Role of Interferon-Stimulated Responsive Element-like Element in Interleukin-8 Promoter in Helicobacter pylori Infection

Yoshio Yamaoka, Takahiko Kudo, Hong Lu, Antonella Casola, Allan R. Brasier, David Y. Graham

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Background & Aims: Gastric mucosal interleukin (IL)-8 levels are related to the presence of both the cag pathogenicity island (PAI) and OipA. We investigated the regions of the IL-8 promoter and the upstream signaling involved in IL-8 gene transcription. Methods: We cocultured parental Helicobacter pylori and isogenic oipA, hopZ, or cagE gene knockout mutants with gastric cancer cells. The regulatory sites in the IL-8 promoter were examined by luciferase reporter gene assay, electrophoretic mobility shift assays, and immunoblot analyses. Phosphorylated signal transducers and activators of transcription 1 (STAT1) levels in the antral gastric mucosa were measured by enzyme-linked immunosorbent assay. Results: Maximal H. pylori-induced IL-8 gene transcription required the presence of the interferon-stimulated responsive element (ISRE)-like element, nuclear factor (NF)-κB and activator protein (AP)-1 binding sites. In vitro studies showed that OipA and the cag PAI were involved in inducing interferon regulatory factor (IRF)-1 to bind and activate the ISRE-like element and that the cag PAI, but not OipA, was involved in activating AP-1 and NF-κB. Both in vitro and in vivo studies showed that OipA, but not the cag PAI, was involved in STAT1 phosphorylation, as upstream signaling of IRF-1. Conclusions: OipA and the cag PAI are both necessary for full activation of the IL-8 promoter but act via different pathways that diverge upstream of IRF-1 where only OipA is involved in the STAT1-IRF1-ISRE pathway. The mucosal inflammatory response to H. pylori infection is complex and involves different pathways converging on the IL-8 promoter.

Original languageEnglish (US)
Pages (from-to)1030-1043
Number of pages14
JournalGastroenterology
Volume126
Issue number4
DOIs
StatePublished - Apr 2004

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Helicobacter Infections
Interleukin-8
Helicobacter pylori
Genomic Islands
Interferons
Interferon Regulatory Factor-1
STAT1 Transcription Factor
Transcription Factor AP-1
Gene Knockout Techniques
Electrophoretic Mobility Shift Assay
Gastric Mucosa
Luciferases
Reporter Genes
Protein Binding
Genes
Stomach Neoplasms
Stomach
Enzyme-Linked Immunosorbent Assay
Binding Sites
Phosphorylation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Role of Interferon-Stimulated Responsive Element-like Element in Interleukin-8 Promoter in Helicobacter pylori Infection. / Yamaoka, Yoshio; Kudo, Takahiko; Lu, Hong; Casola, Antonella; Brasier, Allan R.; Graham, David Y.

In: Gastroenterology, Vol. 126, No. 4, 04.2004, p. 1030-1043.

Research output: Contribution to journalArticle

Yamaoka, Yoshio ; Kudo, Takahiko ; Lu, Hong ; Casola, Antonella ; Brasier, Allan R. ; Graham, David Y. / Role of Interferon-Stimulated Responsive Element-like Element in Interleukin-8 Promoter in Helicobacter pylori Infection. In: Gastroenterology. 2004 ; Vol. 126, No. 4. pp. 1030-1043.
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AB - Background & Aims: Gastric mucosal interleukin (IL)-8 levels are related to the presence of both the cag pathogenicity island (PAI) and OipA. We investigated the regions of the IL-8 promoter and the upstream signaling involved in IL-8 gene transcription. Methods: We cocultured parental Helicobacter pylori and isogenic oipA, hopZ, or cagE gene knockout mutants with gastric cancer cells. The regulatory sites in the IL-8 promoter were examined by luciferase reporter gene assay, electrophoretic mobility shift assays, and immunoblot analyses. Phosphorylated signal transducers and activators of transcription 1 (STAT1) levels in the antral gastric mucosa were measured by enzyme-linked immunosorbent assay. Results: Maximal H. pylori-induced IL-8 gene transcription required the presence of the interferon-stimulated responsive element (ISRE)-like element, nuclear factor (NF)-κB and activator protein (AP)-1 binding sites. In vitro studies showed that OipA and the cag PAI were involved in inducing interferon regulatory factor (IRF)-1 to bind and activate the ISRE-like element and that the cag PAI, but not OipA, was involved in activating AP-1 and NF-κB. Both in vitro and in vivo studies showed that OipA, but not the cag PAI, was involved in STAT1 phosphorylation, as upstream signaling of IRF-1. Conclusions: OipA and the cag PAI are both necessary for full activation of the IL-8 promoter but act via different pathways that diverge upstream of IRF-1 where only OipA is involved in the STAT1-IRF1-ISRE pathway. The mucosal inflammatory response to H. pylori infection is complex and involves different pathways converging on the IL-8 promoter.

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