There are few effective treatments for sclerotic skin disorders including systemic scleroderma, chronic graft-versus-host disease (GVHD) and morphea. Because interferon (IFN)-γ directly inhibits the proliferation of skin fibroblasts and the production of collagen in vitro, IFN-γ is known as an antifibrotic factor. However, administration of recombinant IFN-γ could not inhibit fibrosis in patients with systemic scleroderma. To elucidate the role of IFN-γ on skin fibrosis, we established a new murine model of scleroderma. We found that chicken ovalbumin (OVA)-specific CD8 T cell (OT-I cell)-transferred transgenic mice that express membrane-bound OVA under the control of a keratin 14 promoter (K14-mOVA Tg mice), which develop acute GVHD-like mucocutaneous disease 14 days after the transfer, present chronic GVHD-like scleroderma 28 days after the transfer. While GFP+IFN-γ-/-OT-I cells-transferred K14-mOVA Tg mice developed acute GVHD-like mucocutaneous disease as severe as GFP+OT-I cell-transferred mice 14 days after the transfer, GFP+IFN-γ-/-OT-I cells-transferred K14-mOVA Tg mice developed significantly milder scleroderma than GFP+OT-I cell-transferred mice 28 days after the transfer, which were assessed by dermal thickness (the averages: 93.1 v.s. 118.6μm), the numbers of infiltrating αSMA+ fibroblasts (126 v.s. 291/HPF), and hydroxyproline contents (5.9 v.s. 10.9μg/mg). In addition, the levels of mRNA of Col1a2 (30.5 v.s. 90.0), αSMA (0.6 v.s. 1.3) 28 days after the transfer, TGFβ (0.7 v.s. 1.3) 14 days after the transfer were significantly lower in the skins of GFP+IFN-γ-/-OT-I cell-transferred K14-mOVA Tg mice than in those of GFP+OT-I cell-transferred mice by quantitative real-time PCR. Moreover, immunostaining with anti-GFP antibodies detected more GFP+OT-I cells infiltrating in the skins of K14-mOVA Tg mice than GFP+IFN-γ-/-OT-I cells 21 days after the transfer, which correlated to the levels of mRNA of IFN-γ-inducible chemokines (CXCL9, CXCL10 and CXCL11). Collectively, IFN-γ may play a crucial role as a trigger in the pathogenesis of skin fibrosis.

Interferon-γ deficiency attenuates skin fibrosis in a murine model of chronic graft-versus-host disease-like scleroderma