Studies on the role of granzyme A, a binding molecule for monitor peptide, in the CCK release mediated by the peptide

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Monitor peptide, a subtype of the pancreatic secretory trypsin inhibitors found in rats, promotes the release of cholecystokinin probably via the binding to putative receptor(s) on the luminal surface of the hormone-producing cells in the intestine. The authors previously found a specific binding protein for the monitor peptide on the surface of small-intestinal mucosal cells dispersed with collagenase, and hypothesized that this protein may function as the receptor for the monitor peptide to mediate the cholecystokinin release. The authors recently demonstrated that the binding protein is granzyme A (GrA), a protease produced in cytotoxic T lymphocytes. In this study, the authors first showed the existence of GrA on the intraepithelial lymphocytes scattered in the intestinal epithelial layers but not on the epithelial lining cells including the hormone-producing cells. These results strongly suggested that GrA is unlikely to serve as the receptor for the monitor peptide to mediate the cholecystokinin release. Later, the authors found the inhibition of GrA activity with trypsin-like specificity by monitor peptide, and suggested that this peptide controls the reaction catalyzed by this enzyme in the body. It has been reported that GrA promotes the release of inflammatory cytokines or chemokines in monocytes and the other types of cells. Therefore, it is possible that GrA produced in the intestinal intraepithelial lymphocytes also stimulates the production of cytokines. The authors found that GrA activity was significantly increased in the colonic mucosae of rats that continue to drink sodium dextran sulfate (DSS) that experimentally induces ulcerative colitis and that the severe inflammation induced by DSS was reduced by intraperitoneal injection of the monitor peptide concomitantly. These results suggested that GrA in the intestine functions as a pro-inflammatory mediator and that the monitor peptide controls the inflammation mediated by GrA.