Protease-Activated Receptor-1 Down-regulates the Murine Inflammatory and Humoral Response to Helicobacter pylori

Background & Aims Helicobacter pylori infection results in a diversity of pathologies, from asymptomatic gastritis to adenocarcinoma. The reason for these diverse outcomes is multifactorial and includes host factors that regulate severity of Helicobacter -induced gastritis. Protease-activated receptors (PAR) are environmental sensors that can detect tissue damage and pathogens. Whereas PAR-2 has proinflammatory activity and PAR-1 can protect the gastric mucosa against chemical damage, neither has previously been examined for their potential roles in regulating Helicobacter pathogenesis. Methods PAR-1−/− , PAR-2−/− , and wild-type mice were infected with H pylori for up to 2 months then colonization levels determined by colony-forming assay, gastritis by histology, and serum antibody levels by enzyme-linked immunosorbent assay. Responsiveness of primary epithelial cells to PAR-1 activation was assessed by calcium mobilization assay. Primary epithelial cells, macrophages, and dendritic cells were cocultured with H pylori and nuclear factor (NF)-κB, and cytokine secretion was determined by enzyme-linked immunosorbent assay. Results Two months postinfection, H pylori levels were significantly reduced in PAR-1−/− and increased in PAR-2−/− mice. This effect on colonization was inversely correlated with inflammation severity. Infection of PAR-1−/− mice induced an increased serum antibody response. Primary epithelial cells were activated by a PAR-1-activating peptide. H pylori stimulation of primary epithelial cells, but not macrophages or dendritic cells, from PAR-1−/− mice induced increased levels of NF-κB and the proinflammatory cytokine macrophage-inflammatory protein (MIP)-2. PAR-1 also down-regulated MIP-2 secretion in response to cag pathogenicity island activity. Conclusions PAR-1 protects the host against severe Helicobacter -induced gastritis. This may be mediated by suppressing the production of proinflammatory cytokines such as MIP-2.