{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T04:09:30Z","timestamp":1770869370411,"version":"3.50.1"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tachyphylaxis of the \u03b22-adrenergic receptor limits the efficacy of bronchodilatory \u03b22-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce \u03b22-adrenergic responsiveness in a cyclo-oxygenase (COX)-2\u2013mediated, prostaglandin E2 (PGE2)\u2013dependant manner. Herein, we show that sphingosine 1-phosphate (S1P), a bioactive sphingolipid that plays an important role in pathophysiology of asthma, also induces \u03b22-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to \u03b22-agonists. We treated ASM cells with S1P (1 \u03bcM) 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-\u03b1, 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 \u03b22-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting \u03b22-agonist, salbutamol, and the long-acting \u03b22-agonist, formoterol. Taken together, these data indicate that S1P represses \u03b22-adrenergic activity in ASM cells by increasing COX-2\u2013mediated PGE2 production, and suggest that this bioactive sphingolipid found elevated in asthma may contribute to \u03b22-adrenergic desensitization.<\/jats:p>","DOI":"10.1165\/rcmb.2014-0443oc","type":"journal-article","created":{"date-parts":[[2015,6,22]],"date-time":"2015-06-22T15:58:58Z","timestamp":1434988738000},"page":"128-135","source":"Crossref","is-referenced-by-count":21,"title":["Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and \u03b22-Adrenergic Receptor Desensitization"],"prefix":"10.1093","volume":"54","author":[{"given":"Nowshin N.","family":"Rumzhum","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Mostafizur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian G.","family":"Oliver","sequence":"additional","affiliation":[{"name":"Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia; and"},{"name":"School of Medical and Molecular Biosciences, University of Technology, Sydney, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaina J.","family":"Ammit","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, 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