title: IL33 Is a Stomach Alarmin That Initiates a Skewed Th2 Response to Injury and Infection.
abstract: OBJECTIVE
  Interleukin (IL)33 is a recently described alarmin that is highly expressed in the gastric mucosa and potently activates Th2 immunity. It may play a pivotal role duringHelicobacter pyloriinfection. Here, we delineate the role of IL33 in the normal gastric mucosa and in response to gastropathy.
  
  
  METHODS
  IL33 expression was evaluated in mice and human biopsy specimens infected withH pyloriand in mice after dosing with aspirin. IL33 expression was localized in the gastric mucosa using immunofluorescence. Mice were given 1 or 7 daily doses of recombinant IL33 (1 μg/dose), and the stomach and the spleen responses were quantified morphologically, by flow cytometry and using quantitative reverse-transcription polymerase chain reaction and immunoblotting.
  
  
  RESULTS
  In mice, the IL33 protein was localized to the nucleus of a subpopulation of surface mucus cells, and co-localized with the surface mucus cell markers Ulex Europaeus 1 (UEA1), and Mucin 5AC (Muc5AC). A small proportion of IL33-positive epithelial cells also were Ki-67 positive. IL33 and its receptor Interleukin 1 receptor-like 1 (ST2) were increased 4-fold after acute (1-day)H pyloriinfection, however, this increase was not apparent after 7 days and IL33 expression was reduced 2-fold after 2 months. Similarly, human biopsy specimens positive forH pylorihad a reduced IL33 expression. Chronic IL33 treatment in mice caused systemic activation of innate lymphoid cell 2 and polarization of macrophages to the M2 phenotype. In the stomach, IL33-treated mice developed transmural inflammation and mucous metaplasia that was mediated by Th2/signal transducer and activator of transcription 3 signaling. Rag-1-/-mice, lacking mature lymphocytes, were protected from IL33-induced gastric pathology.
  
  
  CONCLUSIONS
  IL33 is highly expressed in the gastric mucosa and promotes the activation of T helper 2-cytokine-expressing cells. The loss of IL33 expression after prolongedH pyloriinfection may be permissive for the T helper 1-biased immune response observed duringH pyloriinfection and subsequent precancerous progression.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Jon N
authors.initials: JN
authors.lastname: Buzzelli
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Heather V
authors.initials: HV
authors.lastname: Chalinor
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Pavlic
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Sutton
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Trevelyan R
authors.initials: TR
authors.lastname: Menheniott
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
keywords: AB, Alcian blue; DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal–regulated kinase; FBS, fetal bovine serum; Gastric Cancer; HBSS, Hank’s balanced salt solution; Helicobacter pylori; IL, interleukin; IL33; ILC, innate lymphoid cell; Inflammatory Response; NF-κB, nuclear factor-κB; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; QRT-PCR, quantitative reverse-transcription polymerase chain reaction; SMC, surface mucus cells; SPF, specific pathogen free; SS1, Sydney strain 1; STAT, signal transducer and activator of transcription; TFF, trefoil factor; Th, T-helper; WT, wild type; mRNA, messenger RNA