BACKGROUND AND 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. While PAR-2 has proinflammatory activity and PAR-1 can protect the gastric mucosa against chemical damage, neither have 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 two months, then colonization levels determined by colony-forming assay, gastritis by histology and serum antibody levels by ELISA. Responsiveness of primary epithelial cells to PAR-1 activation was assessed by calcium mobilization assay. Primary epithelial cells, macrophages and dendritic cells were co-cultured with H. pylori and NF-kappaB and cytokine secretion determined by ELISA. RESULTS: Two months post-infection, 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-kappaB and the proinflammatory cytokine, MIP-2. PAR-1 also downregulated MIP-2 secretion in response to cag pathogenicity island activity. DISCUSSION: 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.
Wee, J. LK., Chionh, Y-T., Ng, G. Z., Harbour, S. N., Allison, C. C., Pagel, C. N., Mackie, E. J., Mitchell, H. M., Ferrero, R. L., & Sutton, P. (2010). Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori. Gastroenterology, 138, 573 - 582. https://doi.org/10.1053/j.gastro.2009.08.043