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Inhibitors of dipeptidyl peptidase IV-like activity mediate antifibrotic effects in normal and keloid-derived skin fibroblasts.
Thielitz, Anja; Vetter, Robert W; Schultze, Bianca; Wrenger, Sabine; Simeoni, Luca; Ansorge, Siegfried; Neubert, Klaus; Faust, Jürgen; Lindenlaub, Petra; Gollnick, Harald P M; Reinhold, Dirk.
Afiliación
  • Thielitz A; University Clinic of Dermatology and Venereology, Otto-von-Guericke University, Magdeburg, Germany. anja.thielitz@med.ovgu.de
J Invest Dermatol ; 128(4): 855-66, 2008 Apr.
Article en En | MEDLINE | ID: mdl-17943180
Suppression of collagen and matrix synthesis and inhibition of the fibrogenic cytokine transforming growth factor-beta(1) (TGF-beta(1)) is a major therapeutic goal in the treatment of fibrosis and keloids. Inhibitors of dipeptidyl peptidase IV (DP IV)-like activity affect cell growth and cytokine production and are currently under investigation for the treatment of metabolic, autoimmune and inflammatory diseases. We show here that the inhibitors of DP IV-like activity, Lys[Z(NO(2))]-thiazolidide and Lys[Z(NO(2))]-pyrrolidide, suppress proliferation in human skin fibroblasts and keloid-derived skin fibroblasts in vitro. They significantly decrease TGF-beta(1) expression and secretion of procollagen type I C-terminal peptide in supernatants of both cell types. Furthermore, they abrogate the TGF-beta(1)-induced stimulation of collagen synthesis, matrix deposition, and TGF-beta(1) and fibronectin expression. Both inhibitors lead to dephosphorylation of mitogen-activated protein kinases pp38 and pERK1/2, which are activated upon TGF-beta1 stimulation and have been implicated in fibrogenesis. In a mouse model of dermal fibrosis, induced by repetitive intracutaneous injections of TGF-beta(1), the profibrotic effect of TGF-beta(1) detected by dermal thickening, collagen I, and alpha-smooth muscle actin expression, is significantly suppressed in the presence of inhibitors. Inhibition of DP IV-like enzymatic activity may therefore represent a promising therapeutic approach for the treatment of fibrotic skin disorders and keloids.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirrolidinas / Piel / Tiazoles / Inhibidores de la Dipeptidil-Peptidasa IV / Queloide / Lisina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Invest Dermatol Año: 2008 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Buscar en Google
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PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirrolidinas / Piel / Tiazoles / Inhibidores de la Dipeptidil-Peptidasa IV / Queloide / Lisina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Invest Dermatol Año: 2008 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos