Helicobacter pylori Activates the Histidine Decarboxylase Promoter through a Mitogen-activated Protein Kinase Pathway Independent of Pathogenicity Island-encoded Virulence Factors

Abstract

Helicobacter pylori infection of the gastric mucosa is accompanied by an activated histamine metabolism. Histamine plays a central role in the regulation of gastric acid secretion and is involved in the pathogenesis of gastroduodenal ulcerations. Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production, and its activity is regulated through transcriptional mechanisms. The present study investigated the effect of H. pylori infection on the transcriptional activity of the human HDC (hHDC) promoter in a gastric epithelial cell line (AGS) and analyzed the underlying molecular mechanisms. Our studies demonstrate that H. pylori infection potently transactivated the hHDC promoter. The H. pylori-responsive element of the hHDC gene was mapped to the sequence ؉1 to ؉27 base pairs, which shows no homology to known cis-acting elements and also functions as a gastrin-responsive element. H. pylori regulates the activity of this element via a Raf-1/ MEK/ERK pathway, which was activated in a Ras-independent manner. Furthermore, we found that H. pyloriinduced transactivation of the hHDC promoter was independent of the cag pathogenicity island and the vacuolating cytotoxin A gene and therefore may be exerted through (a) new virulence factor(s). A better understanding of H. pylori-directed hHDC transcription can provide novel insights into the molecular mechanisms of H. pylori-dependent gene regulation in gastric epithelial cells and may lead to new therapeutic approaches.

Helicobacter pylori Stimulates Gastric Epithelial Cell MMP-1 Secretion via CagA-dependent and -independent ERK Activation

“…Although H. pylori-stimulated gastric epithelial cell ERK activation has been reported, studies have differed regarding its CagA dependence (37)(38)(39)(40). Our data indicate both CagA-independent and -dependent processes.…”

“…In synovial fibroblasts, ERK activation mediates cytokine-and growth factor-stimulated MMP-1 secretion, enhancing tissue destruction in inflammatory arthritis (36). Although H. pylori stimulates ERK activation in gastric epithelial cells (37)(38)(39)(40)(41), the kinetics of ERK activation, as well as the role of CagA in this process, are not fully understood. H. pylori activation of gastric epithelial cell ERK may regulate both chemokine secretion and nuclear factor-B activation (42), contributing to proinflammatory responses.…”

Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility

“…Cells were seeded in tissue culture plates for 48 h before infection and serum-starved for 16 h. Phase-contrast microscopy was performed using an inverted microscope (model TS 100, INTAS). H. pylori strains P1, P12 and Hp26695 and their isogenic mutants DCagA and DPAI have been described elsewhere (Schmitt and Haas 1994;Corthesy-Theulaz et al, 1996;Tomb et al, 1997;Odenbreit et al, 2000;Wessler et al, 2000). Bacteria were cultured on agar plates containing 10% horse serum under microaerophilic conditions at 371C for 48 h. For infection, bacteria were harvested in phosphate-buffered saline (PBS), pH 7.4 and added to the host cells at a multiplicity of infection (MOI) of 100 for the indicated periods of time.…”

Oxidative Stress Regulates Vascular Endothelial Growth Factor-A Gene Transcription through Sp1- and Sp3-dependent Activation of Two Proximal GC-rich Promoter Elements

“…Expression constructs encoding wild type Sp1 or Sp3 or corresponding mutants lacking their transactivation domain (pPACSp1-DBD and pPACSp3-DBD) have also been described (42). Constructs encoding human ERK1, ERK2, MEK1, or Raf-1 have been used before (36,38). Expression constructs encoding dominant-negative mutants of ERK1 (DN ERK1(K71R)), ERK2 (DN ERK2(K52R)), MKK4 (DN MKK4), Raf-1 (DN Raf-1), and Ras (DN Ras15(G15A)) have previously been employed (36,38).…”