Original Research
IL33 Is a Stomach Alarmin That Initiates a Skewed Th2 Response to Injury and Infection

https://doi.org/10.1016/j.jcmgh.2014.12.003Get rights and content
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Background & Aims

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 during Helicobacter pylori infection. 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 with H pylori and 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 pylori infection, however, this increase was not apparent after 7 days and IL33 expression was reduced 2-fold after 2 months. Similarly, human biopsy specimens positive for H pylori had 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 prolonged H pylori infection may be permissive for the T helper 1–biased immune response observed during H pylori infection and subsequent precancerous progression.

Keywords

IL33
Helicobacter pylori
Inflammatory Response
Gastric Cancer

Abbreviations used in this paper

AB
Alcian blue
DC
dendritic cell
ELISA
enzyme-linked immunosorbent assay
ERK
extracellular signal–regulated kinase
FBS
fetal bovine serum
HBSS
Hank’s balanced salt solution
IL
interleukin
ILC
innate lymphoid cell
mRNA
messenger RNA
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

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Conflicts of interest The authors disclose no conflicts.

Funding This study was supported by the Victorian Government’s Operational Infrastructure Support Program and National Health and Medical Research Council Australia (APP1006688).