Allergy and Clinical Immunology, 2016, 71 (3), pp. 387 - 396
Issue Date:: 2016-03-01

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Field	Value	Language
dc.contributor.author	Rumzhum, NN	en_US
dc.contributor.author	Patel, BS	en_US
dc.contributor.author	Prabhala, P	en_US
dc.contributor.author	Gelissen, IC	en_US
dc.contributor.author	Oliver, BG https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.available	2020-05-25T19:18:55Z
dc.date.issued	2016-03-01	en_US
dc.identifier.citation	Allergy: European Journal of Allergy and Clinical Immunology, 2016, 71 (3), pp. 387 - 396	en_US
dc.identifier.issn	0105-4538	en_US
dc.identifier.uri	http://hdl.handle.net/10453/41773
dc.description.abstract	© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background IL-17A plays an important role in respiratory disease and is a known regulator of pulmonary inflammation and immunity. Recent studies have linked IL-17A with exacerbation in asthma and COPD. We have shown that the enzyme cyclooxygenase-2 (COX-2) and its prostanoid products, prostaglandin E2 (PGE2) in particular, are key contributors in in vitro models of infectious exacerbation; however, the impact of IL-17A was not known. Methods and Results We address this herein and show that IL-17A induces a robust and sustained upregulation of COX-2 protein and PGE2 secretion from airway smooth muscle (ASM) cells. COX-2 can be regulated at transcriptional, post-transcriptional and/or post-translational levels. We have elucidated the underlying molecular mechanisms responsible for the sustained upregulation of TNF-α-induced COX-2 by IL-17A in ASM cells and show that is not via increased COX-2 gene expression. Instead, TNF-α-induced COX-2 upregulation is subject to regulation by the proteasome, and IL-17A acts to increase TNF-α-induced COX-2 protein stability as confirmed by cycloheximide chase experiments. In this way, IL-17A acts to amplify the COX-2-mediated effects of TNF-α and greatly enhances PGE2 secretion from ASM cells. Conclusion As PGE2 is a multifunctional prostanoid with diverse roles in respiratory disease, our studies demonstrate a novel function for IL-17A in airway inflammation by showing for the first time that IL-17A impacts on the COX-2/PGE2 pathway, molecules known to contribute to disease exacerbation.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/
dc.relation.ispartof	Allergy: European Journal of Allergy and Clinical Immunology	en_US
dc.relation.isbasedon	10.1111/all.12810	en_US
dc.subject.classification	Allergy	en_US
dc.subject.mesh	Respiratory System	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Myocytes, Smooth Muscle	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Dinoprostone	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Receptors, Adrenergic, beta-2	en_US
dc.subject.mesh	RNA, Messenger	en_US
dc.subject.mesh	Cyclic AMP	en_US
dc.subject.mesh	Interleukin-17	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Cyclooxygenase 2	en_US
dc.subject.mesh	Protein Stability	en_US
dc.subject.mesh	Adrenergic beta-2 Receptor Agonists	en_US
dc.subject.mesh	Proteasome Inhibitors	en_US
dc.title	IL-17A increases TNF-α-induced COX-2 protein stability and augments PGE<inf>2</inf> secretion from airway smooth muscle cells: Impact on β<inf>2</inf>-adrenergic receptor desensitization	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	71	en_US
utslib.for	1107 Immunology	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	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	71	en_US

Abstract:

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background IL-17A plays an important role in respiratory disease and is a known regulator of pulmonary inflammation and immunity. Recent studies have linked IL-17A with exacerbation in asthma and COPD. We have shown that the enzyme cyclooxygenase-2 (COX-2) and its prostanoid products, prostaglandin E2 (PGE2) in particular, are key contributors in in vitro models of infectious exacerbation; however, the impact of IL-17A was not known. Methods and Results We address this herein and show that IL-17A induces a robust and sustained upregulation of COX-2 protein and PGE2 secretion from airway smooth muscle (ASM) cells. COX-2 can be regulated at transcriptional, post-transcriptional and/or post-translational levels. We have elucidated the underlying molecular mechanisms responsible for the sustained upregulation of TNF-α-induced COX-2 by IL-17A in ASM cells and show that is not via increased COX-2 gene expression. Instead, TNF-α-induced COX-2 upregulation is subject to regulation by the proteasome, and IL-17A acts to increase TNF-α-induced COX-2 protein stability as confirmed by cycloheximide chase experiments. In this way, IL-17A acts to amplify the COX-2-mediated effects of TNF-α and greatly enhances PGE2 secretion from ASM cells. Conclusion As PGE2 is a multifunctional prostanoid with diverse roles in respiratory disease, our studies demonstrate a novel function for IL-17A in airway inflammation by showing for the first time that IL-17A impacts on the COX-2/PGE2 pathway, molecules known to contribute to disease exacerbation.

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http://hdl.handle.net/10453/41773