5 years ago

TGF-β1/SMADs signaling pathway activation protects intestinal epithelium from Clostridium difficile toxin A-induced damage.

Araujo APB, Quesada-Gómez C, Gomes FCA, Leitão RFC, Meloni M, Santos AAQA, Stipursky J, Ureña DL, Brito GAC, Foschetti DA, Tinoco-Veras CM
Clostridium difficile, the main cause of diarrhea in hospitalized patients, produces toxins A (TcdA) and B (TcdB), which affect intestinal epithelial cell survival, proliferation, and migration, and induce an intense inflammatory response. TGF-β is a pleiotropic cytokine affecting enterocyte and immune/inflammatory responses. However, it has been shown that exposure of intestinal epithelium to a low concentration of TcdA induces the release of TGF-β1, which has a protective effect on epithelial resistance and a TcdA/TGF-β signaling pathway interaction. The activation of this pathway in vivo has not been elucidated. The aim of this study was to investigate the role of the TGF-β1 pathway on TcdA-induced damage in a rat intestinal epithelial cell line (IEC-6) and in a mouse model of an ileal loop. TcdA increased the expression of TGF-β1 and its receptor, TβRII, in vitro and in vivo TcdA induced nuclear translocation of the transcription factors SMAD2/3, a hallmark of TGF-β1 pathway activation, both in IEC cells and in mouse ileal tissue. The addition of recombinant TGF-β1 (rTGF-β) prevented TcdA-induced apoptosis/necrosis, restores proliferation and repair activity in IEC cells in the presence of TcdA. Together, these data show that TcdA induces TGF-β1 signaling pathway activation and suggest that this pathway might play a protective role against the effect of C. difficile-toxin.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28784928

DOI: PubMed:28784928

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