Involvement of tumor necrosis factor alpha in intestinal epithelial cell proliferation following Paneth cell destruction

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)-alpha protein in their cytoplasmic granules, and TNF-alpha has a proliferative effect on 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-alpha inhibitor, pentoxifyl-line (100 mg/kg), neutralizing anti-TNF-alpha antibody (2 mg/kg), or nuclear transcription factor kappaB (NF-kappaB) inhibitors: pyrrolidine dithocarbamate (100 mg/kg) or N-acetyl-L-cystein (100 mg/kg). The activation of NF-kappaB was examined by the electrophoretic mobility shift assay, and cellular proliferation by BrdU labeling. Results: Without any inhibitors, dithizone treatment evoked NF-kappaB activation in the ileal mucosa with its peak levels at 2 h after the injection. TNF-alpha inhibition reduced the NF-kappaB activation, and blocked a transient wave of epithelial cell proliferation 12 h after the injection. NF-kappaB inhibitors also reduced the NF-kappaB activation and epithelial cell proliferation. Conclusion: TNF-alpha released from degenerated Paneth cells was, in part, responsible for the intestinal cell proliferation through the activation of NF-kappaB, suggesting its proliferative effect on intestinal epithelial cells.