Helicobacter pylori upregulates expression of epidermal growth factor-related peptides, but inhibits their proliferative effect in MKN 28 gastric mucosal cells.

Romano, Marco; Ricci, Vittorio; Popolo, Anna Di; Sommi, Patrizia; Blanco, C. Del Vecchio; Bruni, Carmelo B.; Ventura, U.; Cover, Timothy L.; Blaser, Martin J.; Coffey, Robert J.; Zarrilli, Raffaele

doi:10.1172/jci1174

Cited by 80 publications

(66 citation statements)

References 49 publications

(35 reference statements)

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“…Furthermore, Mycobacterium avium infection of macrophages down-regulates IFN-␥ receptor 1 and 2 protein expression (42), and Porphyromonas gingivalis outer membrane vesicles decrease the expression and activity levels of Jak1 and Jak2 in endothelial cells (43). In contrast, in this study we found that H. pylori infection did not decrease the protein expression levels of IL-4R␣ or Jak1, similar to its suppression of EGFrelated peptide signaling in MKN28 gastric mucosal cells without affecting EGF receptor expression (44). Because suppression of IL-4-induced Stat6 activation was time-dependent, it may suggest that induction of epithelial cell signal transduction and gene transcription are important here.…”

Section: H Pylori Infection Does Not Alter Expression Of Either Il-4contrasting

confidence: 50%

Helicobacter pyloriInfection Interferes with Epithelial Stat6-Mediated Interleukin-4 Signal Transduction Independent ofcagA,cagE, or VacA

Ceponis

McKay

Menaker

et al. 2003

The Journal of Immunology

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Helicobacter pylori is a bacterial pathogen evolved to chronically colonize the gastric epithelium, evade immune clearance by the host, and cause gastritis, peptic ulcers, and even gastric malignancies in some infected humans. In view of the known ability of this bacterium to manipulate gastric epithelial cell signal transduction cascades, we determined the effects of H. pylori infection on epithelial IL-4-Stat6 signal transduction. HEp-2 and MKN45 epithelial cells were infected with H. pylori strains LC11 or 8823 (type 1; cagA+/cagE+/VacA+), LC20 (type 2; cagA−, cagE−, VacA−), and cagA, cagE, and vacA isogenic mutants of strain 8823, with some cells receiving subsequent treatment with the Th2 cytokine IL-4, a known Stat6 activator. Immunofluorescence showed a disruption of Stat6-induced nuclear translocation by IL-4 in LC11-infected HEp-2 cells. IL-4-inducible Stat6 DNA binding in HEp-2 and MKN45 cells was abrogated by infection, but MKN45 cell viability was unaffected. A decrease in IL-4-mediated Stat6 tyrosine phosphorylation in nuclear and whole cell lysates was also observed following infection with strains LC11 and LC20, while neither strain altered IL-4 receptor chain α or Janus kinase 1 protein expression. Furthermore, parental strain 8823 and its isogenic cagA, cagE, and vacA mutants also suppressed IL-4-induced Stat6 tyrosine phosphorylation to comparable degrees. Thus, H. pylori did not directly activate Stat6, but blocked the IL-4-induced activation of epithelial Stat6. This may represent an evolutionarily conserved strategy to disrupt a Th2 response and evade the host immune system, allowing for successful chronic infection.

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Section: H Pylori Infection Does Not Alter Expression Of Either Il-4contrasting

confidence: 50%

Helicobacter pyloriInfection Interferes with Epithelial Stat6-Mediated Interleukin-4 Signal Transduction Independent ofcagA,cagE, or VacA

Ceponis

McKay

Menaker

et al. 2003

The Journal of Immunology

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“…Pai et al (1998) showed that H. pylori culture supernatants from VacA strains, but not VacA À strains, inhibited EGFmediated EGFr upregulation and phosphorylation, suggesting that the growth-inhibitory effect is at the level of receptor activation (Pai et al, 1998). On the other hand, Romano et al (1998b) showed that H. pylori broth culture ®ltrates did not affect EGFr phosphorylation by EGFrelated growth factors, while they inhibited EGF-related peptide-dependent increase in cell proliferation, thus suggesting a downstream block to the activation of the receptor. This effect did not seem to be mediated by several known virulence factors, but was dependent on the release of a low (< 12 kDa) molecular mass component (Romano et al, 1998b).…”

Section: Host Response To H Pylori-induced Cell Damagementioning

confidence: 95%

“…On the other hand, Romano et al (1998b) showed that H. pylori broth culture ®ltrates did not affect EGFr phosphorylation by EGFrelated growth factors, while they inhibited EGF-related peptide-dependent increase in cell proliferation, thus suggesting a downstream block to the activation of the receptor. This effect did not seem to be mediated by several known virulence factors, but was dependent on the release of a low (< 12 kDa) molecular mass component (Romano et al, 1998b). A possible explanation for the apparent discrepancy between in vivo and in vitro studies evaluating the effect of H. pylori on gastric cell proliferation might be that in vivo studies are representative of the effect of persistent H. pylori infection, whereas in vitro experimental studies are representative of an acute H. pylori-mediated effect.…”

Section: Host Response To H Pylori-induced Cell Damagementioning

confidence: 95%

“…pylori-dependent inhibition of cell proliferation has been elucidated further by two different reports, showing that H. pylori interferes with the signal transduction pathway activated by the EGFr (Romano et al, 1998b;Pai et al, 1998). Pai et al (1998) showed that H. pylori culture supernatants from VacA strains, but not VacA À strains, inhibited EGFmediated EGFr upregulation and phosphorylation, suggesting that the growth-inhibitory effect is at the level of receptor activation (Pai et al, 1998).…”

Section: Host Response To H Pylori-induced Cell Damagementioning

confidence: 98%

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Molecular response of gastric epithelial cells to Helicobacter pylori-induced cell damage

Zarrilli

Ricci²,

Romano³

1999

Cell Microbiol

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Infection with the Gram‐negative bacterium Helicobacter pylori leads to different clinical and pathological outcomes in humans, including chronic gastritis, peptic ulcer disease and adenocarcinoma of the stomach. H. pylori‐induced damage to gastric mucosal cells is controlled by bacterial virulence factors encoded by genes of the cag pathogenicity island, which trigger the inflammatory response of the host through the activation of nuclear factor κB‐dependent gene transcription. Also, H. pylori infection impairs the processes of gastric mucosal healing through inhibition of epidermal growth factor receptor‐dependent signal transduction pathways and induction of apoptosis. H. pylori infection may influence the progression from chronic gastritis to gastric adenocarcinoma by stimulating cell proliferation and growth factor expression, inhibiting apoptosis and increasing the DNA mutation rate of infected gastric mucosa.

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“…While abl and src non-receptor tyrosine kinases are expressed in all gastric cell lines and cancer tissues examined, the src protein levels do not re¯ect activation status (kinase activity) (O'Neill et al, 1997;Takaishi et al, 2000). It is worth noting that H. pylori, an infectious pathogen, can up-regulate tyrosine kinase signal transduction pathways including src, EGFR, erbB2, MAPK and MKK4, following infection (Elitsur et al, 1999;Haruma et al, 2000;Meyer-Ter-Vehn et al, 2000;Naumann et al, 1999;Romano et al, 1998). Recently, H. pylori infection has been linked to peptic ulcer disease and gastric adenocarcinoma formation (EUROGAST Study Group, 1993;Segal et al, 1997;Kuniyasu et al, 2000).…”

Section: Other Protein Tyrosine Kinases In Gastric Cancermentioning

confidence: 99%

Tyrosine kinases and gastric cancer

et al. 2000

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Carcinoma of the stomach is one of the most prevalent cancer types in the world today. Two major forms of gastric cancer are distinguished according to their morphological and clinicopathological classi®cations (well dierentiated/intestinal type and poorly dierentiated/diuse type), characteristics that could also be attributed to the altered expression of dierent types of oncogenes or tumor suppressor genes. Signi®cant dierences exist for gastric cancer incidence comparing people of dierent ethnic origins, implicating various genetic and epigenetic factors for gastric oncogenesis. There are only a limited number of molecular markers available for gastric cancer detection and prognostic evaluation, among which are tyrosine kinases. There is convincing evidence that tyrosine kinases are involved in oncogenesis and disease progression for many human cancers. Ampli®cations of certain tyrosine kinases (cmet, k-sam and erbB2/neu) have been associated with human gastric cancer progression. Alternatively spliced transcripts and enhanced protein-expression levels for some of these tyrosine kinases are correlated with clinical outcomes for gastric cancer patients. With advent of high throughput techniques, it is now possible to detect nearly all expressed tyrosine kinases in a single screen. This increases the chance to identify additional tyrosine kinases as predictive markers for gastric cancers. In this article, we will ®rst review the literature data concerning certain tyrosine kinases implicated in gastric carcinogenesis and then summarize more recent work which provide comprehensive tyrosine kinase pro®les for gastric cancer specimens and cell lines. Two new gastric cancer molecular markers (tie-1 and mkk4) have been identi®ed through the use of these pro®les and demonstrated eective as clinical prognostic indicators. Oncogene (2000) 19, 5680 ± 5689.

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Helicobacter pylori upregulates expression of epidermal growth factor-related peptides, but inhibits their proliferative effect in MKN 28 gastric mucosal cells.

Cited by 80 publications

References 49 publications

Helicobacter pyloriInfection Interferes with Epithelial Stat6-Mediated Interleukin-4 Signal Transduction Independent ofcagA,cagE, or VacA

Helicobacter pyloriInfection Interferes with Epithelial Stat6-Mediated Interleukin-4 Signal Transduction Independent ofcagA,cagE, or VacA

Molecular response of gastric epithelial cells to Helicobacter pylori-induced cell damage

Tyrosine kinases and gastric cancer

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