title: 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.
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.
  
  
  METHODS
  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 p22(phox) or p47(phox).
  
  
  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 p22(phox) and p47(phox) compared to S ODN controls.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Kyung Don
authors.initials: KD
authors.lastname: Ju
authors.forename: Joo Weon
authors.initials: JW
authors.lastname: Lim
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D002108:Ceruletide / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010195:Pancreatitis / Q000503:physiopathology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020032:Tyrphostins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D002108:Ceruletide; D019255:NADPH Oxidases; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases