Rationale: Studies have implied the positive association of JAK2/STAT3
signaling with the onset and severity of acute pancreatitis (AP). However, definitive
functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in
vivo is missing and its potential as a therapeutic target and the underlying mechanisms
remain to be determined.
Objectives: The aim of this study was to explore the role of JAK2/STAT3 signaling in the
pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a
Methods and Results: Using the caerulin-induced acute pancreatitis rat model, we
showed that JAK2/STAT3 signaling was activated in pancreas and systemic
inflammation was increased during AP. Pharmacological suppression of JAK2 by its
inhibitor AG490 robustly protected against tissue damage, attenuated JAK2/STAT3
signaling and inflammatory responses. Local pancreatic tissue damage and phosphor-
JAK2 in the pancreatic tissue were enhanced in animals fed with high fat diet compared
to chow-diet fed animals. Interestingly, JAK2 inhibitor AG490 significantly inhibited
pancreas necrosis and systemic inflammation in animals fed with high fat or chow-diet,
but did not affect STAT3 signaling.
Conclusion: These results establish that JAK2 activation plays a significant role in the
pathogenesis of caerulin-induced AP in animals on both chow and high-fat diets by
regulating necrosis and systemic inflammation. Thus, our results not only clarify novel
signaling mechanisms in AP but also suggest that JAK2 might constitute a target in the
management of hyperlipidemia-intensified caerulin-induced AP.