Inhibition of JAK2 Signaling Alleviates Hyperlipidemia-Intensified Caerulin-Induced Acute Pancreatitis In Vivo

Title:Inhibition of JAK2 Signaling Alleviates Hyperlipidemia-Intensified Caerulin-Induced Acute Pancreatitis In Vivo

Volume: 17 Issue: 5

Author(s): F. Zhu*, Y. Guan and R. Zhang

Affiliation:

• Department of Gastroenterology, Shanghai East Hospital, Shanghai Tongji University, No. 150 Jimo Road, Pudong New District, Shanghai 200120,China

Keywords: Pancreatitis, JAK2/STAT3 signaling, necrosis, inflammation, hyperlipidemia, caerulin.

Abstract: 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 therapeutic target.

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.

Cite this article as:

Zhu F. *, Guan Y. and Zhang R. , Inhibition of JAK2 Signaling Alleviates Hyperlipidemia-Intensified Caerulin-Induced Acute Pancreatitis In Vivo, Current Molecular Medicine 2017; 17 (5) . https://dx.doi.org/10.2174/1566524018666171205123723