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Helicobacter pylori protein JHP0290 binds to multiple cell types and induces macrophage apoptosis via tumor necrosis factor (TNF)-dependent and independent pathways.

ABSTRACT: Activated macrophages at the sub-mucosal space play a major role in generating innate immune responses during H. pylori infection. Final disease outcome largely depends on how H. pylori and bacterium-derived products modulate macrophage responses. Here, we report that JHP0290, a functionally unknown protein from H. pylori, regulates macrophage functions. Recombinant purified JHP0290 (rJHP0290) had the ability to bind to several cell types including macrophages, human gastric epithelial cell lines, human monocyte-derived dendritic cells (MoDC) and human neutrophils. Exposure to rJHP0290 induced apoptosis in macrophages concurrent with release of proinflammatory cytokine tumor necrosis factor (TNF). A mutant strain of H. pylori disrupted in the jhp0290 gene was significantly impaired in its ability to induce apoptosis and TNF in macrophages confirming the role of endogenous protein in regulating macrophage responses. Intracellular signaling involving Src family of tyrosine kinases (SFKs) and ERK MAPK were required for rJHP0290-induced TNF release and apoptosis in macrophages. Furthermore, rJHP0290-induced TNF release was partly dependent on activation of nuclear transcription factor-?B (NF-?B). Neutralizing antibodies against TNF partially blocked rJHP0290-induced macrophage apoptosis indicating TNF-independent pathways were also involved. These results provide mechanistic insight into the potential role of the protein JHP0290 during H. pylori-associated disease development. By virtue of its ability to induce TNF, an acid suppressive proinflammatory cytokine and induction of macrophage apoptosis, JHP0290 possibly helps in persistent survival of the bacterium inside the stomach.

SUBMITTER: Pathak SK

PROVIDER: S-EPMC3815203 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Helicobacter pylori protein JHP0290 binds to multiple cell types and induces macrophage apoptosis via tumor necrosis factor (TNF)-dependent and independent pathways.

Pathak Sushil Kumar SK Tavares Raquel R de Klerk Nele N Spetz Anna-Lena AL Jonsson Ann-Beth AB

PloS one 20131101 11

Activated macrophages at the sub-mucosal space play a major role in generating innate immune responses during H. pylori infection. Final disease outcome largely depends on how H. pylori and bacterium-derived products modulate macrophage responses. Here, we report that JHP0290, a functionally unknown protein from H. pylori, regulates macrophage functions. Recombinant purified JHP0290 (rJHP0290) had the ability to bind to several cell types including macrophages, human gastric epithelial cell line ...[more]

PMID: 24223737

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Project description:BackgroundThe hepatocyte growth factor (HGF) receptor, c-Met, is strongly implicated in late-stage cancer progression and poor patient prognosis. The stomach pathogen, Helicobacter pylori ( H. pylori ), was recently proposed to stimulate c-Met phosphorylation dependent upon interaction of c-Met with the bacterial CagA protein required for H. pylori -induced cancer cell motility and invasion.Materials and methodsIn this report, we employed short hairpin RNA (shRNA), western blot analysis using antibodies recognizing phosphorylation at discrete c-Met residues, and immunofluorescence microscopy to investigate the CagA-c-Met interaction.ResultsThe data showed that shRNA-mediated c-Met knockdown did not reduce H. pylori -induced cell motility, suggesting that c-Met was not required for motility. Surprisingly, c-Met knockdown did not reduce the level of an H. pylori -induced protein recognized by a phospho-c-Met antibody. This 125 kD protein was 10 kD smaller than c-Met, suggesting that H. pylori did not phosphorylate c-Met but cross-reacted with another protein. This hypothesis was confirmed when c-Met phosphorylation inhibitors did not lower the levels of the bacteria-induced 125 kD protein, and c-Met immunoprecipitation (IP) did not detect this 125 kD protein from H. pylori -treated lysates. This protein was identified as a product of antibody cross reactivity with phosphorylated CagA. We also confirmed that CagA interacts with c-Met, but this interaction may have caused previous authors to misinterpret phosphorylated CagA as c-Met phosphorylation. Finally, pretreatment with the proteasomal inhibitor, lactacystin, caused prolonged HGF-induced c-Met phosphorylation and facilitated a CagA-negative H. pylori to stimulate AGS cell motility, suggesting that sustained c-Met phosphorylation compensates for the loss of CagA-dependent signaling.ConclusionsThese data demonstrate that H. pylori stimulates cancer cell motility independent of the c-Met receptor. We further hypothesize that although H. pylori does not target c-Met, the bacteria may still utilize c-Met effector signaling to stimulate CagA-independent cancer cell motility, which may provide a further mechanism of H. pylori -dependent gastric cancer progression.

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Helicobacter pylori protein JHP0290 binds to multiple cell types and induces macrophage apoptosis via tumor necrosis factor (TNF)-dependent and independent pathways.

Publications

Helicobacter pylori protein JHP0290 binds to multiple cell types and induces macrophage apoptosis via tumor necrosis factor (TNF)-dependent and independent pathways.

Similar Datasets

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