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A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream inflammatory signaling involved in progression of chronic pancreatitis, and to use withaferin A (WA), a small molecule inhibitor of nuclear factor κB (NFκB), to prevent progression of chronic pancreatitis.

Methods

Two different protocols were used to induce pancreatitis in mice: standard and stringent administration of cerulein. The severity of pancreatitis was assessed by means of pancreatic histology and serum amylase levels. Immunohistochemistry and flow-cytometric analysis was performed to visualize immune cell infiltration into the pancreas. Real-time PCR and Western blot were used to analyze the downstream signaling mechanism involved in the development of chronic pancreatitis.

Results

The severity of cerulein-induced pancreatitis was reduced significantly by WA, used as either preventive or curative treatment. Immune cell infiltration into the pancreas and acinar cell death were efficiently reduced by WA treatment. Expression of proinflammatory and proapoptotic genes regulated by NFκB activation was increased by cerulein treatment, and WA suppressed these genes significantly. Sustained endoplasmic reticulum stress activation by cerulein administration was reduced. NLRP3 inflammasome activation in cerulein-induced pancreatitis was identified, and this was also potently blocked by WA. The human pancreatitis tissue gene signature correlated with the mouse model.

Conclusions

Our data provide evidence for the role of NFκB in the pathogenesis of chronic pancreatitis, and strongly suggest that WA could be used as a potential therapeutic drug to alleviate some forms of chronic pancreatitis.

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Acknowledgments

The authors gratefully acknowledge Morihito Takita, Prathab Balaji Saravanan, and Faisal Kunnathodi. Technical assistance by Nofit Borenstein-Auerbach, Omar Khan, Ana Rahman, and Yoshiko Tamura is also acknowledged. The manuscript editing service provided by Cynthia Orticio is highly appreciated.

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Authors and Affiliations

  1. Institute of Biomedical Studies, Baylor University, Waco, TX, USA

    Mazhar A. Kanak

  2. Department of Surgery, University of Virginia, Charlottesville, VA, USA

    Rauf Shahbazov

  3. Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA

    Gumpei Yoshimatsu, Michael C. Lawrence & Bashoo Naziruddin

  4. Department of Surgery, Transplantation Division, Virginia Commonwealth University, Richmond, VA, USA

    Mazhar A. Kanak & Marlon F. Levy

  5. Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA

    Bashoo Naziruddin

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  1. Mazhar A. Kanak
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  2. Rauf Shahbazov
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Correspondence to Mazhar A. Kanak or Bashoo Naziruddin.

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Kanak, M.A., Shahbazov, R., Yoshimatsu, G. et al. A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis. J Gastroenterol 52, 352–365 (2017). https://doi.org/10.1007/s00535-016-1238-5

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  • DOI: https://doi.org/10.1007/s00535-016-1238-5

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