title: Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis.
abstract: OBJECTIVE
  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 (HCO(3)(-)), and digestive enzyme secretions all were impaired in most patients with AIP. Corticosteroids improved both HCO(3)(-) and digestive enzyme secretion. A large fraction of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a central role in pancreatic duct HCO(3)(-) 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 HCO(3)(-) 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 HCO(3)(-) secretion in patients with AIP by regenerating acinar cells and correcting CFTR localization in pancreatic duct cells. Mislocalization of CFTR may explain aberrant HCO(3)(-) secretion in other forms of pancreatitis.
authors.affiliation: Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. sko@med.nagoya-u.ac.jp
authors.forename: Shigeru B H
authors.initials: SB
authors.lastname: Ko
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Mizuno
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Sakiko
authors.initials: S
authors.lastname: Azuma
authors.forename: Satoru
authors.initials: S
authors.lastname: Naruse
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamao
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
mesh_terms: D000071916:AC133 Antigen; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D051398:Aquaporin 1 / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010183:Pancreatic Ducts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010189:Pancreatic Juice / Q000201:enzymology; D010195:Pancreatitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology; D021381:Protein Transport; D012038:Regeneration / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000071916:AC133 Antigen; C496020:AQP1 protein, human; D000305:Adrenal Cortex Hormones; D015703:Antigens, CD; D001639:Bicarbonates; C505032:CFTR protein, human; D006023:Glycoproteins; D007074:Immunoglobulin G; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051398:Aquaporin 1