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

监测肽是大鼠胰腺分泌型胰蛋白酶抑制剂的一种亚型，可能通过与肠内产胰蛋白酶细胞管腔表面的假定受体结合来促进胆囊收缩素的释放。作者先前在分散有胶原酶的小肠粘膜细胞表面上发现了监测肽的特异性结合蛋白，并假设该蛋白质可能作为监测肽的受体发挥作用以介导胆囊收缩素的释放。作者最近证明，结合蛋白是颗粒酶A（GrA），一种细胞毒性T淋巴细胞中产生的蛋白酶。在这项研究中，作者首次发现GrA存在于分散在肠上皮层中的上皮内淋巴细胞上，而不存在于上皮衬里细胞，包括产生细胞。这些结果强烈地表明GrA不可能作为监测肽的受体来介导胆囊收缩素的释放。后来，作者发现监测肽具有胰蛋白酶样特异性地抑制GrA活性，并提出该肽控制该酶在体内催化的反应。据报道，GrA促进单核细胞和其他类型细胞中炎性细胞因子或趋化因子的释放。因此，肠上皮内淋巴细胞中产生的GrA也可能刺激细胞因子的产生。作者发现，在继续饮用实验诱导溃疡性结肠炎的葡聚糖硫酸钠（DSS）的大鼠的结肠粘膜中，GrA活性显著增加，并且伴随腹膜内注射监测肽减少了DSS诱导的严重炎症。这些结果表明，GrA在肠道中作为促炎介质发挥作用，并且监测肽控制由GrA介导的炎症。

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.