ROLES FOR INTERLEUKIN-1-BETA, PHORBOL ESTER AND A POSTTRANSCRIPTIONALREGULATOR IN THE CONTROL OF BRADYKININ B1 RECEPTOR GENE-EXPRESSION

Bradykinin B1 receptor (BKB1R) is involved in a variety of pathophysio logical processes, particularly those related to inflammation. The gen e for this receptor is known to be upregulated by interleukin (IL)-1 b eta, a proinflammatory cytokine. However, the molecular mechanisms inv olved in the regulation of the BKB1R gene expression have not been def ined. We demonstrated that IL-1 beta induces a rapid increase in BKB1R mRNA level and the binding of desArg(10)-kallidin in human embryo lun g fibroblasts (IMR90). This increase in BKB1R mRNA level is protein sy nthesis-independent as indicated by treatment of cells with cyclohexim ide (CHX) or puromycin (PUR). By testing the IL-1 beta effect on BKB1R mRNA degradation, we showed that the IL-1 beta upregulation of BKB1R expression is achieved through both transcriptional activation and pos t-transcriptional mRNA stabilization. In addition to the IL-1 beta eff ects, translation inhibitors, CHX and PUR increase the steady state BK B1R mRNA level by inhibiting BKB1R mRNA degradation. Removal of the CH X block with subsequent resumption of protein synthesis results in a s izable increase of desArg(10)-kallidin binding. Using signalling pathw ay inhibitors, we show that IL-1 beta functions through a protein tyro sine kinase, not protein kinase C or protein kinase A. However, activa tion of protein kinase C by phorbol 12-myristate 13-acetate increases the level of BKB1R mRNA and the binding of desArg(10)-kallidin. This i ncrease is blocked by NF-kappa B activation inhibitors.