Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression.

Abstract

To examine the intrapancreatic production of tumor necrosis factor (TNF) alpha and define its cell of origin during acute pancreatitis. Acute necrotizing pancreatitis was induced in adult male mice by administering cerulein (50 micrograms/kg intraperitoneally four times over 3 hours). Animals were killed at 0, 0.5, 1, 2, 4, 6, and 8 hours, with the severity of pancreatitis established by blind histologic grading and serum amylase, lipase, and TNF levels. The expression of TNF messenger RNA within the pancreas was established by the reverse transcription polymerase chain reaction. Intrapancreatic TNF protein was analyzed by enzyme-linked immunosorbent assay, Western blot, and immunohistochemical methods. Acute pancreatitis was manifest within 1 hour of the first cerulein injection and increased in severity through 8 hours. There was no constitutive expression of TNF messenger RNA within the pancreas, but transcripts were induced within 30 minutes following the onset of pancreatitis, increasing through 4 hours. Intrapancreatic and serum TNF peptide levels became detectable at 1 hour and increased over 6 hours (both P < .001 vs control), with intrapancreatic levels rising faster and attaining concentrations three times higher than time-matched serum levels (P < .01). Immunohistochemical staining demonstrated the progressive infiltration of macrophages into the pancreas that stained heavily for TNF (P < .01 vs control). Tumor necrosis factor gene expression is induced locally during acute pancreatitis, resulting in large amounts of intrapancreatic TNF with levels consistently higher than those found in the serum. The overall rise in both tissue and serum TNF concentrations correlates directly with the severity of pancreatic damage and inflammation. The infiltrating macrophage appears to contribute most to this process.