Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway

Chan-Jung Liang, Yuh-Siu Yen, Ling Yi Hung, Shu-Huei Wang, Chi-Ming Pu, Hsiung-Fei Chien, Jaw-Shiun Tsai, Chiang-Wen Lee, Feng-Lin Yen, Yuh-Lien Chen

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Abstract

Keloids are characterized by the vigorously continuous production of extracellular matrix protein and aberrant cytokine activity in the dermis. There is a growing body of evidence that thalidomide, α-N- phthalimidoglutarimide, has anti-fibrotic properties. The aims were to examine possible therapeutic effects of thalidomide on fibronectin expression in transforming growth factor-β1 (TGF-β1)-treated normal fibroblasts (NFs) and keloid-derived fibroblasts (KFs) and the underlying mechanism of action, especially the involvement of mitogen-activated protein kinase (MAPKs) and Sma- and Mad-related family (Smads) pathways. In surgically removed human tissues, TGF-β1 and fibronectin immunoreactivity was high in keloid tissue, but barely detectable in normal tissue. TGF-β1 induced significant fibronectin expression in NFs and KFs and the effect was inhibited by pretreatment with thalidomide. TGF-β1 also induced phosphorylation of MAPKs (ERK1/2, p38, and JNK) and Smad2/3 and pretreatment with PD98059 (an ERK1/2 inhibitor), SB203580 (a p38 inhibitor), or SP600125 (a JNK inhibitor) inhibited TGF-β1-induced fibronectin expression. Furthermore, pretreatment with thalidomide inhibited the TGF-β1-induced phosphorylation of p38 and Smad3, but not that of ERK1/2, JNK, and Smad2. In addition, thalidomide pretreatment inhibited the TGF-β-induced DNA binding activity of AP-1 and Smad3/4, caused fibronectin degradation by increasing the activity of matrix metalloproteinase 9, and decreased production of TGF-β1 and fibronectin and the number of fibroblasts in an in vivo keloid model. These results show that thalidomide has an antifibrotic effect on keloid fibroblasts that is caused by suppression of TGF-β1-induced p38 and Smad3 signaling. Our findings indicate that thalidomide may be a potential candidate drug for the treatment and prevention of keloids. © 2013 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1594-1602
Number of pages9
JournalBiochemical Pharmacology
Volume85
Issue number11
DOIs
Publication statusPublished - 2013
Externally publishedYes

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Keywords

  • Fibroblasts
  • Fibronectin
  • Keloid
  • Mitogen-activated protein kinases (MAPKs)
  • SMADS
  • Thalidomide
  • 2 (2 amino 3 methoxyphenyl)chromone
  • 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole
  • anthra[1,9 cd]pyrazol 6(2h) one
  • fibronectin
  • gelatinase B
  • mitogen activated protein kinase 1
  • mitogen activated protein kinase 3
  • mitogen activated protein kinase p38
  • Smad2 protein
  • Smad3 protein
  • thalidomide
  • transforming growth factor beta1
  • adult
  • article
  • cell count
  • clinical article
  • controlled study
  • DNA binding
  • fibroblast
  • human
  • human cell
  • human tissue
  • keloid
  • male
  • priority journal
  • protein expression
  • protein phosphorylation
  • signal transduction
  • Adult
  • Animals
  • Base Sequence
  • Electrophoretic Mobility Shift Assay
  • Female
  • Fibronectins
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • p38 Mitogen-Activated Protein Kinases
  • RNA, Small Interfering
  • Smad3 Protein
  • Transforming Growth Factor beta1

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