Involvement of Tumor Necrosis Factor Alpha in Intestinal Epithelial Cell Proliferation Following Paneth Cell Destruction

Abstract

Background : An intravenous injection of diphenylthiocarbazone (dithizone), a zinc chelator, induces selective killing of Paneth cells which have a large amount of zinc in their cytoplasmic granules. A transient wave of intestinal epithelial cell proliferation occurs at 12 h after the injection. Paneth cells have tumor necrosis factor (TNF)- α protein in their cytoplasmic granules, and TNF- α has a proliferative effect on intestinal epithelial cells in vitro. The aim of this study is to clarify the in vivo role of TNF- α in intestinal epithelial cell proliferation using a dithizone-treated rat model. Methods : Male Wistar rats received a dithizone (100 mg/kg of body weight) injection with or without TNF- α inhibitor, pentoxifylline (100 mg/kg), neutralizing anti-TNF- α antibody (2 mg/kg), or nuclear transcription factor &#115 B (NF- &#115 B) inhibitors; pyrrolidine dithiocarbamate (100 mg/kg) or N -acetyl-L-cystein (100 mg/kg). The activation of NF- &#115 B was examined by the electrophoretic mobility shift assay, and cellular proliferation by BrdU labeling. Results : Without any inhibitors, dithizone treatment evoked NF- &#115 B activation in the ileal mucosa with its peak level at 2 h after the injection. TNF- α inhibition reduced the NF- &#115 B activation, and blocked a transient wave of epithelial cell proliferation 12 h after the injection. NF- &#115 B inhibitors also reduced the NF- &#115 B activation and epithelial cell proliferation. Conclusions : TNF- α released from degenerated Paneth cells was, in part, responsible for the intestinal cell proliferation through the activation of NF- &#115 B, suggesting its proliferative effect on intestinal epithelial cells.

• Nf-KAPPA-B
• Paneth Cell
• Proliferation
• Tnf-ALPHA