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Helicobacter pylori and toll-like receptor agonists induce syndecan-4 expression in an NF-kappaB-dependent manner.

ABSTRACT: The syndecans are a family of transmembrane heparan sulfate proteoglycans (HSPG) that have been implicated in a wide variety of biological functions including the regulation of growth factor signaling, adhesion, tumorigenesis, and inflammation. In the current studies, we examined the regulation of syndecan-4 gene expression in gastric epithelial cells and macrophages in response to infection with live Helicobacter pylori and purified toll-like receptor (TLR) agonists. H. pylori, PAM3CSK4 (a TLR2 agonist), and Escherichia coli flagellin (a TLR5 agonist) all induced the rapid expression of syndecan-4 mRNA in MKN45 gastric epithelial cells. Similarly, lipopolysaccharide (LPS) (a TLR4 agonist) also induced the expression of syndecan-4 in macrophages. The H. pylori- and TLR-induced increase in syndecan-4 mRNA was blocked by the proteosome inhibitor MG-132 suggesting a role for nuclear factor kappaB (NF-kappaB) in the regulation of syndecan-4 gene expression. An 895-bp fragment of the human syndecan-4 promoter was cloned upstream of the luciferase reporter. When transfected into MKN45 cells, the activity of this promoter was inducible by H. pylori and TLR agonists. Inducible activity of the syndecan-4 promoter was blocked by cotransfection with a dominant negative IkappaBalpha expression plasmid. Electrophoretic mobility shift assays (EMSA) demonstrated the presence of a highly conserved NF-kappaB-binding site. Mutation of this site within the context of the full-length syndecan-4 promoter resulted in a complete loss of responsiveness to H. pylori and TLR agonists. These results thus demonstrate that the response of the syndecan-4 gene to infectious agents, or their products, is a direct result of NF-kappaB binding to the promoter and induction of de novo transcription.

SUBMITTER: Smith MF

PROVIDER: S-EPMC1370916 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Helicobacter pylori and toll-like receptor agonists induce syndecan-4 expression in an NF-kappaB-dependent manner.

Smith Michael F MF Novotny Jennifer J Carl Virginia S VS Comeau Laurey D LD

Glycobiology 20051129 3

The syndecans are a family of transmembrane heparan sulfate proteoglycans (HSPG) that have been implicated in a wide variety of biological functions including the regulation of growth factor signaling, adhesion, tumorigenesis, and inflammation. In the current studies, we examined the regulation of syndecan-4 gene expression in gastric epithelial cells and macrophages in response to infection with live Helicobacter pylori and purified toll-like receptor (TLR) agonists. H. pylori, PAM3CSK4 (a TLR2 ...[more]

PMID: 16319082

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Project description:AimTo elucidate the sequential gene expression profile in AGS cells co-cultured with wild-type Helicobacter pylori (H pylori) as a model of H pylori-infected gastric epithelium, and to further examine the contribution of cag-pathogenicity islands (cagPAI)-coding type IV secretion system and the two pathways, nuclear factor kappa B (NF-kappaB) and extracellular signal-regulated kinases (ERK) on wild-type H pylori-induced gene expression.MethodsGene expression profiles induced by H pylori were evaluated in AGS gastric epithelial cells using cDNA microarray, which were present in the 4 600 independent clones picked up from the human gastric tissue. We also analyzed the contribution of NF-kappaB and ERK signaling on H pylori-induced gene expression by using inhibitors of specific signal pathways. The isogenic mutant with disrupted cagE (Delta cagE) was used to elucidate the role of cagPAI-encoding type IV secretion system in the gene expression profile.ResultsAccording to the expression profile, the genes were classified into four clusters. Among them, the clusters characterized by continuous upregulation were most conspicuous, and it contained many signal transducer activity-associated genes. The role of cagPAI on cultured cells was also investigated using isogenic mutant cagE, which carries non-functional cagPAI. Then the upregulation of more than 80% of the induced genes (476/566) was found to depend on cagPAI. Signal transducer pathway through NF-kappaB or ERK are the major pathways which are known to be activated by cagPAI-positive H pylori. The role of these pathways in the whole signal activation by cagPAI-positive H pylori was analyzed. The specific inhibitors against NF-kappaB or ERK pathway blocked the activation of gene expression in 65% (367/566) or 76% (429/566) of the genes whose activation appealed to depend on cagPAI.ConclusionThese results suggest that more than half of the genes induced by cagPAI-positive H pylori depend on NF-kappaB and ERK signaling activation, and these pathways may play a role in the gene expression induced by host-bacterial interaction which may associate with H pylori-related gastro-duodenal diseases.

Dataset Information

Helicobacter pylori and toll-like receptor agonists induce syndecan-4 expression in an NF-kappaB-dependent manner.

Publications

Helicobacter pylori and toll-like receptor agonists induce syndecan-4 expression in an NF-kappaB-dependent manner.

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