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MUCOSAL BIOLOGY

The role of Sp1 in IL-1β and H. pylori-mediated regulation of H,K-ATPase gene transcription

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina

Submitted 15 May 2008 ; accepted in final form 30 August 2008

Helicobacter pylori infection of the gastric body induces transient hypochlorhydria and contributes to mucosal progression toward gastric carcinoma. Acid secretion is mediated by parietal cell H,K-ATPase, in which the catalytic -subunit (HK) promoter activity in transfected gastric epithelial [gastric adenocarcinoma (AGS)] cells is repressed by H. pylori through NF-B p50 homodimer binding to the promoter. IL-1β, an acid secretory inhibitor whose mucosal level is increased by H. pylori, upregulates HK promoter activity in AGS cells. Because IL-1β also activates NF-B signaling, we investigated disparate HK regulation by H. pylori and IL-1β, testing the hypothesis that IL-1β-induced HK promoter activation is mediated by the transcription factor Sp1. DNase I footprinting revealed Sp1 binding to the HK promoter at –56 to –39 bp. IL-1β stimulated the activity of three HK promoter constructs containing NF-B and Sp1 sites transfected into AGS cells and also stimulated a construct containing only an Sp1 site. This stimulation was abrogated by mutating the HK promoter Sp1 binding site. Gelshift assays showed that IL-1β increased Sp1 but not p50 binding to cognate HK probes and that Sp1 also interacts with an HK NF-B site when bound to its cognate HK cis-response element. H. pylori did not augment Sp1 binding to an HK Sp1 probe, and small interfering RNA-mediated knockdown of Sp1 expression abrogated IL-1β-induced HK promoter stimulation. We conclude that IL-1β upregulates HK gene transcription by inducing Sp1 binding to HK Sp1 and NF-B sites and that the H. pylori perturbation of HK gene expression is independent of Sp1-mediated basal HK transcription.

adenosine 5'-triphosphatase; Helicobacter pylori; interleukin-1β