Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis☆, ☆☆

Fu, Shu; Ramanujam, Kalathur S.; Wong, Annie; Fantry, George T.; Drachenberg, Cinthia B.; James, Stephen P.; Meltzer, Stephen J.; Wilson, Keith T.

doi:10.1016/s0016-5085(99)70496-8

Cited by 382 publications

(330 citation statements)

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“…inflammatory bowel disease, Helicobacter pylori-associated chronic gastritis and Barrett's oesophagus (Cordon-Cardo and Prives, 1999;O'Byrne and Dalgleish, 2001). These pre-malignant conditions exhibit prominent stromal mononuclear cell COX-2 expression (Wilson et al, 1998;Fu et al, 1999) and carcinogenesis in these conditions is prevented to a similar extent by long-term use of NSAIDs (Farrow et al, 1998). Thus, paracrine COX-2-mediated stromal-epithelial cell signalling may be a generic mechanism linking chronic inflammation and the early stages of gastro-intestinal carcinogenesis and requires further investigation in other organ systems.…”

Section: Discussionmentioning

confidence: 99%

“…A similar pattern of COX-2 expression has also been noted in tumours from several murine intestinal tumorigenesis models (Oshima et al, 1996;Taketo, 1998;Hull et al, 1999;Shattuck-Brandt et al, 1999, although there appears to be increased heterogeneity in the COX-2-expressing stromal cell population in mice compared with humans (Taketo, 1998;Hull et al, 1999;Shattuck-Brandt et al, 1999. Stromal mononuclear cell (as well as epithelial cell) COX-2 expression has also been observed in other premalignant conditions of the human gastro-intestinal tract, including Barrett's oesophagus (Fu et al, 1999;Morris et al, 2001) and Helicobacter pylori-associated chronic gastritis (Wilson et al, 1998;Sung et al, 2000).…”

Section: Introductionmentioning

confidence: 97%

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Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Chapple

Hawcroft

et al. 2002

Oncogene

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In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cellcell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-b type II receptor expression and resistance to the antiproliferative activity of transforming growth factor-b 1 ) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1 -2 mM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce antineoplastic effects in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Chapple

Hawcroft

et al. 2002

Oncogene

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“…Eradication of H. pylori prevents the development of new cancers or continued growth of occult cancers in patients with early carcinoma (3), suggesting that H. pylori infection may play a role not only in the initiation, but also in the promotion of gastric carcinoma. Cyclooxygenase-2 (COX-2) 4 is the rate-limiting enzyme for the production of prostanoids (prostaglandins and thromboxanes) from arachidonic acid. Up-regulation of COX-2 plays a central role in the inflammatory changes and tissue damages associated with the chronic H. pylori infection, and is also involved in the gastric tumorigenesis (4,5).…”

Section: Helicobacter Pylori-induced Invasion and Angiogenesis Of Gasmentioning

confidence: 99%

“…Cyclooxygenase-2 (COX-2) 4 is the rate-limiting enzyme for the production of prostanoids (prostaglandins and thromboxanes) from arachidonic acid. Up-regulation of COX-2 plays a central role in the inflammatory changes and tissue damages associated with the chronic H. pylori infection, and is also involved in the gastric tumorigenesis (4,5). The expression of COX-2 protein is significantly higher in patients with gastric cancer than those with nonulcer dyspepsia (6).…”

Section: Helicobacter Pylori-induced Invasion and Angiogenesis Of Gasmentioning

confidence: 99%

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Chang¹,

Lin

et al. 2005

The Journal of Immunology

139

113

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Cyclooxygenase-2 (COX-2) plays a crucial role in Helicobacter pylori-associated gastric cancer. In this study, we report that H. pylori-induced COX-2 expression enhances the cancer cell invasion and angiogenesis via TLR2 and TLR9, which can be attenuated by the specific COX-2 inhibitor NS398 or celecoxib. The cAMP response element (CRE) and AP1 sites, but not κB on the COX-2 promoter, are involved in MAPKs-regulated COX-2 expression. Differential bindings of the CREB-1, ATF-2, c-jun to the CRE site, and the c-fos, c-jun, ATF-2 to the AP1 site are demonstrated by DNA affinity protein-binding, supershift, and chromatin immunoprecipitation assays. Activations of these transcription factors were attenuated by different MAPKs inhibitors. The mutants of TLR2, TLR9, or MAPKs inhibited H. pylori-induced COX-2 promoter, CRE, and AP-1 activities. MAPKs inhibitors attenuated the H. pylori-induced COX-2 mRNA and protein expressions. These results indicate that H. pylori acts through TLR2 and TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, ATF-2, c-jun, and c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis.

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“…Activation of NOS-2 has been identified as a culprit of transcriptional disturbances leading to apoptosis, and the sustained NO generation due to NOS induction appears to be a factor in colonic neoplasia, premalignant Barrett's esophagus, and H. pylori-associated gastric carcinogenesis (7,8). Furthermore, evidence obtained with several cell culture systems indicates that stimulation of NO production through NOS-2 induction or the exogenous NO donors leads to the inhibition of proteoglycan synthesis and the loss of extracellular matrix proteins (9).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide as a Modulator of Gastric Mucin Synthesis: Role of ERK and p38 Mitogen‐Activated Protein Kinase Activation

Slomiany

2002

IUBMB Life

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SummaryNitric oxide (NO) is an important biological messenger in the regulation of tissue homeostasis and pathophysiological processes. Here, we investigated the effect of NO on gastric mucus glycoprotein (mucin) synthesis, apoptotic processes, and the involvement of extracellular signal-regulated kinase (ERK) and p38 mitogenactivated protein kinase (MAPK). Exposure of gastric mucosal cells to NO donor led to a dose-dependent decrease (up to 48%) in mucin synthesis, accompanied by a marked increase in caspase-3 activity and apoptosis. Inhibition of ERK with PD98059 accelerated (up to 23.8%) the NO-induced decrease in mucin synthesis, and cause further enhancement in caspase-3 activity and apoptosis. Blockade of p38 kinase with SB203580 produced reversal in the NO-induced reduction in mucin synthesis, and substantially countered the induced increase in caspase-3 activity and apoptosis. Moreover, caspase-3 inhibitor not only blocked the NO-induced increase in caspase-3 activity but also produced an increase in mucin synthesis. Thus, the detrimental influence of NO on mucin synthesis is closely linked to caspase-3 activation and apoptosis, and involves ERK and p38 kinase participation. Activation of p38 kinase leads to the upregulation of proapoptotic signal, while ERK activation stimulates the anti-apoptotic pathway. IUBMB Life, 54: 267-273, 2002

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Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis☆, ☆☆

Cited by 382 publications

References 57 publications

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Nitric Oxide as a Modulator of Gastric Mucin Synthesis: Role of ERK and p38 Mitogen‐Activated Protein Kinase Activation

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