title: Induction of Airway Allergic Inflammation by Hypothiocyanite via Epithelial Cells.
abstract: Hypothiocyanite (OSCN-) serves as a potent innate defense system against microbes in the lungs. OSCN-is generated by the catalysis of peroxidases using thiocyanate transported via several anion transporters, including pendrin/SLC26A4 and hydrogen peroxide (H2O2) generated by Duox1 and Duox2. We previously demonstrated that expression of pendrin, peroxidases, and Duox1/Duox2 is up-regulated in bronchial asthma patients and/or asthma model mice and that these molecules are important in accelerating airway inflammation. However, it remained unclear how activating these molecules would lead to airway inflammation. In this study, we examined whether OSCN-produced via the pendrin/peroxidase/Duox pathway causes inflammation via airway epithelial cells. In an in vitro OSCN-production system, OSCN-, but not H2O2, activated NF-κB, a transcription factor critical for inflammatory responses, in the airway epithelial cells. OSCN-was sensed by protein kinase A (PKA) followed by formation of the dimerization of PKA. The dimerized PKA, the active form, was critical in activating NF-κB. Detoxifying H2O2, mainly by catalase, enabled the dominant abilities of OSCN-to dimerize PKA and activate NF-κB, compared with untreated H2O2Furthermore, OSCN-in high doses caused necrosis of the cells, inducing release of IL-33, a trigger to initiate type 2 inflammation. These results demonstrate that OSCN-in low doses activates NF-κB via PKA in airway epithelial cells, whereas OSCN-in high doses causes necrosis, suggesting an important role in airway allergic inflammation for the production of OSCN-via the pendrin/peroxidase/Duox pathway.
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nunomura
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nanri
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiraishi
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Mitamura
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Yoshihara
authors.affiliation: the Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale, Arizona 85259.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and kizuhara@cc.saga-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006967:Hypersensitivity / Q000209:etiology / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016877:Oxidants / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects / Q000473:pathology*; D013861:Thiocyanates / Q000009:adverse effects*
chemical_list: D000890:Anti-Infective Agents; D016877:Oxidants; D013861:Thiocyanates; C014607:hypothiocyanite ion; D006861:Hydrogen Peroxide
keywords: NF-κB; anion transport; asthma; epithelial cell; hydrogen peroxide; inflammation; peroxidase; protein kinase A (PKA)