title: Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis.
abstract: OBJECTIVE
  The type of immune response during development of acute pancreatitis (AP) determines disease severity. Pancreatic epithelial cells express the interleukin (IL)-22 receptor A1 (IL-22RA1). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates expression of IL-22. We investigated sources and role of IL-22 in the pancreas, along with the effects of AhR activation on IL-22 expression and AP progression in mice.
  
  
  METHODS
  We analyzed the effects of recombinant IL-22, a monoclonal antibody against IL-22, and agonists and antagonists of AhR in mice with AP (induced with caerulein or a choline-deficient diet supplemented with DL-ethionine) and control mice. We also analyzed transgenic mice with AhR deficiency (AhR(d) and AhR(-/-) mice).
  
  
  RESULTS
  CD4(+) T cells were the main source of IL-22 in pancreatic tissues from healthy mice. During development of AP, numbers of IL-22(+) CD4(+) T cells were reduced, whereas IL-22RA1 was up-regulated. Consistent with high levels of IL-22RA1 expression, pancreatic acinar cells responded to IL-22 signaling via signal transducers and activators of transcription 3; administration of IL-22 reduced AP and associated lung injury in mice. AhR was required for production of IL-22 and protected mice from AP. Mice that did not respond to AhR activation developed AP, but administration of IL-22 reduced AP; blockade of IL-22 reversed the ability of activated AhR to protect against AP.
  
  
  CONCLUSIONS
  AhR activation protects mice from AP by inducing expression of IL-22. AhR therefore mediates interactions between pancreatic leukocytes and epithelial cells and might be developed as a therapeutic target.
authors.affiliation: Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.forename: David T C
authors.initials: DT
authors.lastname: Nguyen
authors.forename: Aida
authors.initials: A
authors.lastname: Habtezion
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002108:Ceruletide / Q000009:adverse effects; D002796:Choline Deficiency / Q000150:complications; D004195:Disease Models, Animal; D005260:Female; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D010766:Phosphorylation; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000097043:Interleukin-22
chemical_list: D002108:Ceruletide; D007378:Interleukins; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22