TY - JOUR T1 - α<sub>1</sub>-Adrenergic Receptor Stimulates Interleukin-6 Expression and Secretion through Both mRNA Stability and Transcriptional Regulation: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB JF - Molecular Pharmacology JO - Mol Pharmacol SP - 144 LP - 152 DO - 10.1124/mol.108.054320 VL - 76 IS - 1 AU - Dianne M. Perez AU - Robert S. Papay AU - Ting Shi Y1 - 2009/07/01 UR - http://molpharm.aspetjournals.org/content/76/1/144.abstract N2 - Our previous studies have demonstrated that activation of α1-adrenergic receptors (ARs) increased interleukin-6 (IL-6) mRNA expression and protein secretion, which is probably an important yet unknown mechanism contributing to the regulation of cardiac function. Using Rat-1 fibroblasts stably transfected with the α1A-AR subtype and primary mouse neonatal cardiomyocytes, we elucidated the basic molecular mechanisms responsible for the α1-AR modulation of IL-6 expression. IL-6 mRNA production mediated by α1-AR peaked at 1 to 2 h. Studies of the mRNA decay rate indicated that α1-AR activation enhanced IL-6 mRNA stability. Analysis of IL-6 promoter activity using a series of deletion constructs indicated that α1-ARs enhanced IL-6 transcription through several transcriptional elements, including nuclear factor κB (NF-κB). Inhibition of α1-AR mediated IL-6 production and secretion by actinomycin D and the increase of intracellular IL-6 levels by α1-AR activation suggest that α1-AR mediated IL-6 secretion through de novo synthesis. Both IL-6 transcription and protein secretion mediated by α1-ARs were significantly reduced by chemical inhibitors for p38 mitogen-activated protein kinase (MAPK) and NF-κB and by a dominant-negative construct of p38 MAPK. Serum level of IL-6 was elevated in transgenic mice expressing a constitutively active mutant of the α1A-AR subtype but not in a similar mouse model expressing the α1B-AR subtype. Our results indicate that α1-ARs stimulated IL-6 expression and secretion through regulating both mRNA transcription and stability, involving p38 MAPK and NF-κB pathways. ER -