Transforming growth factor-beta(1) inhibits beta(2)-adrenoceptor gene transcription

Transforming growth factor-beta (1) (TGF-beta (1)) has been shown to modula te beta -adrenoceptor number and function in cultured human tracheal smooth muscle cells and cardiac fibroblasts, but the mechanisms is unclear. In th is study, we have characterized the beta (2)-adrenoceptor expression by rad ioligand binding assay, Northern blot analysis and measurement of intracell ular cAMP accumulation in a human embryonic lung fibroblast cell line (HEL2 99 cells). Treatment with TGF-beta (1) caused a time-dependent decrease in beta (2)-adrenoceptor mRNA, and in receptor number after 24 h. Furthermore, nuclear run-on assays showed a 35% reduction in the transcription rate of the beta (2)-adrenoceptor gene with no alteration in stability of the beta (2)-adrenoceptor mRNA. After TGF-beta (1) treatment, the basal, procaterol- and forskolin-stimulated cAMP accumulations were also decreased. Cyclohexi mide inhibited TGF-beta (1)-mediated reduction of beta (2)-adrenoceptor mRN A and protein, whilst alone caused induction of beta (2)-adrenoceptor mRNA without any effect on receptor number. In summary, TGF-beta (1) induces bet a (2)-adrenoceptor desensitization through the alteration in adenylyl cycla se activity and down-regulation of beta (2)-adrenoceptor mRNA and protein t hrough the reduction in the rate of beta (2)-adrenoceptor gene transcriptio n.