Corticosteroids Correct Aberrant CFTR Localization in the Duct and Regenerate Acinar Cells in Autoimmune Pancreatitis

Shigeru B.H. Ko, Nobumasa Mizuno, Yasushi Yatabe, Toshiyuki Yoshikawa, Hiroshi Ishiguro, Akiko Yamamoto, Sakiko Azuma, Satoru Naruse, Kenji Yamao, Shmuel Muallem, Hidemi Goto

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Abstract

Background & Aims: Corticosteroids are now widely accepted as a treatment for autoimmune pancreatitis (AIP). However, the molecular mechanism by which steroid treatment improves AIP remains largely unknown. The aim of this study was to elucidate cellular mechanisms by which corticosteroids improve both pancreatic exocrine function and histopathology in AIP. Methods: Pancreatic exocrine function was evaluated by the secretin-stimulated function test and pancreatic biopsy specimens were processed for histologic analysis at the time of diagnosis and 3 months after initiation of steroid treatment. Expression and localization of proteins was assayed by immunohistochemistry. Analysis of immunoglobulin (Ig)G4-positive plasma cells was used to verify inflammation in AIP. Results: The number of IgG4-positive plasma cells in pancreatic sections was decreased by steroid treatment, indicating reduced inflammation. Fluid, bicarbonate (HCO3 -), and digestive enzyme secretions all were impaired in most patients with AIP. Corticosteroids improved both HCO3 - and digestive enzyme secretion. A large fraction of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a central role in pancreatic duct HCO3 - secretion, was mislocalized to the cytoplasm of duct cells before treatment. Corticosteroids corrected the localization of CFTR to the apical membrane, accounting for the improved HCO3 - secretion. Steroid treatment resulted in regeneration of acinar cells, accounting for restored digestive enzyme secretion. Conclusions: Corticosteroids reduce inflammation and restore both digestive enzyme and HCO3 - secretion in patients with AIP by regenerating acinar cells and correcting CFTR localization in pancreatic duct cells. Mislocalization of CFTR may explain aberrant HCO3 - secretion in other forms of pancreatitis.

Original languageEnglish
Pages (from-to)1988-1996.e3
JournalGastroenterology
Volume138
Issue number5
DOIs
Publication statusPublished - 2010 May

Keywords

  • Aquaporin Water Channel
  • CD133
  • CFTR
  • Exocrine Function Test

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Ko, S. B. H., Mizuno, N., Yatabe, Y., Yoshikawa, T., Ishiguro, H., Yamamoto, A., Azuma, S., Naruse, S., Yamao, K., Muallem, S., & Goto, H. (2010). Corticosteroids Correct Aberrant CFTR Localization in the Duct and Regenerate Acinar Cells in Autoimmune Pancreatitis. Gastroenterology, 138(5), 1988-1996.e3. https://doi.org/10.1053/j.gastro.2010.01.001