Abstract
Fibrosis is characterized by transdifferentiation of quiescent fibroblasts to myofibroblasts that results in overexpression and deposition of extracellular matrix proteins that subsequently leads to organ impairment or dysfunction. Dupuytren's disease, a benign fibroproliferative disorder of the palmar fascia, represents an ideal model to study tissue fibrosis. Fibroblasts isolated from nodules and cords of Dupuytren’s disease (DF) served as model of fibrosis. Here we report that DF and control fibroblasts (CF) derived from tendon pulleys of the hand express endogenous Interferon gamma (IFNG).
Application of recombinant transforming growth factor beta 1 (TGFB1) resulted in upregulation of profibrotic proteins and subsequent elevated expression levels of SMAD7. Surprisingly, TGFB1 additionally induced transcription of IFNG in stimulated DF and CF. As a consequence, IFNG signaling is presumably enhanced by an autocrine mechanism leading to upregulation of SMAD7, thereby indicating a new negative feedback mechanism of TGFB1 signaling. On the other hand cell infection with adSMAD7, an adenovirus coding for SMAD7, leads to downregulation of IFNG and subsequent signaling, indicating a further novel negative feedback mechanism of IFNG signaling. AdIFNG, an adenovirus coding for human IFNG, in combination with recombinant TGFB1 initiate higher levels of IFNG than separate stimulation, thus indicating a co-inducing effect of TGFB1 on IFNG transcription. Therefore, our results point to new perspectives concerning IFNG-TGFB1-crosstalking and its possible relevance in a standard model of fibrosis.
Expression of interferon-gamma (IFN-δ), IL-10, IL-12 and transforming growth factor-beta (TGF-β) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA)
