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Potential role of NADPH oxidase-mediated activation of Jak2/Stat3 and mitogen-activated protein kinases and expression of TGF-β1 in the pathophysiology of acute pancreatitis

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Abstract

Objective

NADPH oxidase is potentially associated with acute pancreatitis by producing reactive oxygen species (ROS). We investigated whether NADPH oxidase mediates the activation of Janus kinase (Jak)2/signal transducers and activators of transcription (Stat)3 and mitogen-activated protein kinases (MAPKs) to induce the expression of transforming growth factor-β1 (TGF-β1) in cerulein-stimulated pancreatic acinar cells.

Treatment

AR42J cells were treated with an NADPH oxidase inhibitor diphenyleneiodonium (DPI) or a Jak2 inhibitor AG490. Other cells were transfected with antisense or sense oligonucleotides (AS or S ODNs) for NADPH oxidase subunit p22phox or p47phox.

Methods

TGF-β1 was determined by enzyme-linked immonosorbent assay. STAT3-DNA binding activity was measured by electrophoretic mobility shift assay. Levels of MAPKs as well as total and phospho-specific forms of Jak1/Stat3 were assessed by Western blot analysis.

Results

Cerulein induced increases in TGF-β1, Stat3-DNA binding activity and the activation of MAPKs in AR42J cells. AG490 suppressed these cerulein-induced changes, similar to inhibition by DPI. Cerulein-induced activation of Jak2/Stat3 and increases in MAPKs and TGF-β1 levels were inhibited in the cells transfected with AS ODN for p22phox and p47phox compared to S ODN controls.

Conclusion

Inhibition of NADPH oxidase may be beneficial for prevention and treatment of pancreatitis by suppressing Jak2/Stat3 and MAPKs and expression of TGF-β1 in pancreatic acinar cells.

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Acknowledgments

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0001669) and a grant (Joint Research Project under the Korea-Japan Basic Scientific Cooperation Program) from NRF (F01-2009-000-10101-0). H. Kim is grateful to Brain Korea 21 Project, College of Human Ecology, Yonsei University.

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Authors and Affiliations

  1. Department of Pharmacology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Kyung Don Ju & Kyung Hwan Kim

  2. Department of Food and Nutrition, Brain Korea 21 Project, College of Human Ecology, Yonsei University, Seoul, 120-749, Korea

    Joo Weon Lim & Hyeyoung Kim

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  1. Kyung Don Ju
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Correspondence to Hyeyoung Kim.

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Ju, K.D., Lim, J.W., Kim, K.H. et al. Potential role of NADPH oxidase-mediated activation of Jak2/Stat3 and mitogen-activated protein kinases and expression of TGF-β1 in the pathophysiology of acute pancreatitis. Inflamm. Res. 60, 791–800 (2011). https://doi.org/10.1007/s00011-011-0335-4

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