Role of protease-activated receptor in mucosal injury of upper alimentary tract

我研究了人食管和胃上皮细胞上蛋白酶激活受体（PAR）的表达，以及这些培养细胞中PAR介导的细胞因子产生的机制。1.PAR-1和PAR-2在未刺激的培养食管（HEEL）和胃（MKN-45）上皮细胞上组成型表达。此外，从人体活检材料中获得的食管和胃粘膜中的 PAR-1 和 PAR-2 被染色。2.PAR-1 激动剂（凝血酶）和 PAR-2 激动剂（胰蛋白酶和类胰蛋白酶）导致 HEEC 和 MKN-45 细胞诱导产生 IL-8，且呈时间和剂量依赖性。3.IL-8 的产生通过 PAR 抗体、MAPK 抑制剂和转染显着增加。 NFkappaB或AP-1突变载体。这些数据表明丝氨酸蛋白酶，如凝血酶、胰蛋白酶或类胰蛋白酶，促进培养的食管和胃上皮细胞产生IL-8，其机制与蛋白酶激活受体、G蛋白偶联受体的激活有关，随后激活MAPK(p-38、JNK、ERK1/2)和转录因子(NFkappaB、AP-1)。这些结果表明，来自十二指肠的食道和胃中的胰蛋白酶和来自胃肠粘膜肥大细胞的类胰蛋白酶可能与 PAR 激活的 IL-8 产生引起的粘膜损伤有关。

I investigated expression of protease-activated receptor(PAR) on both human esophageal and gastric epithelial cells, and mechanisms of PAR-mediated cytokine production from these cultured cells.1.PAR-1 and PAR-2 were constitutively expressed on unstimulated cultured esophageal (HEEL) and gastric (MKN-45) epithelial cells. In addition, PAR-1 and PAR-2 were stained in the esophageal and gastric mucosa obtained from human biopsy materials.2.PAR-1 agonist (thrombin) and PAR-2 agonist (trypsin and tryptase) resulted in induction of IL-8 production from HEEC and MKN-45 cells time- and dose- dependently.3.Increased IL-8 production was significantly by antibody to PAR, MAPK inhibitor and transfection of NFkappaB or AP-1 mutant vector.These data indicate that serine proteases, such as thrombin, trypsin or tryptase, promote IL-8 production from cultured esophageal and gastric epithelial cells, which mechanisms are associated with activation of protease-activated receptor, G-protein coupled receptor, followed by the activation of MAPK(p-38, JNK, ERK1/2) and transcription factor (NFkappaB, AP-1). These results suggest that trypsin which comes in esophagus and stomach from duodenum and tryptase derived from mast cells in the gastrointestinal mucosa may be related to mucosal injury via PAR-activated IL-8 production.