H. pylori might help regulate gastric immunity
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Chronic Helicobacter pylori infection suppresses interleukin-33 cytokine in the stomach, which inhibits the CD4+ T helper cell 2 (or Th2) response and may set the stage for gastric carcinoma, investigators reported online in Cellular and Molecular Gastroenterology and Hepatology.
But long-term rises in IL-33 also can trigger precancerous changes in the stomach by causing the immune system to skew excessively toward Th2 instead of Th1 immunity, said Jon Buzzelli and his associates at the University of Melbourne in Parkville, Australia.
“Despite the immune response being vastly different ... the outcome appears to be similar, as preneoplastic changes occur in both settings,” the researchers added. “In keeping with recent findings, these data suggest that H. pylori may be a beneficial organism that under certain circumstances may help to ensure that gastric immunity is tightly regulated.” (Cellular and Molecular Gastroenterology and Hepatology 2015 [https://dx.doi.org/10.1016/j.jcmgh.2014.12.003 5])
IL-33 is a member of a diverse group of cytokines called alarmins, which quickly trigger an immune response to injury or infection when released by dying cells. Fasted mice in the study that were given oral aspirin to induce gastric injury had elevated IL-33 expression, compared with controls 4 hours later, the investigators reported. “This demonstrates that IL-33 responds immediately to gastric insult through relocalization and transcriptional changes, and may be involved in gastric wound healing,” they added.
The researchers also found that gastric IL-33 levels in mice rose fourfold just 1 day after they were infected with H. pylori. But 2 months later, the mice’s IL-33 levels had fallen below those of controls, resembling the researchers’ comparison of H. pylori–positive and uninfected human stomach specimens, they said.
Furthermore, the drop in IL-33 caused a tilt away from Th2 toward Th1 immunity, which appeared to trigger precancerous changes to the gastric mucosa, the researchers added. “The inhibition of gastric IL-33 in response to chronic H. pylori infection may be a key event in gastric cancer progression,” they concluded.
But eliminating H. pylori might also cause problems in some cases, the findings suggested. The declining prevalence of helicobacteriosis in humans has accompanied a rise in Barrett’s esophagus, which precedes esophageal cancer, they noted. When the researchers administered extra IL-33 to mice – mimicking the absence of H. pylori – the cardia of their stomachs expanded and became markedly metaplastic, which precedes Barrett’s esophagus in humans, they noted. H. pylori might help prevent Barrett’s esophagus by suppressing IL-33 and thereby regulating Th2 immunity, they concluded.
The researchers also found that mice born and reared in a pathogen-free environment had lower IL-33 levels, compared with those in conventional housing, they said. Gastric IL-33 expression appeared to rise as bacterial load and diversity increased, supporting the idea that IL-33 functions in this setting as an alarmin, they added.
The investigators also examined whether the TFF2 gene – which helps regulate homeostasis in mucus cells – promoted IL-33 expression in the stomach, as it does in the lungs. Indeed, TFF2 knockout mice had about 40% less gastric IL-33, compared with wild-type mice, they said. Humans with chronic helicobacteriosis also have low TFF2 expression, which continues to fall as gastric cancer grows, they noted.
The study was funded by the Victorian Government’s Operational Infrastructure Support Program and National Health & Medical Research Council, Australia. The researchers reported no conflicts of interest.