title: Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis.
abstract: OBJECTIVE
  Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc).
  
  
  METHODS
  The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3.
  
  
  RESULTS
  TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation.
  
  
  CONCLUSIONS
  The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc.
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Sumova
authors.affiliation: Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Avouac
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.affiliation: Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Becvar
authors.affiliation: Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Senolt
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012871:Skin Diseases / Q000139:chemically induced / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D051900:Smad3 Protein; C474830:TRB3 protein, mouse; C474831:TRIB3 protein, human; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Fibroblasts; Systemic Sclerosis; Treatment