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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 [http://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.
Gastric adenocarcinoma is the second-leading cause of cancer-related death worldwide, and chronic infection with Helicobacter pylori is the strongest known risk factor for the development of this malignancy. H. pylori colonization rates hover around 80%-90% in developing countries, but only a fraction of infected individuals ever develop disease. It is increasingly apparent that gastric carcinogenesis is multifactorial, influenced by host responses, H. pylori virulence, and environmental cofactors.
Parasitic helminth infections among H. pylori-infected individuals have been associated with a lower risk for the development of gastric cancer, and experimental data from animal models of Helicobacter infection have demonstrated that concurrent helminth infection attenuates the host immune response and reduces gastric atrophy. Infection with H. pylori typically induces a Th1-polarized immune response, while helminths drive Th2 responses.
Concurrent infections with helminths is endemic in regions of some developing countries that have a high prevalence of H. pylori infection, but a lower than expected rate of gastric cancer. Buzzelli et al. provide fresh insights into the role that IL-33 plays in polarizing Th2 immune responses by demonstrating that chronic, but not acute, H. pylori infection suppresses IL-33, which ultimately leads to a predominant Th1 response. These findings may represent a novel mechanism (e.g., manipulation of IL-33) explaining why populations harboring concurrent helminth and H. pylori infection have a reduced risk of gastric cancer.
Jennifer M. Noto, Ph.D., and Richard M. Peek Jr., M.D., AGAF, of the department of medicine, division of gastroenterology, hepatology, and department of nutrition and cancer biology, Vanderbilt University, Nashville, Tenn. Dr. Noto and Dr. Peek declared that no conflict of interest exists. They acknowledge the following funding sources: NIH R01CA077955, R01DK058587, P01CA116087, and P30DK058404.
Gastric adenocarcinoma is the second-leading cause of cancer-related death worldwide, and chronic infection with Helicobacter pylori is the strongest known risk factor for the development of this malignancy. H. pylori colonization rates hover around 80%-90% in developing countries, but only a fraction of infected individuals ever develop disease. It is increasingly apparent that gastric carcinogenesis is multifactorial, influenced by host responses, H. pylori virulence, and environmental cofactors.
Parasitic helminth infections among H. pylori-infected individuals have been associated with a lower risk for the development of gastric cancer, and experimental data from animal models of Helicobacter infection have demonstrated that concurrent helminth infection attenuates the host immune response and reduces gastric atrophy. Infection with H. pylori typically induces a Th1-polarized immune response, while helminths drive Th2 responses.
Concurrent infections with helminths is endemic in regions of some developing countries that have a high prevalence of H. pylori infection, but a lower than expected rate of gastric cancer. Buzzelli et al. provide fresh insights into the role that IL-33 plays in polarizing Th2 immune responses by demonstrating that chronic, but not acute, H. pylori infection suppresses IL-33, which ultimately leads to a predominant Th1 response. These findings may represent a novel mechanism (e.g., manipulation of IL-33) explaining why populations harboring concurrent helminth and H. pylori infection have a reduced risk of gastric cancer.
Jennifer M. Noto, Ph.D., and Richard M. Peek Jr., M.D., AGAF, of the department of medicine, division of gastroenterology, hepatology, and department of nutrition and cancer biology, Vanderbilt University, Nashville, Tenn. Dr. Noto and Dr. Peek declared that no conflict of interest exists. They acknowledge the following funding sources: NIH R01CA077955, R01DK058587, P01CA116087, and P30DK058404.
Gastric adenocarcinoma is the second-leading cause of cancer-related death worldwide, and chronic infection with Helicobacter pylori is the strongest known risk factor for the development of this malignancy. H. pylori colonization rates hover around 80%-90% in developing countries, but only a fraction of infected individuals ever develop disease. It is increasingly apparent that gastric carcinogenesis is multifactorial, influenced by host responses, H. pylori virulence, and environmental cofactors.
Parasitic helminth infections among H. pylori-infected individuals have been associated with a lower risk for the development of gastric cancer, and experimental data from animal models of Helicobacter infection have demonstrated that concurrent helminth infection attenuates the host immune response and reduces gastric atrophy. Infection with H. pylori typically induces a Th1-polarized immune response, while helminths drive Th2 responses.
Concurrent infections with helminths is endemic in regions of some developing countries that have a high prevalence of H. pylori infection, but a lower than expected rate of gastric cancer. Buzzelli et al. provide fresh insights into the role that IL-33 plays in polarizing Th2 immune responses by demonstrating that chronic, but not acute, H. pylori infection suppresses IL-33, which ultimately leads to a predominant Th1 response. These findings may represent a novel mechanism (e.g., manipulation of IL-33) explaining why populations harboring concurrent helminth and H. pylori infection have a reduced risk of gastric cancer.
Jennifer M. Noto, Ph.D., and Richard M. Peek Jr., M.D., AGAF, of the department of medicine, division of gastroenterology, hepatology, and department of nutrition and cancer biology, Vanderbilt University, Nashville, Tenn. Dr. Noto and Dr. Peek declared that no conflict of interest exists. They acknowledge the following funding sources: NIH R01CA077955, R01DK058587, P01CA116087, and P30DK058404.
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 [http://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.
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 [http://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.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: H. pylori may help regulate gastric immunity in some circumstances.
Major finding: Chronic gastric H. pylori infection lowered expression of IL-33, a cytokine that helps activate the CD4+ T helper cell 2 response.
Data source: Immunofluorescence, flow cytometry, and quantitative real-time polymerase chain reaction studies of tissue specimens from humans and mice.Disclosures: The study was funded by the Victorian Government’s Operational Infrastructure Support Program and NH&MRC Australia. The researchers reported no conflicts of interest.
