TAK1 is a key modulator of the profibrogenic phenotype of human ileal myofibroblasts in Crohn’s disease

Alessia Rosaria Grillo, Melania Scarpa, Renata D’Incà, Paola Brun, Marco Scarpa, Andrea Porzionato, Raffaele De Caro, Diego Martines, Andrea Buda, Imerio Angriman, Giorgio Palù, Giacomo Carlo Sturniolo, Ignazio Castagliuolo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)G443-G454
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number6
DOIs
Publication statusPublished - Sep 15 2015

Keywords

  • Fibrogenesis
  • Intestinal myofibroblasts
  • TAK1

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology
  • Medicine(all)

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