Expression and Cytoprotective Effect of Protease-activated Receptor-1 in Gastric Epithelial Cells

Abstract

Thrombin is a serine protease involved in many physiological functions and its receptor. the protease-activated receptor-1 (PAR-1), has a wide tissue distribution. We hypothesized that PAR-1 is expressed in gastric epithelial cells and that thrombin can modulate defence mechanisms through PAR-1. The rat gastric epithelial cell line (RMG1) and gastric biopsy specimens from gastritis patients were used in the study. Reverse transcriptase polymerase chain reaction analysis showed that the thrombin receptors PAR-1, PAR3 and PAR-4 are expressed by RGM1 gastric epithelial cell line. Immunohistochemical and electron microspcopic studies also showed PAR-1 expression in human gastric epithelial cells. Thrombin stimulated the secretion of mucin and prostaglandin E2 (PGE2) formation in RGM1 cells in a dose-dependent manner. PAR-1 agonist also stimulated PGE2 formation. In addition, thrombin significantly increases the expression of the PGE2 receptors EP2-R and EP4-R in RGM1 cells. In conclusion, the results of the present study showed for the first time that gastric epithelial cells express thrombin receptors and that these receptors may play a protective role in the gastric mucosa.

Basic and Translational Research on Proteinase-Activated Receptors: Implication of Proteinase/Proteinase-Activated Receptor in Gastrointestinal Inflammation

“…Toyoda et al have reported that PAR 1 protects the gastric mucosa because the secretion of gastric mucin and PGE 2 is promoted by administration of a PAR 1 -activating peptide (31). In addition, Kawabata et al have reported that PAR 2 has a role in both aggressive and protective responses for the gastric mucosa (32,33).…”

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

“…Activation of PAR-1 appears to be cytoprotective in a gastric epithelial cell line (Toyoda et al 2003) and in a rat model (Kawabata et al 2004). In both studies, the protective effect was dependent upon cyclooxygenase activity.…”

“…The bulk of evidence points toward expression of PAR-1 and PAR-2, although PAR-3 and PAR-4 may also be present (Toyoda et al 2003, Mule et al 2004. In all regions of the gastrointestinal tract, PARs are expressed on epithelia and thus are in a position to respond to luminal or mucosal serine proteinases.…”

Proteinase-activated receptors in the gastrointestinal system: a functional linkage to prostanoids

“…Although we failed to visualize expression of immunoreactive PAR1 in the mucosal epithelial cells of rat and human gastric tissues (Kawabata et al, 2004c), functional PAR1 was detectable in the rat normal gastric mucosal epithelial RGM1 cell line (Sekiguchi et al, 2005;Toyoda et al, 2003) and in the human gastric carcinoma MKN-1 cell line (Miyata et al, 2000). Interestingly, PAR1 stimulation caused delayed (after cosal injury, might stimulate 'unknown cells' that are most probably muscularis mucosa cells expressing both PAR1 and COX-1, as described above, and subsequently cause formation of PGs, leading to suppression of acid secretion by parietal cells in the gastric mucosa ( Fig.…”

“…Interestingly, some of gastrointestinal functions of PAR1 or PAR2 are attributable to endogenous PGs, although activation of capsaicin-sensitive sensory neurons is also one of the important mechanisms for PAR2-triggered gastrointestinal events including gastric mucosal protection (Kawabata, 2002;Kawabata et al, 2001a;Sekiguchi et al, 2004). Of note is that stimulation of PAR1 or PAR2 actually causes formation of PGs in certain gastrointestinal tissues/ cells (Kong et al, 1997;Kubo et al;Sekiguchi et al, 2005;Toyoda et al, 2003). …”