title: IL-17A increases TNF-α-induced COX-2 protein stability and augments PGE2 secretion from airway smooth muscle cells: impact on β2 -adrenergic receptor desensitization.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: N N
authors.initials: NN
authors.lastname: Rumzhum
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: B S
authors.initials: BS
authors.lastname: Patel
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Prabhala
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: I C
authors.initials: IC
authors.lastname: Gelissen
authors.affiliation: Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.|School of Life Sciences, University of Technology, Sydney, NSW, Australia.
authors.forename: B G
authors.initials: BG
authors.lastname: Oliver
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D020381:Interleukin-17; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: COX-2 protein stability; IL-17A; PGE
  2; cAMP; receptors, adrenergic, beta-2