Dual regulation of beta2-adrenoceptor messenger RNA expression in human lung fibroblasts by beta2-cAMP signaling; delayed upregulated inhibitors oppose a rapid in onset, direct stimulation of gene expression.
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Kampfer N, Lamyel F, Schutz I, Warnken M, Hoffmann K, von Kugelgen I, Racke K
Dual regulation of beta2-adrenoceptor messenger RNA expression in human lung fibroblasts by beta2-cAMP signaling; delayed upregulated inhibitors oppose a rapid in onset, direct stimulation of gene expression.
Naunyn Schmiedebergs Arch Pharmacol. 2014 Jul;387(7):649-57. doi: 10.1007/s00210-014-0971-7. Epub 2014 Apr 8.
- PubMed ID
- 24705868 [ View in PubMed]
- Abstract
Based on their bronchodilatory effect, beta2-adrenoceptor agonists constitute essential elements in the treatment of bronchial asthma and COPD. As treatment with beta2-adrenoceptor agonists has been associated with worsening of airway hyper-reactivity, possibly because of loss of beta-adrenoceptor function, molecular mechanism of the regulation of beta2-adrenoceptor expression were studied. MRC-5 human lung fibroblasts were cultured in absence or presence of test substances followed by beta2-adrenoceptor messenger RNA (mRNA) determination by qPCR. After inhibition of mRNA synthesis by actinomycin D, beta2-adrenoceptor mRNA decreased with a half-life of 23 min, whereas inhibition of protein synthesis by cycloheximide caused an about 5- and 6-fold increase within 1.5 and 4 h, respectively. beta2-Adrenoceptor mRNA was increased by about 100 % after 1 h exposure to formoterol or olodaterol but decreased by about 60 % after 4 h agonist exposure. Both effects of beta2-adrenoceptor agonists were mimicked by forskolin, a direct activator of adenylyl cyclase and cholera toxin, which stimulates adenylyl cyclase by permanent activation of Gs. beta2-Adrenoceptor agonist-induced upregulation of beta2-adrenoceptor mRNA was blocked by the beta2-adrenoceptor antagonist ICI 118551 and prevented by actinomycin D, but not by cycloheximide. Moreover, in presence of cycloheximide, beta2-adrenoceptor agonist-induced reduction in beta2-adrenoceptor mRNA was converted into stimulation, resulting in a more than 10-fold increase. In conclusion, expression of beta2-adrenoceptors in human lung fibroblasts is highly regulated at transcriptional level. The beta2-adrenoceptor gene is under strong inhibitory control of short-living suppressor proteins. beta2-Adrenoceptor activation induces via adenylyl cyclase - cyclic adenosine monophosphate (cAMP) signaling a rapid in onset direct stimulation of the beta2-adrenoceptor gene transcription, an effect opposed by a delayed upregulation of inhibitory factors.