Previously we reported that prior administration of lipopolysaccharide (LPS) mitigates subsequently produced cerulein (Cn) pancreatitis. To clarify the mechanism further, the pathological features of Cn pancreatitis were examined in detail after treating rats with very low doses of LPS. LPS pretreatment reduced the formation of pancreatic edema during Cn pancreatitis in a dose-and time-dependent manner. In contrast, the elevation of serum amylase and the histological findings, including acinar cell vacuolization and infiltration of inflammatory cells, were not affected. The lowest dose of LPS, 500 nglkg, was sufficient to inhibit pancreatic edema formation completely. LPS at a dose of 5 [mu] g/kg was fully effective when it was given from 30 min to 12 h before the induction of pancreatitis. Pretreatment with tumor necrosis factor-[alpha](TNF [alpha]) inhibited the pancreatic edema in a manner similar to that of LPS. Moreover, the inhibitory effect of LPS was partially attenuated by the administration of anti-TNF-[alpha] antibody before the injection of LPS. Actinomycin D (0.5 mg/kg) abolished the effect of LPS, whereas cycloheximide (0.5 mg/kg) given alone reduced pancreatic edema formation during pancreatitis. From these results, it was concluded that very low doses of LPS can induce, partially via TNF-[alpha], a state refractory to pancreatic edema formation during Cn pancreatitis, and this phenomenon seems to be regulated at the transcriptional level.