title: Progranulin Overproduction Due to Fli-1 Deficiency Contributes to the Resistance of Dermal Fibroblasts to Tumor Necrosis Factor in Systemic Sclerosis.
abstract: OBJECTIVE
  Progranulin is a growth factor that is active in wound repair and is an antagonist of tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation. Because long-standing activation of gene programs related to wound healing is a hallmark of systemic sclerosis (SSc), we sought to investigate the role of progranulin in SSc.
  
  
  METHODS
  Progranulin expression levels in human and murine skin samples were determined by immunohistochemical analysis and quantitative reverse transcription-polymerase chain reaction. The role of progranulin in fibroblast activation was examined using a gene-silencing technique. Progranulin levels in serum obtained from 60 patients with SSc and 16 healthy control subjects were determined by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Progranulin expression was increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, both in vivo and in vitro. Transcription factor Fli-1, a deficiency of which is involved in the activation of SSc dermal fibroblasts, served as a potent repressor of the progranulin gene, and Fli-1(+/-) mice and bleomycin-treated wild-type mice exhibited up-regulated expression of progranulin in dermal fibroblasts. SSc dermal fibroblasts were resistant to the antifibrotic effect of TNF, but this resistance was reversed by gene silencing of progranulin. Serum progranulin levels were elevated in patients with early diffuse cutaneous SSc (dcSSc), especially in those with inflammatory skin symptoms, and were positively correlated with the C-reactive protein level.
  
  
  CONCLUSIONS
  Progranulin overproduction due to Fli-1 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the antifibrotic effect of TNF. Progranulin may also be involved in the inflammatory process associated with progressive skin sclerosis in early dcSSc.
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Akamata
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Noda
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toyama
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Tada
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kadono
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D000077155:Granulins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D000077153:Progranulins; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045743:Scleroderma, Diffuse / Q000235:genetics* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism; D012867:Skin; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha