Kelli Boyd
Faculty Member
Last active: 3/20/2014

IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia.

Newcomb DC, Boswell MG, Sherrill TP, Polosukhin VV, Boyd KL, Goleniewska K, Brody SL, Kolls JK, Adler KB, Peebles RS
Am J Respir Cell Mol Biol. 2013 48 (6): 711-6

PMID: 23392574 · PMCID: PMC3727878 · DOI:10.1165/rcmb.2013-0017OC

Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production.

MeSH Terms (22)

Adoptive Transfer Animals Bronchoalveolar Lavage Fluid Female Interleukin-13 Interleukin-17 Lung Metaplasia Mice Mice, Inbred BALB C Mice, Knockout Mucus Neutrophils Ovalbumin Peptide Fragments Receptors, Interleukin-17 Respiratory Syncytial Viruses Respiratory Syncytial Virus Infections STAT1 Transcription Factor STAT6 Transcription Factor Th17 Cells Transcriptional Activation

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