Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis

Gastroenterology. 2012 Dec;143(6):1670-80. doi: 10.1053/j.gastro.2012.08.051. Epub 2012 Sep 27.

Abstract

Background & aims: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • CD4-Positive T-Lymphocytes / pathology
  • Ceruletide / adverse effects
  • Choline Deficiency / complications
  • Disease Models, Animal
  • Female
  • Interleukins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Pancreatitis / etiology
  • Pancreatitis / physiopathology*
  • Pancreatitis / prevention & control*
  • Phosphorylation
  • Receptors, Aryl Hydrocarbon / deficiency
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / physiology*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / physiology

Substances

  • Interleukins
  • Receptors, Aryl Hydrocarbon
  • STAT3 Transcription Factor
  • Ceruletide
  • interleukin-22