Transforming Growth Factor ?1/SMAD Signaling Pathway Activation Protects the Intestinal Epithelium from Clostridium difficile Toxin A-Induced Damage.

ABSTRACT: 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. Transforming growth factor ? (TGF-?) 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-?1, which has a protective effect on epithelial resistance and a TcdA/TGF-? 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-?1 pathway in 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-?1 and its receptor, T?RII, in vitro and in vivo TcdA induced nuclear translocation of the transcription factors SMAD2/3, a hallmark of TGF-?1 pathway activation, both in IEC cells and in mouse ileal tissue. The addition of recombinant TGF-?1 (rTGF-?) prevented TcdA-induced apoptosis/necrosis and restored proliferation and repair activity in IEC-6 cells in the presence of TcdA. Together, these data show that TcdA induces TGF-?1 signaling pathway activation and suggest that this pathway might play a protective role against the effect of C. difficile-toxin.

SUBMITTER: Tinoco-Veras CM 

PROVIDER: S-EPMC5607421 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature