Post-transcriptional regulation of bradykinin b1 and b2 receptor gene expression in human lung fibroblasts by tumor necrosis factor-alpha: Modulationby dexamethasone

The cellular and molecular mechanisms governing bradykinin B1 and B2 recept or expression and function are poorly understood. We investigated the regul ation of both B1 and B2 receptors in human embryonic lung fibroblasts (HEL 299) by the proinflammatory cytokines tumor necrosis factor alpha (TNF-alph a) and interleukin 1 beta (IL-1 beta). TNF-alpha and IL-1 beta 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 protei n, as measured by radioligand binding assay with [H-3]des-Arg(10)-kallidin, and [H-3]bradykinin, respectively. The induced B1 receptors were functiona lly coupled, because the B1 agonist, des-Arg(10)-kallidin, induced an incre ase in arachidonic acid release in TNF-alpha-stimulated cells but not in co ntrol cells. The induction of B1 and the up-regulation of B2 receptors by T NF-alpha was partly mediated through activation of p38 mitogen-activated pr otein kinase and that of B2 receptor by protein kinase A. TNF-alpha and IL- 1 beta regulation of both B1 and B2 receptors was inhibited by dexamethason e. When compared with vehicle-treated cells, dexamethasone increased the ra te 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 thr ough post-transcriptional mechanisms.