Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Abstract

Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ–mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori–induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ–activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain–containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori–induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238CagAm failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238CagAm differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori–induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori–induced IFN-γ resistance.

Synergistic effects of combined curcumin and antibiotic in ameliorating an animal model of Helicobacter pylori infection

“…ELISA assays were performed to investigate the mechanism of synergistic benefits of combined therapy. Similar to current result, it has been reported that the levels of IFN-γ as a potent inflammatory cytokine was increased by H. pylori infection [30]. Attained data showed that curcumin (by direct anti-inflammatory and anti-microbial effects) and erythromycin (by decreasing the agent's induced inflammation), could regress the levels of cytokine.…”

Macrophage polarization in pathology

“…In both human gastric epithelial and monocytic cells, H. pylori inhibits IFNc signaling through activation of Src homology-2 domain-containing phosphatase (SHP)2, in CagA-and ROS-dependent manners [127], thus favoring gastric cancer development [128][129][130].…”

Effects of curcumin on Helicobacter pylori infection

“…−, no activity; +, activity. To better explore the mechanisms of curcumin effects on this infection, IFN-γ, IL-4, and somatostatin represent good molecules for this purpose, as it is known that IFN-γ levels are elevated by H. pylori infection (28). IL-4 is an anti-inflammatory cytokine, unknown to be depressed by H. pylori (29) and somatostatin is a regulatory peptide needed for IL-4 mediated resolution of H. pylori-related gastritis (30).…”