In Vitro Evidence for a Direct Antifibrotic Role of the Immunosuppressive Drug Mycophenolate Mofetil

TLDR

Mycophenolate mofetil (MMF) is an immunosuppressant used after transplantation and has shown some efficacy in preventing fibrotic complications in autoimmune conditions such as systemic sclerosis and graft‑versus‑host disease. The study aimed to determine whether MMF directly modulates fibroblast extracellular matrix remodeling. In vitro, MMF dose‑ and time‑dependently suppressed type I collagen synthesis and transcription of COL1A1/COL1A2, increased MMP‑1 expression, reduced fibroblast contractility, α‑smooth muscle actin production, and motility, revealing a direct antifibrotic mechanism that could underlie its therapeutic benefits in systemic sclerosis and GVHD.

Abstract

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 <i>COL1A1</i> and <i>COL1A2</i> 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 α-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.