Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori.
OBJECTIVE
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)-kappaB, 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-kappaB 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.
Wee
Janet L K
JL
Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Australia.
Chionh
Yok-Teng
YT
Ng
Garrett Z
GZ
Harbour
Stacey N
SN
Allison
Cody
C
Pagel
Charles N
CN
Mackie
Eleanor J
EJ
Mitchell
Hazel M
HM
Ferrero
Richard L
RL
Sutton
Philip
P
D000818:Animals; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000378:metabolism* / Q000503:physiopathology; D016481:Helicobacter Infections / Q000378:metabolism* / Q000503:physiopathology; D016480:Helicobacter pylori / Q000276:immunology / Q000502:physiology*; D056724:Immunity, Humoral / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2