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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

Fingerprint

Keloid
Thalidomide
Transforming Growth Factors
Fibroblasts
Fibronectins
Phosphorylation
Tissue
Mitogen-Activated Protein Kinases
Extracellular Matrix Proteins
Mitogen-Activated Protein Kinase 1
Matrix Metalloproteinase 9
Transcription Factor AP-1
Therapeutic Uses
Dermis
Cytokines
Degradation
DNA

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

Cite this

Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway. / Liang, Chan-Jung; Yen, Yuh-Siu; Hung, Ling Yi; Wang, Shu-Huei; Pu, Chi-Ming; Chien, Hsiung-Fei; Tsai, Jaw-Shiun; Lee, Chiang-Wen; Yen, Feng-Lin; Chen, Yuh-Lien.

In: Biochemical Pharmacology, Vol. 85, No. 11, 2013, p. 1594-1602.

Research output: Contribution to journalArticle

Liang, Chan-Jung ; Yen, Yuh-Siu ; Hung, Ling Yi ; Wang, Shu-Huei ; Pu, Chi-Ming ; Chien, Hsiung-Fei ; Tsai, Jaw-Shiun ; Lee, Chiang-Wen ; Yen, Feng-Lin ; Chen, Yuh-Lien. / Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway. In: Biochemical Pharmacology. 2013 ; Vol. 85, No. 11. pp. 1594-1602.
@article{9160511140644041be114afb96dd0cc8,
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. {\circledC} 2013 Elsevier Inc. All rights reserved.",
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",
author = "Chan-Jung Liang and Yuh-Siu Yen and Hung, {Ling Yi} and Shu-Huei Wang and Chi-Ming Pu and Hsiung-Fei Chien and Jaw-Shiun Tsai and Chiang-Wen Lee and Feng-Lin Yen and Yuh-Lien Chen",
note = "被引用次數:6 Export Date: 16 March 2016 CODEN: BCPCA 通訊地址: Chen, Y.-L.; Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Ren-Ai Rd, Taipei 100, Taiwan; 電子郵件: ylchenv@ntu.edu.tw 化學物質/CAS: 2 (2 amino 3 methoxyphenyl)chromone, 167869-21-8; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole, 152121-47-6; Smad2 protein, 253862-89-4; Smad3 protein, 237417-78-6, 237417-96-8, 237418-00-7; anthra[1,9 cd]pyrazol 6(2h) one, 129-56-6; fibronectin, 86088-83-7; gelatinase B, 146480-36-6; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; thalidomide, 50-35-1; Fibronectins; RNA, Small Interfering; SMAD3 protein, human; Smad3 Protein; Thalidomide, 4Z8R6ORS6L; Transforming Growth Factor beta1; p38 Mitogen-Activated Protein Kinases, 2.7.11.24 參考文獻: Rekha, A., Keloids - A frustrating hurdle in wound healing (2004) Int Wound J, 1, pp. 145-148; Marneros, A.G., Krieg, T., Keloids - Clinical diagnosis, pathogenesis, and treatment options (2004) J Dtsch Dermatol Ges, 2, pp. 905-913; Seifert, O., Mrowietz, U., Keloid scarring: Bench and bedside (2009) Arch Dermatol Res, 301, pp. 259-272; Wolfram, D., Tzankov, A., P{\"u}lzl, P., Piza-Katzer, H., Hypertrophic scars and keloids - A review of their pathophysiology, risk factors, and therapeutic management (2009) Dermatol Surg, 35, pp. 171-181; Al-Attar, A., Mess, S., Thomassen, J.M., Kauffman, C.L., Davison, S.P., Keloid pathogenesis and treatment (2006) Plast Reconstr Surg, 117, pp. 286-300; Kelly, A.P., Medical and surgical therapies for keloids (2004) Dermatol Ther, 17, pp. 212-218; Hsu, Y.C., Chen, M.J., Yu, Y.M., Ko, S.Y., Chang, C.C., Suppression of TGF-β1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: Its potential therapeutic use in the chemoprevention of keloid (2010) Arch Dermatol Res, 302, pp. 717-724; Leask, A., Abraham, D.J., TGF-beta signaling and the fibrotic response (2004) FASEB J, 18, pp. 816-827; Kryger, Z.B., Sisco, M., Roy, N.K., Lu, L., Rosenberg, D., Mustoe, T.A., Temporal expression of the transforming growth factor-Beta pathway in the rabbit ear model of wound healing and scarring (2007) J Am Coll Surg, 205, pp. 78-88; Derynck, R., Zhang, Y.E., Smad-dependent and Smad-independent pathways in TGF-beta family signalling (2003) Nature, 425, pp. 577-584; He, S., Liu, X., Yang, Y., Huang, W., Xu, S., Yang, S., Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts (2010) Br J Dermatol, 162, pp. 538-546; Lim, I.J., Phan, T.T., Tan, E.K., Nguyen, T.T., Tran, E., Longaker, M.T., Synchronous activation of ERK and phosphatidylinositol 3-kinase pathways is required for collagen and extracellular matrix production in keloids (2003) J Biol Chem, 278, pp. 40851-40858; Phan, T.T., Lim, I.J., Chan, S.Y., Tan, E.K., Lee, S.T., Longaker, M.T., Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: Implications for the treatment of excessive scars (2004) J Trauma, 57, pp. 1032-1037; McBride, W., Health of thalidomide victims and their progeny (2004) Lancet, 363, p. 169; Tseng, S., Pak, G., Washenik, K., Pomeranz, M.K., Shupack, J.L., Rediscovering thalidomide: A review of its mechanism of action, side effects and potential uses (1996) J Am Acad Dermatol, 35, pp. 969-979; Sheskin, J., The treatment of lepra reaction in lepromatous leprosy. Fifteen years' experience with thalidomide (1980) Int J Dermatol, 19, pp. 318-322; Barnhill, R.L., Doll, N.J., Millikan, L.E., Hastings, R.C., Studies on the anti-inflammatory properties of thalidomide: Effects on polymorphonuclear leukocytes and monocytes (1984) J Am Acad Dermatol, 11, pp. 814-819; D'Amato, R.J., Loughnan, M.S., Flynn, E., Folkman, J., Thalidomide is an inhibitor of angiogenesis (1994) Proc Natl Acad Sci USA, 91, pp. 4082-4085; Lv, P., Luo, H.S., Zhou, X.P., Chireyath, P.S., Xiao, Y.J., Si, X.M., Thalidomide prevents rat liver cirrhosis via inhibition of oxidative stress (2006) Pathol Res Pract, 202, pp. 777-788; Tucci-Viegas, V.M., Hochman, B., Fran{\cc}a, J.P., Ferreira, L.M., Keloid explant culture: A model for keloid fibroblasts isolation and cultivation based on the biological differences of its specific regions (2010) Int Wound J, 7, pp. 339-348; Liang, C.J., Wang, S.H., Chen, Y.H., Chang, S.S., Hwang, T.L., Leu, Y.L., Viscolin reduces VCAM-1 expression in TNF-α-treated endothelial cells via the JNK/NF-κB and ROS pathway (2011) Free Radic Biol Med, 51, pp. 1337-1346; Massagu{\'e}, J., Wotton, D., Transcriptional control by the TGF-beta/Smad signaling system (2000) EMBO J, 19, pp. 1745-1754; Zhang, G.Y., Cheng, T., Luan, Q., Liao, T., Nie, C.L., Zheng, X., Vitamin D: A novel therapeutic approach for keloid, an in vitro analysis (2011) Br J Dermatol, 164, pp. 729-737; Eriksson, T., Bjorkman, S., Hoglund, P., Clinical pharmacology of thalidomide (2001) Eur J Clin Pharmacol, 57, pp. 365-376; Meierhofer, C., Dunzendorfer, S., Wiedermann, C.J., Theoretical basis for the activity of thalidomide (2001) BioDrugs, 15, pp. 681-703; Yeh, T.S., Ho, Y.P., Huang, S.F., Yeh, J.N., Jan, Y.Y., Chen, M.F., Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats (2004) J Hepatol, 41, pp. 606-612; Sampaio, E.P., Sarno, E.N., Galilly, R., Cohn, Z.A., Kaplan, G., Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes (1991) J Exp Med, 173, pp. 699-703; Yasui, K., Kobayashi, N., Yamazaki, T., Agematsu, K., Thalidomide as an immunotherapeutic agent: The effects on neutrophil-mediated inflammation (2005) Curr Pharm des, 11, pp. 395-401; Lee, C.J., Kim, K.W., Lee, H.M., Nahm, F.S., Lim, Y.J., Park, J.H., The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model (2007) Spinal Cord, 45, pp. 149-157; Tabata, C., Tabata, R., Kadokawa, Y., Hisamori, S., Takahashi, M., Mishima, M., Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice (2007) J Immunol, 179, pp. 708-714; Laffitte, E., Revuz, J., Thalidomide: An old drug with new clinical applications (2004) Expert Opin Drug Saf, 3, pp. 47-56; Govinden, R., Bhoola, K.D., Genealogy, expression, and cellular function of transforming growth factor-beta (2003) Pharmacol Ther, 98, pp. 257-265; Kobayashi, T., Liu, X., Wen, F.Q., Kohyama, T., Shen, L., Wang, X.Q., Smad3 mediates TGF-beta1-induced collagen gel contraction by human lung fibroblasts (2006) Biochem Biophys Res Commun, 339, pp. 290-295; Flanders, K.C., Smad3 as a mediator of the fibrotic response (2004) Int J Exp Pathol, 85, pp. 47-64; Yan, J.D., Yang, S., Zhang, J., Zhu, T.H., BMP6 reverses TGF-beta1-induced changes in HK-2 cells: Implications for the treatment of renal fibrosis (2009) Acta Pharmacol Sin, 30, pp. 994-1000; Furukawa, F., Matsuzaki, K., Mori, S., Tahashi, Y., Yoshida, K., Sugano, Y., P38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts (2003) Hepatology, 38, pp. 879-889; Isono, M., Chen, S., Hong, S.W., Iglesias-De La Cruz, M.C., Ziyadeh, F.N., Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta-induced fibronectin in mesangial cells (2002) Biochem Biophys Res Commun, 296, pp. 1356-1365; Ferguson, H.E., Kulkarni, A., Lehmann, G.M., Garcia-Bates, T.M., Thatcher, T.H., Huxlin, K.R., Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts (2009) Am J Respir Cell Mol Biol, 41, pp. 722-730; Luo, S., Benathan, M., Raffoul, W., Panizzon, R.G., Egloff, D.V., Abnormal balance between proliferation and apoptotic cell death in fibroblasts derived from keloid lesions (2001) Plast Reconstr Surg, 107, pp. 87-96; Lim, C.P., Phan, T.T., Lim, I.J., Cao, X., Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration (2006) Oncogene, 25, pp. 5416-5425; Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Identification of a primary target of thalidomide teratogenicity (2010) Science, 327, pp. 1345-1350; Zhu, Y.X., Braggio, E., Shi, C.X., Bruins, L.A., Schmidt, J.E., Van Wier, S., Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide (2011) Blood, 118, pp. 4771-4779",
year = "2013",
doi = "10.1016/j.bcp.2013.02.038",
language = "English",
volume = "85",
pages = "1594--1602",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "11",

}

TY - JOUR

T1 - Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway

AU - Liang, Chan-Jung

AU - Yen, Yuh-Siu

AU - Hung, Ling Yi

AU - Wang, Shu-Huei

AU - Pu, Chi-Ming

AU - Chien, Hsiung-Fei

AU - Tsai, Jaw-Shiun

AU - Lee, Chiang-Wen

AU - Yen, Feng-Lin

AU - Chen, Yuh-Lien

N1 - 被引用次數:6 Export Date: 16 March 2016 CODEN: BCPCA 通訊地址: Chen, Y.-L.; Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Ren-Ai Rd, Taipei 100, Taiwan; 電子郵件: ylchenv@ntu.edu.tw 化學物質/CAS: 2 (2 amino 3 methoxyphenyl)chromone, 167869-21-8; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole, 152121-47-6; Smad2 protein, 253862-89-4; Smad3 protein, 237417-78-6, 237417-96-8, 237418-00-7; anthra[1,9 cd]pyrazol 6(2h) one, 129-56-6; fibronectin, 86088-83-7; gelatinase B, 146480-36-6; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; thalidomide, 50-35-1; Fibronectins; RNA, Small Interfering; SMAD3 protein, human; Smad3 Protein; Thalidomide, 4Z8R6ORS6L; Transforming Growth Factor beta1; p38 Mitogen-Activated Protein Kinases, 2.7.11.24 參考文獻: Rekha, A., Keloids - A frustrating hurdle in wound healing (2004) Int Wound J, 1, pp. 145-148; Marneros, A.G., Krieg, T., Keloids - Clinical diagnosis, pathogenesis, and treatment options (2004) J Dtsch Dermatol Ges, 2, pp. 905-913; Seifert, O., Mrowietz, U., Keloid scarring: Bench and bedside (2009) Arch Dermatol Res, 301, pp. 259-272; Wolfram, D., Tzankov, A., Pülzl, P., Piza-Katzer, H., Hypertrophic scars and keloids - A review of their pathophysiology, risk factors, and therapeutic management (2009) Dermatol Surg, 35, pp. 171-181; Al-Attar, A., Mess, S., Thomassen, J.M., Kauffman, C.L., Davison, S.P., Keloid pathogenesis and treatment (2006) Plast Reconstr Surg, 117, pp. 286-300; Kelly, A.P., Medical and surgical therapies for keloids (2004) Dermatol Ther, 17, pp. 212-218; Hsu, Y.C., Chen, M.J., Yu, Y.M., Ko, S.Y., Chang, C.C., Suppression of TGF-β1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: Its potential therapeutic use in the chemoprevention of keloid (2010) Arch Dermatol Res, 302, pp. 717-724; Leask, A., Abraham, D.J., TGF-beta signaling and the fibrotic response (2004) FASEB J, 18, pp. 816-827; Kryger, Z.B., Sisco, M., Roy, N.K., Lu, L., Rosenberg, D., Mustoe, T.A., Temporal expression of the transforming growth factor-Beta pathway in the rabbit ear model of wound healing and scarring (2007) J Am Coll Surg, 205, pp. 78-88; Derynck, R., Zhang, Y.E., Smad-dependent and Smad-independent pathways in TGF-beta family signalling (2003) Nature, 425, pp. 577-584; He, S., Liu, X., Yang, Y., Huang, W., Xu, S., Yang, S., Mechanisms of transforming growth factor beta(1)/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts (2010) Br J Dermatol, 162, pp. 538-546; Lim, I.J., Phan, T.T., Tan, E.K., Nguyen, T.T., Tran, E., Longaker, M.T., Synchronous activation of ERK and phosphatidylinositol 3-kinase pathways is required for collagen and extracellular matrix production in keloids (2003) J Biol Chem, 278, pp. 40851-40858; Phan, T.T., Lim, I.J., Chan, S.Y., Tan, E.K., Lee, S.T., Longaker, M.T., Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: Implications for the treatment of excessive scars (2004) J Trauma, 57, pp. 1032-1037; McBride, W., Health of thalidomide victims and their progeny (2004) Lancet, 363, p. 169; Tseng, S., Pak, G., Washenik, K., Pomeranz, M.K., Shupack, J.L., Rediscovering thalidomide: A review of its mechanism of action, side effects and potential uses (1996) J Am Acad Dermatol, 35, pp. 969-979; Sheskin, J., The treatment of lepra reaction in lepromatous leprosy. Fifteen years' experience with thalidomide (1980) Int J Dermatol, 19, pp. 318-322; Barnhill, R.L., Doll, N.J., Millikan, L.E., Hastings, R.C., Studies on the anti-inflammatory properties of thalidomide: Effects on polymorphonuclear leukocytes and monocytes (1984) J Am Acad Dermatol, 11, pp. 814-819; D'Amato, R.J., Loughnan, M.S., Flynn, E., Folkman, J., Thalidomide is an inhibitor of angiogenesis (1994) Proc Natl Acad Sci USA, 91, pp. 4082-4085; Lv, P., Luo, H.S., Zhou, X.P., Chireyath, P.S., Xiao, Y.J., Si, X.M., Thalidomide prevents rat liver cirrhosis via inhibition of oxidative stress (2006) Pathol Res Pract, 202, pp. 777-788; Tucci-Viegas, V.M., Hochman, B., França, J.P., Ferreira, L.M., Keloid explant culture: A model for keloid fibroblasts isolation and cultivation based on the biological differences of its specific regions (2010) Int Wound J, 7, pp. 339-348; Liang, C.J., Wang, S.H., Chen, Y.H., Chang, S.S., Hwang, T.L., Leu, Y.L., Viscolin reduces VCAM-1 expression in TNF-α-treated endothelial cells via the JNK/NF-κB and ROS pathway (2011) Free Radic Biol Med, 51, pp. 1337-1346; Massagué, J., Wotton, D., Transcriptional control by the TGF-beta/Smad signaling system (2000) EMBO J, 19, pp. 1745-1754; Zhang, G.Y., Cheng, T., Luan, Q., Liao, T., Nie, C.L., Zheng, X., Vitamin D: A novel therapeutic approach for keloid, an in vitro analysis (2011) Br J Dermatol, 164, pp. 729-737; Eriksson, T., Bjorkman, S., Hoglund, P., Clinical pharmacology of thalidomide (2001) Eur J Clin Pharmacol, 57, pp. 365-376; Meierhofer, C., Dunzendorfer, S., Wiedermann, C.J., Theoretical basis for the activity of thalidomide (2001) BioDrugs, 15, pp. 681-703; Yeh, T.S., Ho, Y.P., Huang, S.F., Yeh, J.N., Jan, Y.Y., Chen, M.F., Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats (2004) J Hepatol, 41, pp. 606-612; Sampaio, E.P., Sarno, E.N., Galilly, R., Cohn, Z.A., Kaplan, G., Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes (1991) J Exp Med, 173, pp. 699-703; Yasui, K., Kobayashi, N., Yamazaki, T., Agematsu, K., Thalidomide as an immunotherapeutic agent: The effects on neutrophil-mediated inflammation (2005) Curr Pharm des, 11, pp. 395-401; Lee, C.J., Kim, K.W., Lee, H.M., Nahm, F.S., Lim, Y.J., Park, J.H., The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model (2007) Spinal Cord, 45, pp. 149-157; Tabata, C., Tabata, R., Kadokawa, Y., Hisamori, S., Takahashi, M., Mishima, M., Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice (2007) J Immunol, 179, pp. 708-714; Laffitte, E., Revuz, J., Thalidomide: An old drug with new clinical applications (2004) Expert Opin Drug Saf, 3, pp. 47-56; Govinden, R., Bhoola, K.D., Genealogy, expression, and cellular function of transforming growth factor-beta (2003) Pharmacol Ther, 98, pp. 257-265; Kobayashi, T., Liu, X., Wen, F.Q., Kohyama, T., Shen, L., Wang, X.Q., Smad3 mediates TGF-beta1-induced collagen gel contraction by human lung fibroblasts (2006) Biochem Biophys Res Commun, 339, pp. 290-295; Flanders, K.C., Smad3 as a mediator of the fibrotic response (2004) Int J Exp Pathol, 85, pp. 47-64; Yan, J.D., Yang, S., Zhang, J., Zhu, T.H., BMP6 reverses TGF-beta1-induced changes in HK-2 cells: Implications for the treatment of renal fibrosis (2009) Acta Pharmacol Sin, 30, pp. 994-1000; Furukawa, F., Matsuzaki, K., Mori, S., Tahashi, Y., Yoshida, K., Sugano, Y., P38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts (2003) Hepatology, 38, pp. 879-889; Isono, M., Chen, S., Hong, S.W., Iglesias-De La Cruz, M.C., Ziyadeh, F.N., Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta-induced fibronectin in mesangial cells (2002) Biochem Biophys Res Commun, 296, pp. 1356-1365; Ferguson, H.E., Kulkarni, A., Lehmann, G.M., Garcia-Bates, T.M., Thatcher, T.H., Huxlin, K.R., Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts (2009) Am J Respir Cell Mol Biol, 41, pp. 722-730; Luo, S., Benathan, M., Raffoul, W., Panizzon, R.G., Egloff, D.V., Abnormal balance between proliferation and apoptotic cell death in fibroblasts derived from keloid lesions (2001) Plast Reconstr Surg, 107, pp. 87-96; Lim, C.P., Phan, T.T., Lim, I.J., Cao, X., Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration (2006) Oncogene, 25, pp. 5416-5425; Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Identification of a primary target of thalidomide teratogenicity (2010) Science, 327, pp. 1345-1350; Zhu, Y.X., Braggio, E., Shi, C.X., Bruins, L.A., Schmidt, J.E., Van Wier, S., Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide (2011) Blood, 118, pp. 4771-4779

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Fibroblasts

KW - Fibronectin

KW - Keloid

KW - Mitogen-activated protein kinases (MAPKs)

KW - SMADS

KW - Thalidomide

KW - 2 (2 amino 3 methoxyphenyl)chromone

KW - 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole

KW - anthra[1,9 cd]pyrazol 6(2h) one

KW - fibronectin

KW - gelatinase B

KW - mitogen activated protein kinase 1

KW - mitogen activated protein kinase 3

KW - mitogen activated protein kinase p38

KW - Smad2 protein

KW - Smad3 protein

KW - thalidomide

KW - transforming growth factor beta1

KW - adult

KW - article

KW - cell count

KW - clinical article

KW - controlled study

KW - DNA binding

KW - fibroblast

KW - human

KW - human cell

KW - human tissue

KW - keloid

KW - male

KW - priority journal

KW - protein expression

KW - protein phosphorylation

KW - signal transduction

KW - Adult

KW - Animals

KW - Base Sequence

KW - Electrophoretic Mobility Shift Assay

KW - Female

KW - Fibronectins

KW - Humans

KW - Immunohistochemistry

KW - Male

KW - Mice

KW - Mice, Nude

KW - Middle Aged

KW - p38 Mitogen-Activated Protein Kinases

KW - RNA, Small Interfering

KW - Smad3 Protein

KW - Transforming Growth Factor beta1

U2 - 10.1016/j.bcp.2013.02.038

DO - 10.1016/j.bcp.2013.02.038

M3 - Article

VL - 85

SP - 1594

EP - 1602

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 11

ER -