Regulation of fibrogenic/fibrolytic genes by platelet-derived growth factor C, a novel growth factor, in human dermal fibroblasts.
Platelet-derived growth factor (PDGF) is a potent mitogenic and chemotactic cytokine, and PDGF-C is a novel growth factor belonging to the PDGF family. In this study, to determine whether this growth factor can contribute to fibrosis and tissue remodeling, we examined the effect of PDGF-CC on the expression of fibrogenic/fibrolytic genes such as type I collagen, fibronectin (FN), matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) in normal human dermal fibroblasts in vitro. PDGF elevated the levels of MMP-1 or TIMP-1 protein as well as mRNA, whereas this cytokine had no influence on the expression of type I collagen, FN, or TIMP-2. PDGF-CC also increased the levels of MMP-1 catalytic activity in the cultured media and mRNA expression, which was paralleled that on the levels of promoter activation. Additionally, PDGF-CC induced the mitogenic and migratory activity of human dermal fibroblasts in a dose-dependent manner. On the other hand, we also determined the specificity of the inhibitory effect of monoclonal antibodies against PDGF-CC generated by immunizing balb/c mice with recombinant human PDGF-CC. This antibody could inhibit the regulatory effects of MMP-1 or TIMP-1 synthesis as well as the mitogenic effects on human dermal fibroblasts induced by PDGF-CC, whereas this antibody did not affect those induced by other PDGF forms such as PDGF-AA, -AB, or -BB. These results suggest that this cytokine plays a role in the tissue remodeling.
Jinnin
Masatoshi
M
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Ihn
Hironobu
H
Mimura
Yoshihiro
Y
Asano
Yoshihide
Y
Yamane
Kenichi
K
Tamaki
Kunihiko
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008222:Lymphokines; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D012879:Skin Physiological Phenomena; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D024042:Collagen Type I; D005353:Fibronectins; D008222:Lymphokines; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; C411423:platelet-derived growth factor C; D020782:Matrix Metalloproteinases