Role of the mitogen-activated protein kinases in the expression of the kinin B1 receptors induced by tissue injury.

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.