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Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts

BACKGROUND: 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, w...

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Autores principales: Komiya, Kosaku, Ohta, Shoichiro, Arima, Kazuhiko, Ogawa, Masahiro, Suzuki, Shoichi, Mitamura, Yasutaka, Nunomura, Satoshi, Nanri, Yasuhiro, Yoshihara, Tomohito, Kawaguchi, Atsushi, Kadota, Jun-ichi, Rubin, Bruce K., Izuhara, Kenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319114/
https://www.ncbi.nlm.nih.gov/pubmed/28219384
http://dx.doi.org/10.1186/s12931-017-0519-8
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author Komiya, Kosaku
Ohta, Shoichiro
Arima, Kazuhiko
Ogawa, Masahiro
Suzuki, Shoichi
Mitamura, Yasutaka
Nunomura, Satoshi
Nanri, Yasuhiro
Yoshihara, Tomohito
Kawaguchi, Atsushi
Kadota, Jun-ichi
Rubin, Bruce K.
Izuhara, Kenji
author_facet Komiya, Kosaku
Ohta, Shoichiro
Arima, Kazuhiko
Ogawa, Masahiro
Suzuki, Shoichi
Mitamura, Yasutaka
Nunomura, Satoshi
Nanri, Yasuhiro
Yoshihara, Tomohito
Kawaguchi, Atsushi
Kadota, Jun-ichi
Rubin, Bruce K.
Izuhara, Kenji
author_sort Komiya, Kosaku
collection PubMed
description BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-017-0519-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-53191142017-02-24 Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts Komiya, Kosaku Ohta, Shoichiro Arima, Kazuhiko Ogawa, Masahiro Suzuki, Shoichi Mitamura, Yasutaka Nunomura, Satoshi Nanri, Yasuhiro Yoshihara, Tomohito Kawaguchi, Atsushi Kadota, Jun-ichi Rubin, Bruce K. Izuhara, Kenji Respir Res Research BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-017-0519-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-02-20 2017 /pmc/articles/PMC5319114/ /pubmed/28219384 http://dx.doi.org/10.1186/s12931-017-0519-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Komiya, Kosaku
Ohta, Shoichiro
Arima, Kazuhiko
Ogawa, Masahiro
Suzuki, Shoichi
Mitamura, Yasutaka
Nunomura, Satoshi
Nanri, Yasuhiro
Yoshihara, Tomohito
Kawaguchi, Atsushi
Kadota, Jun-ichi
Rubin, Bruce K.
Izuhara, Kenji
Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts
title Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts
title_full Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts
title_fullStr Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts
title_full_unstemmed Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts
title_short Clarithromycin attenuates IL-13–induced periostin production in human lung fibroblasts
title_sort clarithromycin attenuates il-13–induced periostin production in human lung fibroblasts
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319114/
https://www.ncbi.nlm.nih.gov/pubmed/28219384
http://dx.doi.org/10.1186/s12931-017-0519-8
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