title: TAK1 is a key modulator of the profibrogenic phenotype of human ileal myofibroblasts in Crohn's disease.
abstract: Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) signaling can mediate inflammatory responses as well as tissue remodeling. Intestinal mucosal myofibroblast (IMF) activation drives gut fibrosis in Crohn's disease (CD); however, the molecular pathways involved are largely unknown. Thus we investigated the yet-unknown expression and function of TAK1 in human CD-associated fibrosis. Ileal surgical specimens, ileal biopsies, and IMF isolated from controls and CD patients were analyzed for TAK1 and its active phosphorylated form (pTAK1) by Western blotting, immunohistochemistry, and real-time quantitative PCR. TAK1 pharmacological inhibition and silencing were used to assess its role in collagen and inflammatory cytokine synthesis in IMF. TAK1 and pTAK1 levels increased in ileum specimens from CD patients compared with controls and correlated to tissue fibrosis. Similarly, TAK1 mRNA in ileal biopsies of CD patients correlated with fibrogenic marker expression but not inflammatory cytokines. CD-derived IMF showed higher TAK1 and pTAK1 expression associated with increased collagen1(α)1 mRNA levels compared with control IMF. TGF-β1 promoted pTAK1 nuclear translocation and collagen synthesis. TAK1 inhibition or silencing significantly reduced TGF-β1-stimulated collagen production and normalized the profibrogenic phenotype of CD-derived IMF. Taken together, these data suggest that TAK1 activation and nuclear translocation induce and maintain a fibrogenic phenotype in the IMF. Thus the TAK1 signaling pathway may represent a suitable target to design new, antifibrotic therapies.
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy; Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy; and.
authors.forename: Alessia Rosaria
authors.initials: AR
authors.lastname: Grillo
authors.affiliation: Oncological Surgery Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Scarpa
authors.affiliation: Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy; and.
authors.forename: Renata
authors.initials: R
authors.lastname: D'Incà
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
authors.affiliation: Oncological Surgery Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Scarpa
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Porzionato
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy;
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caro
authors.affiliation: Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy; and.
authors.forename: Diego
authors.initials: D
authors.lastname: Martines
authors.affiliation: Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.affiliation: Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy; and.
authors.forename: Imerio
authors.initials: I
authors.lastname: Angriman
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy; and.
authors.forename: Giacomo Carlo
authors.initials: GC
authors.lastname: Sturniolo
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy; ignazio.castagliuolo@unipd.it.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D000368:Aged; D003094:Collagen / Q000096:biosynthesis; D003424:Crohn Disease / Q000473:pathology*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D020868:Gene Silencing; D005822:Genetic Vectors; D006801:Humans; D007082:Ileum / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000473:pathology*; D021381:Protein Transport; D055815:Young Adult; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003094:Collagen; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7
keywords: TAK1; fibrogenesis; intestinal myofibroblasts