The Effects of Retinoic Acid and MAPK Inhibitors on Phosphorylation of Smad2/3 Induced by Transforming Growth Factor β1
신주혜 (연세대학교)
신미화 (연세대학교)
김영삼 (연세대학교)
정경수 (연세대학교)
송주한 (연세대학교)
김송이 (연세대학교)
김은영 (연세대학교)
정지예 (연세대학교)
강영애 (연세대학교)
장준 (연세대학교)
박무석 (연세대학교)
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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 alltrans 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.
- keywords
- Transforming Growth Factor Beta, Retinoic Acid, Mitogen-Activated Protein Kinases, MEKs, Smad Proteins
참고문헌
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