title: Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway.
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.
authors.affiliation: Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taiwan.
authors.forename: Chan-Jung
authors.initials: CJ
authors.lastname: Liang
authors.forename: Yu-Hsiu
authors.initials: YH
authors.lastname: Yen
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Hung
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Wang
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Pu
authors.forename: Hsiung-Fei
authors.initials: HF
authors.lastname: Chien
authors.forename: Jaw-Shiun
authors.initials: JS
authors.lastname: Tsai
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.forename: Feng-Lin
authors.initials: FL
authors.lastname: Yen
authors.forename: Yuh-Lien
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005353:Fibronectins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D007627:Keloid / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism*; D013792:Thalidomide / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D013792:Thalidomide; D048051:p38 Mitogen-Activated Protein Kinases