β-Adrenergic Receptors Stimulate IL-6 Production in Human Bronchial Smooth Muscle Cells: Enhancement by Non-Raft AC2 But Not Lipid Raft AC6
In human bronchial smooth muscle cells (hBSMC) various isoforms of adenylyl cyclase (AC) are localized to different compartments: AC6 in lipid rafts and caveolae, AC2 outside of rafts. This localization of AC isoforms associates them with different receptors, G proteins and downstream signaling proteins. We hypothesized that specific AC isoforms overexpressed in hBSMC might have differing effects on gene expression. We overexpressed AC2 and AC6 and measured a variety of genes whose expression is influenced by cAMP. Cells were treated with vehicle or the AC activator, forskolin (Fsk). Interleukin 6 (IL-6) mRNA levels were enhanced by Fsk, particularly when AC2 was overexpressed. Fsk-stimulated IL-6 mRNA levels (qRT-PCR) peaked in 1 hr while protein levels (ELISA) peaked at 24 hr. Agonists selective for Gs-coupled GPCR were tested for their ability to stimulate IL-6 in AC2 or AC6 overexpressing cells. Increases in cAMP and IL-6 were observed in response to isoproterenol, PGE2, butaprost and beraprost. AC2, but not AC6, overexpression increased IL-6 production by these agonists. Increasing cAMP levels via Gs/Fsk synergy led to no increase in IL-6 as compared to agonists alone. These data imply that AC2 signaling can lead to IL-6 production by hBSMC but that little correlation exists between cellular cAMP levels and the level of this pro-inflammatory cytokine produced.
A Bogard and RS Ostrom. β -adrenergic receptors stimulate IL-6 production in human bronchial smooth muscle cells: enhancement by non-raft AC2 but not lipid raft AC6. FASEB J, 25(1):1012.5, 2011.
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