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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)42-52
Number of pages11
JournalTuberculosis and Respiratory Diseases
Volume82
Issue number1
DOIs
Publication statusPublished - 2019 Jan

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Infectious Diseases

Cite this

Lee, S. H., Shin, J. H., Shin, M. H., Kim, Y. S., Chung, K. S., Song, J. H., Kim, S. Y., Kim, E. Y., Jung, J. Y., Kang, Y. A., Chang, J., & Park, M. S. (2019). The effects of retinoic acid and MAPK inhibitors on phosphorylation of Smad2/3 induced by transforming growth factor β1. Tuberculosis and Respiratory Diseases, 82(1), 42-52. https://doi.org/10.4046/trd.2017.0111