title: Clarithromycin Suppresses Chloride Channel Accessory 1 and Inhibits Interleukin-13-Induced Goblet Cell Hyperplasia in Human Bronchial Epithelial Cells.
abstract: Activation of the interleukin-13 (IL-13) receptor leads to signal transducer and activator of transcription 6 (STAT6) activation and subsequent induction of SAM pointed domain containing ETS transcription factor (SPDEF) and chloride channel accessory 1 (CLCA1), increasing secretion of the gel-forming mucin MUC5AC. Activation of the epidermal growth factor receptor (EGFR) also leads to MUC5AC production via extracellular signal-regulated kinase (ERK1/2). We examined the effect of clarithromycin IL-13 signaling leading to production. Normal human bronchial epithelial (NHBE) cells were grown for 14 days at an air-liquid interface (ALI) with IL-13 and/or clarithromycin. Histochemical analysis was performed using hematoxylin and eosin (HE) staining and MUC5AC immunostaining. MUC5AC, SPDEF, and CLCA1 mRNA expression were evaluated by real-time PCR. Western analysis was used to assess phosphorylation of STAT6 and ERK1/2. Clarithromycin decreased IL-13-induced goblet cell hyperplasia and MUC5AC mRNA expression in a dose-dependent manner. Clarithromycin decreased IL-13-stimulated SPDEF and CLCA1 mRNA expression in a dose-dependent manner, and at 32 μg/ml CLCA1 was profoundly decreased (P < 0.001). Although clarithromycin had no effect on STAT6 phosphorylation induced by IL-13, it decreased constitutive phosphorylation of ERK1/2 (P < 0.05).
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Akimichi
authors.initials: A
authors.lastname: Nagashima
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan shinkai@yokohama-cu.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shinkai
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinoda
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Tadasuke
authors.initials: T
authors.lastname: Shimokawaji
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Mishina
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Toda
authors.affiliation: Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inayama
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Rubin
authors.affiliation: Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017291:Clarithromycin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053660:Receptors, Interleukin-13 / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C492109:CLCA1 protein, human; D018118:Chloride Channels; D018793:Interleukin-13; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D011500:Protein Synthesis Inhibitors; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D053660:Receptors, Interleukin-13; C403974:SPDEF protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017291:Clarithromycin