Inhibitors of Dipeptidyl Peptidase IV-Like Activity Mediate Antifibrotic Effects in Normal and Keloid-Derived Skin Fibroblasts

Anja Thielitz, Robert W. Vetter, Bianca Schultze, Sabine Wrenger, Luca Simeoni, Siegfried Ansorge, Klaus Neubert, Jürgen Faust, Petra Lindenlaub, Harald P.M. Gollnick, Dirk Reinhold
2008 Journal of Investigative Dermatology  
Suppression of collagen and matrix synthesis and inhibition of the fibrogenic cytokine transforming growth factor-b 1 (TGF-b 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
more » ... s[Z(NO 2 )]-pyrrolidide, suppress proliferation in human skin fibroblasts and keloid-derived skin fibroblasts in vitro. They significantly decrease TGF-b 1 expression and secretion of procollagen type I C-terminal peptide in supernatants of both cell types. Furthermore, they abrogate the TGF-b 1 -induced stimulation of collagen synthesis, matrix deposition, and TGF-b 1 and fibronectin expression. Both inhibitors lead to dephosphorylation of mitogen-activated protein kinases pp38 and pERK1/2, which are activated upon TGF-b1 stimulation and have been implicated in fibrogenesis. In a mouse model of dermal fibrosis, induced by repetitive intracutaneous injections of TGF-b 1 , the profibrotic effect of TGF-b 1 detected by dermal thickening, collagen I, and a-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.
doi:10.1038/sj.jid.5701104 pmid:17943180 fatcat:bgviq2rkhzh3zmdnyfpe334ofi