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The Effects of Retinoic Acid and MAPK Inhibitors on Phosphorylation of Smad2/3 Induced by Transforming Growth Factor β1

 Sang Hoon Lee  ;  Ju Hye Shin  ;  Mi Hwa Shin  ;  Young Sam Kim  ;  Kyung Soo Chung  ;  Joo Han Song  ;  Song Yee Kim  ;  Eun Young Kim  ;  Ji Ye Jung  ;  Young Ae Kang  ;  Joon Chang  ;  Moo Suk Park 
 Tuberculosis and Respiratory Diseases, Vol.82(1) : 42-52, 2019 
Journal Title
 Tuberculosis and Respiratory Diseases 
Issue Date
MEKs ; Mitogen-Activated Protein Kinases ; Retinoic Acid ; Smad Proteins ; Transforming Growth Factor Beta
BACKGROUND: Transforming growth factor β (TGF-β), retinoic acid (RA), p38 mitogen-activated protein kinase (MAPK), and MEK signaling play critical roles in cell differentiation, proliferation, and apoptosis. We investigated the effect of RA and the role of these signaling molecules on the phosphorylation of Smad2/3 (p-Smad2/3) induced by TGF-β1. METHODS: A549 epithelial cells and CCD-11Lu fibroblasts were incubated and stimulated with or without all-trans RA (ATRA) and TGF-β1 and with MAPK or MEK inhibitors. The levels of p-Smad2/3 were analyzed by western blotting. For animal models, we studied three experimental mouse groups: control, bleomycin, and bleomycin+ATRA group. Changes in histopathology, lung injury score, and levels of TGF-β1 and Smad3 were evaluated at 1 and 3 weeks. RESULTS: When A549 cells were pre-stimulated with TGF-β1 prior to RA treatment, RA completely inhibited the p-Smad2/3. However, when A549 cells were pre-treated with RA prior to TGF-β1 stimulation, RA did not completely suppress the p-Smad2/3. When A549 cells were pre-treated with MAPK inhibitor, TGF-β1 failed to phosphorylate Smad2/3. In fibroblasts, p38 MAPK inhibitor suppressed TGF-β1-induced p-Smad2. In a bleomycin-induced lung injury mouse model, RA decreased the expression of TGF-β1 and Smad3 at 1 and 3 weeks. CONCLUSION: RA had inhibitory effects on the phosphorylation of Smad induced by TGF-β1 in vitro, and RA also decreased the expression of TGF-β1 at 1 and 3 weeks in vivo. Furthermore, pre-treatment with a MAPK inhibitor showed a preventative effect on TGF-β1/Smad phosphorylation in epithelial cells. As a result, a combination of RA and MAPK inhibitors may suppress the TGF-β1-induced lung injury and fibrosis.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
강영애(Kang, Young Ae) ORCID logo https://orcid.org/0000-0002-7783-5271
김송이(Kim, Song Yee) ORCID logo https://orcid.org/0000-0001-8627-486X
김영삼(Kim, Young Sam) ORCID logo https://orcid.org/0000-0001-9656-8482
김은영(Kim, Eun Young) ORCID logo https://orcid.org/0000-0002-3281-5744
박무석(Park, Moo Suk) ORCID logo https://orcid.org/0000-0003-0820-7615
송주한(Song, Joo Han)
이상훈(Lee, Sang Hoon) ORCID logo https://orcid.org/0000-0002-7706-5318
장준(Chang, Joon) ORCID logo https://orcid.org/0000-0003-4542-6841
정경수(Jung, Kyung Soo) ORCID logo https://orcid.org/0000-0003-1604-8730
정지예(Jung, Ji Ye) ORCID logo https://orcid.org/0000-0003-1589-4142
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