Helicobacter pylori-induced adrenomedullin modulates IFN-gamma-producing T-cell responses and contributes to gastritis
Open Access
- 16 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (3), 1-15
- https://doi.org/10.1038/s41419-020-2391-6
Abstract
Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, but its relevance to Helicobacter pylori (H. pylori)-induced gastritis is unknown. Here, we found that gastric ADM expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of gastritis; accordingly, blockade of ADM resulted in decreased inflammation within the gastric mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterized by the increased IFN-gamma-producing T cells, whose differentiation was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to produce IL-12, which promoted the IFN-gamma-producing T-cell responses, thereby contributing to the development of H. pylori-associated gastritis. Accordingly, blockade of IFN-gamma or knockout of IFN-gamma decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and IFN-gamma, which collectively exert a pro-inflammatory effect within the gastric microenvironment.This publication has 54 references indexed in Scilit:
- Functional Plasticity in the Type IV Secretion System of Helicobacter pyloriPLoS Pathogens, 2013
- Downregulated Th17 responses are associated with reduced gastritis in Helicobacter pylori–infected childrenMucosal Immunology, 2013
- Adrenomedullin, a neuropeptide with immunoregulatory properties induces semi‐mature tolerogenic dendritic cellsImmunology, 2012
- Dendritic Cells Prevent Rather Than Promote Immunity Conferred by a Helicobacter Vaccine Using a Mycobacterial AdjuvantGastroenterology, 2011
- Helicobacter pylori's Unconventional Role in Health and DiseasePLoS Pathogens, 2009
- Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and InflammationCell Host & Microbe, 2009
- Sphingomyelin Functions as a Novel Receptor for Helicobacter pylori VacAPLoS Pathogens, 2008
- Adrenomedullin signaling is necessary for murine lymphatic vascular developmentJCI Insight, 2008
- The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrityJCI Insight, 2008
- Evaluation of DNA extraction methods from mouse stomachs for the quantification of H. pylori by real-time PCRJournal of Microbiological Methods, 2005