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

BackgroundIL-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 ResultsWe 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--induced COX-2 by IL-17A in ASM cells and show that is not via increased COX-2 gene expression. Instead, TNF--induced COX-2 upregulation is subject to regulation by the proteasome, and IL-17A acts to increase TNF--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- and greatly enhances PGE(2) secretion from ASM cells. ConclusionAs 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.