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High-Dose Linoleic Acid Activated JAK2-STAT3 Signaling Pathway Involved in Cytokine Production and Lipogenesis in Pancreatic Exocrine Cells

[ Vol. 16 , Issue. 7 ]

Author(s):

F. Zhu, Y. Guan and R. Zhang   Pages 668 - 676 ( 9 )

Abstract:


Background: Linoleic acid has been implicated in the pathogenesis of acute pancreatitis. However, molecular mechanisms underlying adverse effects of large-dose linoleic acid remain unclear. Current study aimed to explore the impact of high-dose linoleic acid on the activation of Janus kinase 2 (JAK2)-signal transducers and activators of transcription 3 (STAT3) pathway, cytokine production, and lipogenesis in pancreatic exocrine cells.

Methods: MTT assay was used to detect the viability of AR42J rat pancreatic exocrine cells, and lactate dehydrogenase assay was utilized to detect cytotoxicity. Concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were detected by ELISA, and protein expression of JAK2, p-JAK2, STAT3, p- STAT3, and fatty acid synthase (FAS) was examined by Western Blot. The impact of highdose linoleic acid on JAK2-STAT3 pathway was also examined when JAK2 was inhibited by AG490, and STAT3 expression was interrupted by siRNA.

Results: The cell viability of AR42J rat pancreatic exocrine cells was inhibited, and cytotoxicity was increased by high-dose linoleic acid. JAK2 and STAT3 proteins in pancreatic exocrine cells were activated by high-dose linoleic acid via phosphorylation and nuclear localization of phosphorylated STAT3. Moreover, the expression of downstream proteins in JAK2-STAT3 pathway (IL-6, TNF-α and FAS) was up-regulated by high-dose linoleic acid. The increased levels of IL-6 and TNF-α caused by high-dose linoleic acid were attenuated by JAK2 inhibitor AG490. p-JAK2 protein was up-regulated, whereas p-STAT3, STAT3 and FAS proteins were down-regulated by high-dose linoleic acid in the presence of STAT3-siRNA.

Conclusion: The cytotoxicity was increased and JAK2-STAT3 signaling pathway was activated by high-dose linoleic acid through cytokine production and lipogenesis in rat pancreatic exocrine cells.

Keywords:

JAK2, STAT3, linoleic acid, cytokines, fatty acid synthase.

Affiliation:

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



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