title: IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia.
abstract: 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.
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. dawn.newcomb@vanderbilt.edu
authors: Dawn C
authors: DC
authors: Newcomb
authors: Madison G
authors: MG
authors: Boswell
authors: Taylor P
authors: TP
authors: Sherrill
authors: Vasiliy V
authors: VV
authors: Polosukhin
authors: Kelli L
authors: KL
authors: Boyd
authors: Kasia
authors: K
authors: Goleniewska
authors: Steven L
authors: SL
authors: Brody
authors: Jay K
authors: JK
authors: Kolls
authors: Kenneth B
authors: KB
authors: Adler
authors: R Stokes
authors: RS
authors: Peebles
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008679:Metaplasia / Q000276:immunology / Q000473:pathology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology; D015533:Transcriptional Activation
chemical_list: C098680:Il17a protein, mouse; C491673:Il17ra protein, mouse; D018793:Interleukin-13; D020381:Interleukin-17; C111390:OVA 323-339; D010446:Peptide Fragments; D053722:Receptors, Interleukin-17; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D010047:Ovalbumin
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