Peroxisome proliferator-activated receptor γ activation counters the detrimental effect of Helicobacter pylori lipopolysaccharide on gastric mucin synthesis

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Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ), a member of the subfamily of ligand-dependent nuclear transcription factors, plays a key role in the regulation of the expression of genes associated with inflammation. In this study, using gastric mucosal cells in culture, we assess the role of PPARγ in the disturbances in gastric mucin synthesis and apoptotic processes evoked by Helicobacter pylori lipopolysaccharide (LPS). Exposure of gastric mucosal cells to the LPS led to a concentration-dependent decrease (up to 59.5%) in mucin synthesis, and this effect of the LPS was accompanied by a 6.5-fold increase in apoptosis, induction of COX-2 and NOS-2 protein expression, and the enhancement in PGE2 generation (18.6-fold) and NOS-2 activity (24.1-fold). However, the expression of COX-1 protein was not affected. Activation of PPARγ with a specific synthetic agonist, ciglitazone, countered (up to 90.2%) the LPS-induced reduction in mucin synthesis in a concentration-dependent manner, and this effect of the agent was reflected in a marked decrease in COX-2 and NOS-2 protein expression, reduction (up to 72.4%) in apoptosis and a decline (up to 84.1%) in PGE2 generation and NOS-2 activity (up to 90%). A pronounced prevention (88.2%) in the LPS-induced PGE2 release and the diminished COX-2 protein expression was also attained with the COX-2-selective inhibitor NS-398, but the effect was not associated with the impedance of the LPS inhibitory effect on mucin synthesis. Our findings thus demonstrate that the detrimental influence of H. pylori LPS on gastric mucin synthesis is closely linked to the increase in proapoptotic processes triggered by NOS-2 upregulation, and that PPARγ activation obviates this detrimental effect. Hence, pharmacological manipulation of PPARγ activation may provide therapeutic benefits in countering the disruptive effects of H. pylori on gastric mucosal mucus coat continuity.

Original languageEnglish (US)
Pages (from-to)223-236
Number of pages14
JournalInflammopharmacology
Volume11
Issue number3
DOIs
StatePublished - Sep 22 2003

All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology
  • Pharmacology (medical)

Keywords

  • Apoptosis
  • COX-1
  • COX-2
  • Gastric mucin synthesis
  • Helicobacter pyloril
  • Ipopolysaccharide
  • NOS-2
  • PPARγ activation

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