title: Clarithromycin attenuates IL-13-induced periostin production in human lung fibroblasts.
abstract: Periostin is a biomarker indicating the presence of type 2 inflammation and submucosal fibrosis; serum periostin levels have been associated with asthma severity. Macrolides have immunomodulatory effects and are considered a potential therapy for patients with severe asthma. Therefore, we investigated whether macrolides can also modulate pulmonary periostin production.
  
  
  
  Using quantitative PCR and ELISA, we measured periostin production in human lung fibroblasts stimulated by interleukin-13 (IL-13) in the presence of two 14-member-ring macrolides-clarithromycin or erythromycin-or a 16-member-ring macrolide, josamycin. Phosphorylation of signal transducers and activators of transcription 6 (STAT6), downstream of IL-13 signaling, was evaluated by Western blotting. Changes in global gene expression profile induced by IL-13 and/or clarithromycin were assessed by DNA microarray analysis.
  
  
  
  Clarithromycin and erythromycin, but not josamycin, inhibited IL-13-stimulated periostin production. The inhibitory effects of clarithromycin were stronger than those of erythromycin. Clarithromycin significantly attenuated STAT6 phosphorylation induced by IL-13. Global gene expression analyses demonstrated that IL-13 increased mRNA expression of 454 genes more than 4-fold, while decreasing its expression in 390 of these genes (85.9%), mainly "extracellular," "plasma membrane," or "defense response" genes. On the other hand, clarithromycin suppressed 9.8% of the genes in the absence of IL-13. Clarithromycin primarily attenuated the gene expression of extracellular matrix protein, including periostin, especially after IL-13.
  
  
  
  Clarithromycin suppressed IL-13-induced periostin production in human lung fibroblasts, in part by inhibiting STAT6 phosphorylation. This suggests a novel mechanism of the immunomodulatory effect of clarithromycin in asthmatic airway inflammation and fibrosis.
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.|Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Bldg: KMSB I, Room: 215, Richmond, Virginia, 23298, USA.|Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka Hasama, Yufu, 879-5503, Japan.|Clinical Research Center of Respiratory Medicine, Tenshindo Hetsugi Hospital, 5956 Nihongi Nakahetsugi, Oita, 879-7761, Japan.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Komiya
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Asia International Institute of Infectious Disease Control, Teikyo University, 2-11-1 Kaga Itabashi-ku, Tokyo, 173-8605, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Mitamura
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nunomura
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nanri
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Yoshihara
authors.affiliation: Center for Comprehensive Community Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawaguchi
authors.affiliation: Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka Hasama, Yufu, 879-5503, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kadota
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Bldg: KMSB I, Room: 215, Richmond, Virginia, 23298, USA.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Rubin
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan. kizuhara@cc.saga-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
mesh_terms: D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002460:Cell Line; D017291:Clarithromycin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000008:administration & dosage*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D018793:Interleukin-13; C512835:POSTN protein, human; D017291:Clarithromycin
keywords: Asthma; Fibroblast; IL-13; Macrolide; Periostin