Transforming Growth Factor β1/SMAD Signaling Pathway Activation Protects the Intestinal Epithelium from Clostridium difficile Toxin A-Induced Damage

• Published in: Infection and immunity 2017-10, Vol.85 (10)
• Main Authors: Tinoco-Veras, Christianne Maria, Santos, Ana Angélica Q A, Stipursky, Joice, Meloni, Marcelo, Araujo, Ana Paula Bérgamo, Foschetti, Danielle Abreu, López-Ureña, Diana, Quesada-Gómez, Carlos, Leitão, Renata F C, Gomes, Flávia Carvalho Alcantara, Brito, Gerly Anne de Castro
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Infections; Bacterial Proteins - metabolism; Bacterial Toxins - metabolism; Bacterial Toxins - toxicity; Cell Death - drug effects; Cell Line; Cell Survival; Clostridium difficile - pathogenicity; Enterotoxins - metabolism; Enterotoxins - toxicity; Ileum - immunology; Ileum - microbiology; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestines - immunology; Intestines - microbiology; Mice; Signal Transduction; Smad Proteins - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00430-17

, 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 β (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 has not been elucidated. The aim of this study was to investigate the role of the TGF-β1 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-β1 and its receptor, TβRII, and 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 and restored proliferation and repair activity in IEC-6 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 -toxin.