title: Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein.
abstract: Fibrosis is a common and intractable condition associated with various pathologies. It is characterized by accumulation of an excessive amount of extracellular matrix molecules that primarily include collagen type I. IL-6 is a profibrotic cytokine that is elevated in the prototypic fibrotic autoimmune condition systemic sclerosis and is known to induce collagen I expression, but the mechanism(s) behind this induction are currently unknown. Using healthy dermal fibroblasts in vitro, we analyzed the signaling pathways that underscore the IL-6-mediated induction of collagen. We show that IL-6 trans signaling is important and that the effect is dependent on STAT3; however, the effect is indirect and mediated through enhanced TGF-β signaling and the classic downstream cellular mediator Smad3. This is due to induction of the bone morphogenetic protein (BMP) antagonist Gremlin-1, and we show that Gremlin-1 is profibrotic and is mediated through canonical TGF-β signaling.
authors.affiliation: From the Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: O'Reilly
authors.forename: Marzena
authors.initials: M
authors.lastname: Ciechomska
authors.forename: Rachel
authors.initials: R
authors.lastname: Cant
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; C486399:GREM1 protein, human; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C497790:SMAD3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta
keywords: Cell Biology; Collagen; Extracellular; Fibrogenesis; Interleukin; Interleukin-6; Signal Transduction