Transforming growth factor β1/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. Trans- forming growth factor

(TGF-

) is a pleiotropic cytokine affecting enterocyte and immune/inflammatory responses. However, it has been shown that exposure of in- testinal 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.