Larrivée J F, Bachvarov D R, Houle F, Landry J, Huot J, Marceau F
Centre Hospitalier Universitaire de Québec, Centre de Recherche du Pavillon l'Hôtel-Dieu de Québec, Canada.
J Immunol. 1998 Feb 1;160(3):1419-26.
Several cytokines and LPS regulate the population of the B1 receptors (B1Rs) for kinins; these are responsive to des-Arg9-bradykinin (BK) and Lys-des-Arg9-BK. B1R activation contributes to inflammatory vascular changes and pain. Aortic rings isolated from normal rabbits and incubated in vitro in Krebs physiological medium were used as a model of tissue injury. From a null level of response, these rings exhibit a time- and protein synthesis-dependent increase in the maximal contractile response to des-Arg9-BK. Exposure to exogenous IL-1beta or epidermal growth factor (EGF) considerably increases the process of sensitization to the kinins. Freshly isolated control aortic rings showed high mitogen-activated protein (MAP) kinase activities (persistent activation of p38, but less prolonged for extracellular signal-regulated kinase and c-Jun-N-terminal kinase/stress-activated protein kinase pathways) relatively to the basal activities found in various types of cultured cells. IL-1beta or EGF further increased the activities of the extracellular signal-regulated kinase and c-Jun-N-terminal kinase/stress-activated protein kinase MAP kinases. The inhibitor of the p38 MAP kinase, SB 203580 (10 microM), massively (approximately 75%) and selectively inhibited the spontaneous sensitization to des-Arg9-BK over 6 h. SB 203580 also significantly reduced the development of the response to des-Arg9-BK as stimulated by IL-1 or EGF. Both spontaneous and IL-1beta-stimulated up-regulation of responsiveness to des-Arg9-BK were significantly inhibited by the MAP kinase extracellular signal-regulated kinase kinase 1 inhibitor PD 98059 (approximately 40%). The protein kinase inhibitors failed to inhibit protein synthesis and to acutely inhibit the contractile effect of des-Arg9-BK, suggesting that they do not influence B1 receptor transduction mechanisms. In cultured aortic smooth muscle cells stimulated with EGF, MAP kinase activation preceded B1R mRNA induction. Protein kinase inhibitors reveal the role of cell injury-controlled MAP kinase pathways, and singularly of the p38 pathway, in the induction of B1R.
几种细胞因子和脂多糖可调节激肽的B1受体（B1Rs）数量；这些受体对去-Arg9-缓激肽（BK）和Lys-去-Arg9-BK有反应。B1R激活会导致炎症性血管变化和疼痛。从正常兔分离并在Krebs生理培养基中体外孵育的主动脉环被用作组织损伤模型。从无反应水平开始，这些主动脉环对去-Arg9-BK的最大收缩反应呈现出时间和蛋白质合成依赖性增加。暴露于外源性白细胞介素-1β（IL-1β）或表皮生长因子（EGF）会显著增强对激肽的致敏过程。相对于各种类型培养细胞中发现的基础活性，新鲜分离的对照主动脉环显示出高丝裂原活化蛋白（MAP）激酶活性（p38持续活化，但细胞外信号调节激酶和c-Jun-N端激酶/应激激活蛋白激酶途径的活化时间较短）。IL-1β或EGF进一步增加了细胞外信号调节激酶和c-Jun-N端激酶/应激激活蛋白激酶MAP激酶的活性。p38 MAP激酶抑制剂SB 203580（10 microM）在6小时内大量（约75%）且选择性地抑制了对去-Arg9-BK的自发致敏。SB 203580还显著降低了IL-1或EGF刺激的对去-Arg9-BK反应的发展。MAP激酶细胞外信号调节激酶激酶1抑制剂PD 98059（约40%）显著抑制了对去-Arg9-BK反应性的自发上调和IL-1β刺激的上调。蛋白激酶抑制剂未能抑制蛋白质合成，也未能急性抑制去-Arg9-BK的收缩作用，这表明它们不影响B1受体转导机制。在用EGF刺激的培养主动脉平滑肌细胞中，MAP激酶激活先于B1R mRNA诱导。蛋白激酶抑制剂揭示了细胞损伤控制的MAP激酶途径，特别是p38途径，在B1R诱导中的作用。
