Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and β2-Adrenergic Receptor Desensitization
| Autor: | Brian G. Oliver, Alaina J. Ammit, Md. Mostafizur Rahman, Nowshin N. Rumzhum |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Small interfering RNA medicine.medical_specialty Clinical Biochemistry Bronchi Tachyphylaxis Biology Transfection Dinoprostone Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound Desensitization (telecommunications) Adrenal Cortex Hormones Sphingosine Internal medicine Cyclic AMP medicine Humans Cyclic adenosine monophosphate Sphingosine-1-phosphate Prostaglandin E2 Adrenergic beta-2 Receptor Agonists Molecular Biology Cells Cultured Cyclooxygenase 2 Inhibitors Epithelial Cells Cell Biology respiratory system Up-Regulation respiratory tract diseases Kinetics 030104 developmental biology Endocrinology chemistry Cyclooxygenase 2 RNA Interference lipids (amino acids peptides and proteins) Receptors Adrenergic beta-2 Lysophospholipids medicine.drug |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 54:128-135 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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