In vitro evidence for a direct antifibrotic role of the immunosuppressive drug mycophenolate mofetil.
The immunosuppressive drug mycophenolate mofetil (MMF) is used to prevent organ rejection after transplantation and has shown some efficacy to prevent the fibrotic complications that occur during autoimmune diseases such as systemic sclerosis or during graft-versus-host disease (GVHD). We tested the hypothesis that MMF may exert direct effects on fibroblast extracellular matrix remodeling. Incubation of human lung fibroblast cultures with MMF led to dose- and time-dependent reduction in the synthesis and expression of type I collagen. Inhibition of COL1A1 and COL1A2 mRNA steady-state levels occurred at the level of transcription via repression of their promoters. In contrast, MMF significantly enhanced the expression and the synthesis of interstitial collagenase (matrix metalloproteinase-1). MMF was also found to diminish the capacity of fibroblast to contract mechanically unloaded collagen lattices and to reduce the synthesis of alpha-smooth muscle actin, a marker of the contractile myofibroblast phenotype. In addition, MMF diminished the fibroblasts motility. In conclusion, we provide novel mechanism by which MMF alters fibroblast functions important for wound healing and implicated in the development of tissue fibrosis, e.g., collagen production, extracellular matrix contraction, and cell migration. Such properties may contribute to the beneficial therapeutic effects of MMF against fibrotic lesions developing in systemic sclerosis or during GVHD.
Roos
Nina
N
Institut National de la Santé et de la Recherche Médicale U697, Hôpital Saint-Louis, Pavillon Bazin, 1 Avenue Claude Vellefaux, 75010 Paris, France.
Poulalhon
Nicolas
N
Farge
Dominique
D
Madelaine
Isabelle
I
Mauviel
Alain
A
Verrecchia
Franck
F
D000199:Actins / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D005355:Fibrosis / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000199:Actins; D024042:Collagen Type I; D007166:Immunosuppressive Agents; D020781:Matrix Metalloproteinase 1; D009173:Mycophenolic Acid