Up-regulation in endothelin-1 by Helicobacter pylori lipopolysaccharide interferes with gastric mucin synthesis via epidermal growth factor receptor transactivation
Research Center, C875, UMDJN-NJ Dental School, 110 Bergen Street, P.O. Box 1709, Newark, NJ 07103-2400, USA. Scandinavian Journal of Gastroenterology
(Impact Factor: 2.36).
09/2005; 40(8):921-28. DOI: 10.1080/00365520510015890
Endothelin-1 (ET-1), a key mediator of inflammatory processes associated with bacterial infection, is a 21-amino acid peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1) that acts through G protein-coupled ET(A) and ET(B) receptors. Here we report on the role of ET-1 in the mediation of the detrimental influence of Helicobacter pylori on the synthesis of gastric mucin.
Rat gastric mucosal cells were exposed to H. pylori key virulence factor, lipopolysaccharide (LPS).
The LPS inhibitory effect on gastric mucin synthesis was accompanied by a marked increase in ET-1 generation and enhancement in ECE-1 activity. Inhibition of ECE-1 with phosphoramidon not only led to the impedance of LPS-induced ET-1 generation, but also countered the detrimental effect of LPS on mucin synthesis. Moreover, the LPS inhibitory effect on mucin synthesis was blocked by ET(A) receptor antagonist BQ610, but not by ET(B) receptor antagonist BQ788. Furthermore, the LPS-induced suppression in gastric mucin synthesis was countered in a concentration-dependent fashion by PD153035 (81.7%), a specific inhibitor of epidermal growth factor receptor (EGFR) kinase as well as PP2 (69.8%), a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR transactivation.
Our findings are the first to show that the detrimental effect of H. pylori on gastric mucin synthesis is intimately linked to the events associated with ECE-1 up-regulation, enhancement in ET-1 production, and G protein-coupled ET(A) receptor activation that triggers the EGFR transactivation.
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ABSTRACT: Release of arachidonic acid from membrane glycerophospholipids by cytosolic phospholipase A2 (cPLA2) is a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection. Here, we report on the role of cPLA2 in the disturbances in gastric mucin synthesis evoked by the LPS of H. pylori, a bacterium identified as a primary cause of gastric disease. Using rat gastric mucosal cells, we show that H. pylori LPS detrimental effect on gastric mucin synthesis, associated with up-regulation in PAF and endothelin-1 (ET-1) generation, was subject to suppression by a specific inhibitor of cPLA2, MAFP. Moreover, the LPS-induced changes in mucin synthesis and ET-1 generation were countered by PAF receptor antagonist, BN52020. The impedance by PAF antagonist of the LPS-induced reduction in mucin synthesis was countered by wortmannin, an inhibitor of PI3K, as well as by ERK inhibitor, PD98059. The blockade of ERK caused also inhibition of the LPS-induced cPLA2 activation and amplification in the impedance capacity of PAF antagonist on the LPS-induced ET-1 generation, while the inhibitor of PI3K had no effect. Our findings are the first to demonstrate that the detrimental consequences of H. pylori LPS on gastric mucin synthesis involve ERK-dependent cPLA2 activation that leads to up-regulation in PAF generation and ET-1 production.
International Union of Biochemistry and Molecular Biology Life 05/2006; 58(4):217-23. DOI:10.1080/15216540600732021 · 3.14 Impact Factor
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ABSTRACT: MUC6 was first discovered by screening a gastric mucosa cDNA library and is expressed in the mucous cells of the neck zone and antral glands of the stomach. The aim of the present study was to clarify whether down-regulation has any clinicopathological or prognostic significance in gastric neoplasia.
Expression of MUC6, MUC5AC and MUC2 was examined using tissue microarrays for immunohistochemistry in gastric carcinomas (n = 225), adenomas (n = 40), and normal mucosa (n = 89) and compared with clinicopathological parameters and survival data.
MUC6 expression was lower in gastric carcinomas than in adenomas or normal mucosa (P < 0.05) and inversely correlated with tumor size, depth of invasion, lymphatic and venous invasion, lymph node metastasis and UICC staging (P < 0.05). Positive links with expression of MUC2 and MUC5AC were noted (P < 0.05). MUC6 expression was lower in diffuse-type than intestinal-type lesions (P < 0.05). Kaplan-Meier analysis indicated that cumulative survival of patients with no MUC6 expression was significantly lower than with weak, moderate or strong expression in all and even advanced gastric carcinoma (P < 0.05). Multivariate analysis showed three independent prognostic factors, depth of invasion, lymphatic and venous invasion, to concordantly affect the relationship between MUC6 expression and prognosis.
Down-regulation of MUC6 may contribute to malignant transformation of gastric epithelial cells and underlie the molecular bases of growth, invasion, metastasis and differentiation of gastric carcinoma. Altered expression might therefore be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinoma.
Journal of Cancer Research and Clinical Oncology 01/2007; 132(12):817-23. DOI:10.1007/s00432-006-0135-3 · 3.08 Impact Factor
Available from: osaka-med.ac.jp
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ABSTRACT: Helicobacter pylori (H. pylori) causes pathological changes of gastric epithelial cells induced by pathogenic factors such as CagA and VacA, namely hummingbird cells (HBC) formation and vacuolization, respectively, in cultured cell lines. Cytopathic effects of other pathogenic factors produced by H. pylori have not been reported. In this study, we examined whether H. pylori induces unique morphological changes other than HBC formation and vacuolization, and we established a new marker of the bacterial infection in vitro. The cytotoxicity of H. pylori was examined in the AGS cell line, and a new morphological change, namely multinuclear giant cells (MNGC) formation, was observed in this cell line. The enhancement of MNGC formation was observed following H. pylori infection but was not associated with CagA, which causes HBC formation. We characterized the factor causing MNGC formation enhancement as heat-stable and water-soluble, and finally considered the factor to be H. pylori lipopolysaccharide (LPS). We considered that H. pylori LPS enhances MNGC formation in vitro. The cytopathic effect may provide an important marker that may clarify the mechanism of H. pylori pathogenesis in human gastric epithelial cells.
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