title: The transcription factor JunD mediates transforming growth factor {beta}-induced fibroblast activation and fibrosis in systemic sclerosis.
abstract: OBJECTIVE
  Transforming growth factor β (TGFβ) has been identified as a key player in fibrotic diseases. However, the molecular mechanisms by which TGFβ activates fibroblasts are incompletely understood. Here, the role of JunD, a member of the activator protein 1 (AP-1) family of transcription factors, as a downstream mediator of TGFβ signalling in systemic sclerosis (SSc), was investigated.
  
  
  METHODS
  The expression of JunD was analysed by real-time PCR, immunofluorescence, western blotting and immunohistochemistry. The canonical Smad pathway was specifically targeted by small interfering (si)RNA. The expression of extracellular matrix proteins in JunD deficient (JunD(-/-)) fibroblasts was analysed by real-time PCR and hydroxyproline assays. The mouse model of bleomycin-induced dermal fibrosis was used to assess the role of JunD in experimental fibrosis.
  
  
  RESULTS
  JunD was overexpressed in SSc skin and in cultured fibroblasts in a TGFβ dependent manner. The expression of JunD colocalised with pSmad 3 in fibrotic skin and silencing of Smad 3 or Smad 4 by siRNA prevented the induction of JunD by TGFβ. JunD(-/-) fibroblasts were less responsive to TGFβ and released less collagen upon stimulation with TGFβ. Moreover, JunD(-/-) mice were protected from bleomycin-induced fibrosis with reduced dermal thickening, decreased myofibroblast counts and lower collagen content of lesional skin.
  
  
  CONCLUSIONS
  These data demonstrate that JunD is overexpressed in SSc and that JunD is a mediator of the profibrotic effects of TGFβ. Considering that inhibitors of AP-1 signalling have recently been developed and are available for clinical trials in SSc, these findings may have translational implications.
authors.affiliation: Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Stefan
authors.initials: S
authors.lastname: Vollath
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Jerome
authors.initials: J
authors.lastname: Avouac
authors.forename: Moshe
authors.initials: M
authors.lastname: Yaniv
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: C559371:JunD protein, human; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen