title: Interleukin-13-induced MUC5AC expression is regulated by a PI3K-NFAT3 pathway in mouse tracheal epithelial cells.
abstract: Interleukin-13 (IL-13) plays a critical role in asthma mucus overproduction, while the mechanisms underlying this process are not fully elucidated. Previous studies showed that nuclear factor of activated T cells (NFAT) is involved in the pathogenesis of asthma, but whether it can directly regulate IL-13-induced mucus (particularly MUC5AC) production is still not clear. Here we showed that IL-13 specifically induced NFAT3 activation through promoting its dephosphorylation in air-liquid interface (ALI) cultures of mouse tracheal epithelial cells (mTECs). Furthermore, both Cyclosporin A (CsA, a specific NFAT inhibitor) and LY294002 (a Phosphoinositide 3-kinase (PI3K) inhibitor) significantly blocked IL-13-induced MUC5AC mRNA and protein production through the inhibition of NFAT3 activity. We also confirmed that CsA could not influence the forkhead Box A2 (Foxa2) and mouse calcium dependent chloride channel 3 (mClca3) expression in IL-13-induced MUC5AC production, which both are known to be important in IL-13-stimulated mucus expression. Our study is the first to demonstrate that the PI3K-NFAT3 pathway is positively involved in IL-13-induced mucus production, and provided novel insights into the molecular mechanism of asthma mucus hypersecretion.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Fugui
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yinfang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; State Key Lab. of Respiratory Disease (SKLRS), China. Electronic address: huahaoshen@163.com.
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics*; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018118:Chloride Channels; D002867:Chromones; D016572:Cyclosporine; D051542:Hepatocyte Nuclear Factor 3-beta; D018793:Interleukin-13; D009025:Morpholines; D055271:Mucin 5AC; D009088:Mucoproteins; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; C116464:Clca3a1 protein, mouse; C496503:Foxa2 protein, mouse; C524679:Muc5ac protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Interleukin-13; MUC5AC; Nuclear factor of activated T cells 3; Phosphoinositide 3-kinase