<i>Helicobacter pylori</i> induces apoptosis in gastric epithelial cells through inducible nitric oxide

Watanabe, Sumio; Takagi, Atsushi; Koga, Yuichi; Kamiya, Shigeru

doi:10.1046/j.1440-1746.2000.02062.x

Cited by 38 publications

(25 citation statements)

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“…Although H. pylori infection can induce epithelial cell death at later time points (e.g., 72 h) (22), this was not the case at the time point when we documented inhibition of IL-4-induced Stat6 activation (e.g., 6 h in MKN45 cells), in agreement with an earlier viability study in MKN45 cells (41). Taken into account with H. pylori induction of epidermal growth factor (EGF) receptor phosphorylation after a 4-h infection of AGS gastric epithelial cells (6), and activation of NF-B to elicit continuously increasing IL-8 secretion from MKN45 cells over a 16-h time period (7), this indicates that not all epithelial signal transduction pathways are negatively regulated by infection.…”

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

confidence: 91%

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-4supporting

confidence: 91%

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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“…However, the most important effect of omeprazole lies in its novel antiapoptotic role during ulceration, as evidenced by prevention of DNA fragmentation in vivo. Apoptosis of mucosal cells occurs almost in all types of gastric ulcer (39 -51) where DNA damage and fragmentation occur by various aggressive factors (39,41,(45)(46)(47). Using histological section and terminal deoxynucleotidyltransferase biotin-dUTP nick end labeling (TUNEL) staining technique (39), gastric mucosal cell apoptosis was detected up to 4 h after stress, following which cell proliferation was found to be significantly increased to promote mucosal healing (39).…”

Section: Discussionmentioning

confidence: 99%

“…Induction of tumor necrosis factor-␣ and release of cytochrome c to activate caspase-3-like protease are involved in apoptotic cell death in indomethacin ulcer (41,42). Apoptosis also occurs because of nitric oxide production through induction of nitric-oxide synthase by H. pylori (45). Involvement of ROS and oxidative damage of DNA and DNA fragmentation have also been evident in apoptotic cell death in gastric mucosal injury (39,41,(45)(46)(47).…”

mentioning

confidence: 99%

“…Apoptosis also occurs because of nitric oxide production through induction of nitric-oxide synthase by H. pylori (45). Involvement of ROS and oxidative damage of DNA and DNA fragmentation have also been evident in apoptotic cell death in gastric mucosal injury (39,41,(45)(46)(47). Although omeprazole is believed to offer its antiulcer activity through acid suppression (1,2,5) by inactivating the H ϩ -K ϩ -ATPase (5,7,8,52), very little is known regarding its role in controlling oxidative damage and apoptotic cell death of the gastric mucosa during ulceration.…”

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confidence: 99%

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A Novel Antioxidant and Antiapoptotic Role of Omeprazole to Block Gastric Ulcer through Scavenging of Hydroxyl Radical

Biswas¹,

Bandyopadhyay²,

Chattopadhyay³

et al. 2003

Journal of Biological Chemistry

257

199

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The mechanism of the antiulcer effect of omeprazole was studied placing emphasis on its role to block oxidative damage and apoptosis during ulceration. Dose-response studies on gastroprotection in stress and indomethacin-induced ulcer and inhibition of pylorus ligation-induced acid secretion indicate that omeprazole significantly blocks gastric lesions at lower dose (2.5 mg/kg) without inhibiting acid secretion, suggesting an independent mechanism for its antiulcer effect. Time course studies on gastroprotection and acid reduction also indicate that omeprazole almost completely blocks lesions at 1 h when acid inhibition is partial. The severity of lesions correlates well with the increased level of endogenous hydroxyl radical ( ⅐ OH), which when scavenged by dimethyl sulfoxide causes around 90% reduction of the lesions, indicating that ⅐ OH plays a major role in gastric damage. Omeprazole blocks stress-induced increased generation of ⅐ OH and associated lipid peroxidation and protein oxidation, indicating that its antioxidant role plays a major part in preventing oxidative damage. Omeprazole also prevents stress-induced DNA fragmentation, suggesting its antiapoptotic role to block cell death during ulceration. The oxidative damage of DNA by ⅐ OH generated in vitro is also protected by omeprazole or its analogue, lansoprazole. Lansoprazole when incubated in a ⅐ OH-generating system scavenges ⅐ OH to produce four oxidation products of which the major one in mass spectroscopy shows a molecular ion peak at m/z 385, which is 16 mass units higher than that of lansoprazole (m/z 369). The product shows no additional aromatic proton signal for aromatic hydroxylation in 1 H NMR. The product absorbing at 278 nm shows no alkaline shift for phenols, thereby excluding the formation of hydroxylansoprazole. The product is assigned to lansoprazole sulfone formed by the addition of one oxygen atom at the sulfur center following attack by the ⅐ OH. Thus, omeprazole plays a significant role in gastroprotection by acting as a potent antioxidant and antiapoptotic molecule.

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“…The role of H pylori infection in the gastric carcinogenesis is not clear. It might be involved in imbalance between apoptosis and proliferation [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . Bcl-2 family members have been closely related to apoptosis, which could either promote cell survival (Bcl-2, Bcl-x L , A1, Mcl-1, and Bcl-w) or promote cell death (Bax, Bak, Bcl-x S , Bad, Bid, Bik, Bim, Hrk, Bok) [34][35][36] .…”

Section: Introductionmentioning

confidence: 99%

Effect ofHelicobacter pyloriinfection on expressions of Bcl-2 family members in gastric adenocarcinoma

Zhang

Fang²,

Wang³

et al. 2004

WJG

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Helicobacter pylori induces apoptosis in gastric epithelial cells through inducible nitric oxide

Abstract: These findings suggested that viable H. pylori induces apoptosis of gastric epithelial cells via nitric oxide. Our study indicated that iNOS expression plays an important role in gastric cell injury.

Cited by 38 publications

References 39 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

A Novel Antioxidant and Antiapoptotic Role of Omeprazole to Block Gastric Ulcer through Scavenging of Hydroxyl Radical

Effect ofHelicobacter pyloriinfection on expressions of Bcl-2 family members in gastric adenocarcinoma

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