Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E sub( 2) Secretion, and beta sub( 2)-Adrenergic Receptor Desensitization

• Published in: American journal of respiratory cell and molecular biology Vol. 54; no. 1; p. 128
• Main Authors: Rumzhum, Nowshin N, Rahman, M Mostafizur, Oliver, Brian G, Ammit, Alaina J
• Format: Journal Article
• Language: English
• Published: 01.01.2016
• ISSN: 1535-4989
• DOI: 10.1165/rcmb.2014-0443OC

Tachyphylaxis of the beta sub( 2)-adrenergic receptor limits the efficacy of bronchodilatory beta sub( 2)-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce beta sub( 2)-adrenergic responsiveness in a cyclo-oxygenase (COX)-2-mediated, prostaglandin E sub( 2) (PGE sub( 2))-dependant manner. Herein, we show that sphingosine 1 -phosphate (S1P), a bioactive sphingolipid that plays an important role in pathophysiology of asthma, also induces beta sub( 2)-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to beta sub( 2)-agonists. We treated ASM cells with S1P (1 mu M) for up to 24 hours and then examined the temporal kinetics of COX-2 mRNA expression, protein up-regulation, and PGE sub( 2) secretion. S1P significantly enhanced COX-2 expression and PGE sub( 2) 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- alpha , we observed that S1P-induced COX-2 mRNA expression and protein up-regulation and PGE sub( 2) secretion from ASM cells were significantly enhanced. Notably, S1P induced heterologous beta sub( 2)-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting beta sub( 2)-agonist, salbutamol, and the long-acting beta sub( 2)-agonist, formoterol. Taken together, these data indicate that S1P represses beta sub( 2)-adrenergic activity in ASM cells by increasing COX-2-mediated PGE sub( 2) production, and suggest that this bioactive sphingolipid found elevated in asthma may contribute to beta sub( 2)-adrenergic desensitization.