alpha1-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-kappaB.
Our previous studies have demonstrated that activation of alpha(1)-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 alpha(1A)-AR subtype and primary mouse neonatal cardiomyocytes, we elucidated the basic molecular mechanisms responsible for the alpha(1)-AR modulation of IL-6 expression. IL-6 mRNA production mediated by alpha(1)-AR peaked at 1 to 2 h. Studies of the mRNA decay rate indicated that alpha(1)-AR activation enhanced IL-6 mRNA stability. Analysis of IL-6 promoter activity using a series of deletion constructs indicated that alpha(1)-ARs enhanced IL-6 transcription through several transcriptional elements, including nuclear factor kappaB (NF-kappaB). Inhibition of alpha(1)-AR mediated IL-6 production and secretion by actinomycin D and the increase of intracellular IL-6 levels by alpha(1)-AR activation suggest that alpha(1)-AR mediated IL-6 secretion through de novo synthesis. Both IL-6 transcription and protein secretion mediated by alpha(1)-ARs were significantly reduced by chemical inhibitors for p38 mitogen-activated protein kinase (MAPK) and NF-kappaB 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 alpha(1A)-AR subtype but not in a similar mouse model expressing the alpha(1B)-AR subtype. Our results indicate that alpha(1)-ARs stimulated IL-6 expression and secretion through regulating both mRNA transcription and stability, involving p38 MAPK and NF-kappaB pathways.
Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Dianne M
DM
Perez
Robert S
RS
Papay
Ting
T
Shi
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D020871:RNA Stability; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D015850:Interleukin-6; D016328:NF-kappa B; D018340:Receptors, Adrenergic, alpha-1; D048051:p38 Mitogen-Activated Protein Kinases