Inflammasomes promote the production of pro-inflammatory
cytokines, such as
interleukin (IL)-1β and
IL-18, which are the representative
mediators of inflammation. Abnormal activation of
inflammasomes leads to the development of inflammatory diseases such as
acute pancreatitis (AP). In this study, we demonstrate the inhibitory effects of a new natural compound
fraxinellone on
inflammasome formation and examine the role of
inflammasomes in a mouse model of AP. AP was induced with hourly
intraperitoneal injections of supramaximal concentrations of the stable
cholecystokinin analogue
cerulein (50 μg/kg) for 6 h. Mice were sacrificed 6 h after the final
cerulein injection. Blood and pancreas samples were obtained for further experiments.
Intraperitoneal injection of
fraxinellone significantly inhibited the pancreatic activation of multiple
inflammasome molecules such as
NACHT, LRR and PYD domains-containing protein 3 (NLRP3), PY-CARD, caspase-1,
IL-18, and IL-1β during AP. In addition,
fraxinellone treatment inhibited pancreatic injury, elevation in serum
amylase and
lipase activities, and infiltration of inflammatory cells such as neutrophils and macrophages but had no effect on pancreatic
edema. To investigate whether
inflammasome activation leads to the infiltration of inflammatory cells, we used
parthenolide, a well-known natural inhibitor, and
IL-1 receptor antagonist mice. The inhibition of
inflammasome activation by pharmacological/or genetic modification restricted the infiltration of inflammatory cells, but not
edema, consistent with the results observed with
fraxinellone. Taken together, our study highlights
fraxinellone as a natural inhibitor of
inflammasomes and that
inflammasome inhibition may lead to the suppression of inflammatory cells during AP.