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: New York American Thoracic Society 01.01.2016
• Subjects: Asthma; Cytokines; Drug therapy; Enzymes; Gene expression; Immunoglobulins; Inflammation; Life sciences; Proteins; Statistical analysis; Studies
• ISSN: 1535-4989
• DOI: 10.1165/rcmb.2014-0443OC

Tachyphylaxis of the β^sub 2^-adrenergic receptor limits the efficacy of bronchodilatory β^sub 2^-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce β^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 β^sub 2^-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to β^sub 2^-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 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-α, 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 β^sub 2^-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting β^sub 2^-agonist, salbutamol, and the long-acting β^sub 2^-agonist, formoterol. Taken together, these data indicate that S1P represses β^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 β^sub 2^-adrenergic desensitization.