PANCREATIC ACINAR-CELLS PRODUCE, RELEASE, AND RESPOND TO TUMOR-NECROSIS-FACTOR-ALPHA - ROLE IN REGULATING CELL-DEATH AND PANCREATITIS

The aim of this study was to determine whether tumor necrosis factor-a lpha (TNF alpha) and receptors for TNF alpha are expressed in the exoc rine pancreas, and whether pancreatic acinar cells release and respond to TNF alpha. Reverse transcription PCR, immunoprecipitation, and Wes tern blot analysis demonstrated the presence of TNF alpha and 55- and 75-kD TNF alpha receptors in pancreas from control rats, rats with exp erimental pancreatitis induced by supramaximal doses of cerulein, and in isolated pancreatic acini. Immunohistochemistry showed TNF alpha pr esence in pancreatic acinar cells. ELISA and bioassay measurements of TNF alpha indicated its release from pancreatic acinar cells during in cubation in primary culture. Acinar cells responded to TNF alpha. TNF alpha potentiated NF-kappa B translocation into the nucleus and stimul ated apoptosis in isolated acini while not affecting LDH release, In v ivo studies demonstrated that neutralization of TNF alpha with an anti body produced a mild improvement in the parameters of cerulein-induced pancreatitis. However, TNF alpha neutralization greatly inhibited apo ptosis in a modification of the cerulein model of pancreatitis which i s associated with a high percentage of apoptotic cell death. The resul ts indicate that pancreatic acinar cells produce, release, and respond to TNF alpha. This cytokine regulates apoptosis in both isolated panc reatic acini and experimental pancreatitis.