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

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

Journal Name: Current Molecular Medicine

Volume 17 , Issue 5 , 2017

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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.

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

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Article Details

VOLUME: 17
ISSUE: 5
Year: 2017
Page: [381 - 387]
Pages: 7
DOI: 10.2174/1566524018666171205123723
Price: $58

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