Inhibitors of dipeptidyl peptidase IV-like activity mediate antifibrotic effects in normal and keloid-derived skin fibroblasts.
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.
Thielitz
Anja
A
University Clinic of Dermatology and Venereology, Otto-von-Guericke University, Magdeburg, Germany. anja.thielitz@med.ovgu.de
Vetter
Robert W
RW
Schultze
Bianca
B
Wrenger
Sabine
S
Simeoni
Luca
L
Ansorge
Siegfried
S
Neubert
Klaus
K
Faust
Jürgen
J
Lindenlaub
Petra
P
Gollnick
Harald P M
HP
Reinhold
Dirk
D
D000199:Actins / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000032:analysis; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007627:Keloid / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010766:Phosphorylation; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C558396:Acta2 protein, mouse; D000199:Actins; D024042:Collagen Type I; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011759:Pyrrolidines; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; C110164:lysyl-(Z(nitro))pyrrolidide; C093632:lysyl-(Z(nitro))thiazolidide; D048051:p38 Mitogen-Activated Protein Kinases; D018819:Dipeptidyl Peptidase 4; D008239:Lysine