TY - JOUR T1 - Post-Transcriptional Regulation of Bradykinin B1 and B2 Receptor Gene Expression in Human Lung Fibroblasts by Tumor Necrosis Factor-α: Modulation by Dexamethasone JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1123 LP - 1131 VL - 57 IS - 6 AU - El-Bdaoui Haddad AU - Alison J. Fox AU - Jonathan Rousell AU - Gillian Burgess AU - Peter McIntyre AU - Peter J. Barnes AU - K. Fan Chung Y1 - 2000/06/01 UR - http://molpharm.aspetjournals.org/content/57/6/1123.abstract N2 - The cellular and molecular mechanisms governing bradykinin B1 and B2 receptor expression and function are poorly understood. We investigated the regulation of both B1 and B2 receptors in human embryonic lung fibroblasts (HEL 299) by the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). TNF-α and IL-1β both induced a rapid and transient increase in B1 and B2 receptor mRNA expression that was maximal by 2 h, accompanied by an increase in B1 and B2 receptor protein, as measured by radioligand binding assay with [3H]des-Arg10-kallidin, and [3H]bradykinin, respectively. The induced B1 receptors were functionally coupled, because the B1 agonist, des-Arg10-kallidin, induced an increase in arachidonic acid release in TNF-α-stimulated cells but not in control cells. The induction of B1 and the up-regulation of B2 receptors by TNF-α was partly mediated through activation of p38 mitogen-activated protein kinase and that of B2 receptor by protein kinase A. TNF-α and IL-1β regulation of both B1 and B2 receptors was inhibited by dexamethasone. When compared with vehicle-treated cells, dexamethasone increased the rate of decline of both B1 and B2 receptor mRNAs. Nuclear run-on experiments demonstrate that the induction of B1 and the up-regulation of B2 receptors as well as the inhibitory effect of dexamethasone are entirely mediated through post-transcriptional mechanisms. The American Society for Pharmacology and Experimental Therapeutics ER -