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IL‐17A increases TNF‐α‐induced COX‐2 protein stability and augments PGE 2 secretion from airway smooth muscle cells: impact on β 2 ‐adrenergic receptor desensitization
Author(s) -
Rumzhum N. N.,
Patel B. S.,
Prabhala P.,
Gelissen I. C.,
Oliver B. G.,
Ammit A. J.
Publication year - 2016
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12810
Subject(s) - downregulation and upregulation , prostaglandin e , prostanoid , tumor necrosis factor alpha , inflammation , immunology , receptor , cycloheximide , biology , prostaglandin , microbiology and biotechnology , endocrinology , medicine , biochemistry , protein biosynthesis , gene
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 E 2 (PGE 2 ) 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 PGE 2 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 PGE 2 secretion from ASM cells. Conclusion As PGE 2 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/PGE 2 pathway, molecules known to contribute to disease exacerbation.