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

我研究了蛋白酶激活受体（PAR）在人食管和胃上皮细胞上的表达，以及PAR介导的细胞因子产生的机制。PAR-1和PAR-2在未刺激培养的食管（HEEL）和胃（MKN-45）上皮细胞上组成性表达。另外，从人食管和胃粘膜活检材料中染色PAR-1和PAR-2。PAR-1激动剂（凝血酶）和PAR-2激动剂（胰蛋白酶和胰蛋白酶）诱导HEEC和MKN-45细胞产生IL-8具有时间和剂量依赖性。通过对PAR、MAPK抑制剂的抗体和转染NFkappaB或AP-1突变载体，IL-8的产生显著增加。这些数据表明，丝氨酸蛋白酶，如凝血酶、胰蛋白酶或胰蛋白酶，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、随后激活MAPK（p-38、JNK、ERK1/2）和转录因子（NFkappaB、AP-1）有关。这些结果表明，来自食管和胃十二指肠的胰蛋白酶和来自胃肠道粘膜肥大细胞的胰蛋白酶可能通过par激活的IL-8的产生与粘膜损伤有关。

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.