title: Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and β2-Adrenergic Receptor Desensitization.
abstract: Tachyphylaxis of the β2-adrenergic receptor limits the efficacy of bronchodilatory β2-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce β2-adrenergic responsiveness in a cyclo-oxygenase (COX)-2-mediated, prostaglandin E2 (PGE2)-dependant manner. Herein, we show that sphingosine 1-phosphate (S1P), a bioactive sphingolipid that plays an important role in pathophysiology of asthma, also induces β2-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to β2-agonists. We treated ASM cells with S1P (1 μM) for up to 24 hours and then examined the temporal kinetics of COX-2 mRNA expression, protein up-regulation, and PGE2 secretion. S1P significantly enhanced COX-2 expression and PGE2 secretion, and this was repressed by the selective COX-2 inhibitor celecoxib, the corticosteroid dexamethasone, or small interfering RNA (siRNA) knockdown of COX-2 expression. In combination with another proinflammatory mediator found elevated in asthmatic airways, the cytokine TNF-α, we observed that S1P-induced COX-2 mRNA expression and protein up-regulation and PGE2 secretion from ASM cells were significantly enhanced. Notably, S1P induced heterologous β2-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting β2-agonist, salbutamol, and the long-acting β2-agonist, formoterol. Taken together, these data indicate that S1P represses β2-adrenergic activity in ASM cells by increasing COX-2-mediated PGE2 production, and suggest that this bioactive sphingolipid found elevated in asthma may contribute to β2-adrenergic desensitization.
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Nowshin N
authors.initials: NN
authors.lastname: Rumzhum
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: M Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: 2 Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia; and.|3 School of Medical and Molecular Biosciences, University of Technology, Sydney, New South Wales, Australia.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Oliver
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology*; D034622:RNA Interference; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
chemical_list: C553443:ADRB2 protein, human; D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D052246:Cyclooxygenase 2 Inhibitors; D008246:Lysophospholipids; D018343:Receptors, Adrenergic, beta-2; C060506:sphingosine 1-phosphate; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone; D013110:Sphingosine
keywords: cyclic adenosine monophosphate; cyclo-oxygenase 2; prostaglandin E2; sphingosine 1-phosphate; β2-adrenergic receptor desensitization