{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:40:21Z","timestamp":1789850421542,"version":"4.0.1"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2009,11,1]],"date-time":"2009-11-01T00:00:00Z","timestamp":1257033600000},"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":[[2009,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Prostacyclin receptor (IP-receptor) agonists display anti-inflammatory and antiviral activity in cell-based assays and in preclinical models of asthma and chronic obstructive pulmonary disease. In this study, we have extended these observations by demonstrating that IP-receptor activation also can enhance the ability of glucocorticoids to induce genes with anti-inflammatory activity. BEAS-2B bronchial epithelial cells stably transfected with a glucocorticoid response element (GRE) luciferase reporter were activated in a concentration-dependent manner by the glucocorticoid dexamethasone. An IP-receptor agonist, taprostene, increased cAMP in these cells and augmented luciferase expression at all concentrations of dexamethasone examined. Analysis of the concentration-response relationship that described this effect showed that taprostene increased the magnitude of transcription without affecting the potency of dexamethasone and was, thus, steroid-sparing in this simple system. RO3244794, an IP-receptor antagonist, and oligonucleotides that selectively silenced the IP-receptor gene, PTGIR, abolished these effects of taprostene. Infection of BEAS-2B GRE reporter cells with an adenovirus vector encoding a highly selective inhibitor of cAMP-dependent protein kinase (PKA) also prevented taprostene from enhancing GRE-dependent transcription. In BEAS-2B cells and primary cultures of human airway epithelial cells, taprostene and dexamethasone interacted either additively or cooperatively in the expression of three glucocorticoid-inducible genes (GILZ, MKP-1, and p57kip2) that have anti-inflammatory potential. Collectively, these data show that IP-receptor agonists can augment the ability of glucocorticoids to induce anti-inflammatory genes in human airway epithelial cells by activating a cAMP\/PKA-dependent mechanism. This observation may have clinical relevance in the treatment of airway inflammatory diseases that are either refractory or respond suboptimally to glucocorticoids.<\/jats:p>","DOI":"10.4049\/jimmunol.0902738","type":"journal-article","created":{"date-parts":[[2009,10,31]],"date-time":"2009-10-31T00:45:43Z","timestamp":1256949943000},"page":"6788-6799","source":"Crossref","is-referenced-by-count":32,"title":["Selective Prostacyclin Receptor Agonism Augments Glucocorticoid-Induced Gene Expression in Human Bronchial Epithelial Cells"],"prefix":"10.1093","volume":"183","author":[{"given":"Sylvia M","family":"Wilson","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher F","family":"Rider","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Airways Inflammation Research Group, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary , Calgary, Alberta,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne L","family":"Traves","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Proud","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Newton","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Airways Inflammation Research Group, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary , Calgary, Alberta,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A","family":"Giembycz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,11,15]]},"reference":[{"key":"2025032603213570100_R1","first-page":"3A","article-title":"Pharmacodynamic profile of prostacyclin.","volume-title":"Am. J. Cardiol.","year":"1995"},{"key":"2025032603213570100_R2","first-page":"147","article-title":"Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation.","volume-title":"Pharmacol. Ther.","year":"2004"},{"key":"2025032603213570100_R3","first-page":"149","article-title":"Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-\u03b1 generation.","volume-title":"Br. J. Pharmacol.","year":"1997"},{"key":"2025032603213570100_R4","first-page":"5997","article-title":"A key role for prostaglandin I2 in limiting lung mucosal Th2, but not Th1, responses to inhaled allergen.","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032603213570100_R5","first-page":"809","article-title":"Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells.","volume-title":"J. Leukocyte Biol.","year":"2006"},{"key":"2025032603213570100_R6","first-page":"702","article-title":"Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032603213570100_R7","first-page":"815","article-title":"(4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) is a selective, pseudo-irreversible orthosteric antagonist at the prostacyclin (IP)-receptor expressed by human airway epithelial cells: negative IP-receptor-mediated regulation of CXCL9 and CXCL10 release.","volume-title":"J. Pharmacol. Exp. Ther.","year":"2008"},{"key":"2025032603213570100_R8","first-page":"L238","article-title":"Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor.","volume-title":"Am. J. Physiol.","year":"2005"},{"key":"2025032603213570100_R9","first-page":"859","article-title":"Prostanoid receptors involved in the relaxation of human pulmonary vessels.","volume-title":"Br. J. Pharmacol.","year":"1999"},{"key":"2025032603213570100_R10","first-page":"865","article-title":"Exogenous but not endogenous prostanoids regulate cytokine secretion from murine bone marrow dendritic cells: EP2, DP, and IP but not EP1, EP3, and FP prostanoid receptors are involved.","volume-title":"Int. Immunopharmacol.","year":"2003"},{"key":"2025032603213570100_R11","first-page":"315","article-title":"Augmentation of allergic inflammation in prostanoid IP-receptor deficient mice.","volume-title":"Br. J. Pharmacol.","year":"2002"},{"key":"2025032603213570100_R12","first-page":"314","article-title":"Role of prostaglandin I2 in airway remodeling induced by repeated allergen challenge in mice.","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"2003"},{"key":"2025032603213570100_R13","first-page":"6193","article-title":"Prostaglandin I2-IP signaling blocks allergic pulmonary inflammation by preventing recruitment of CD4+ Th2 cells into the airways in a mouse model of asthma.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032603213570100_R14","first-page":"464","article-title":"Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function.","volume-title":"J. Clin. Invest.","year":"2007"},{"key":"2025032603213570100_R15","first-page":"L648","article-title":"Protective effect of beraprost sodium, a stable prostacyclin analog, in the development of cigarette smoke extract-induced emphysema.","volume-title":"Am. J. Physiol.","year":"2009"},{"key":"2025032603213570100_R16","first-page":"10303","article-title":"Signaling through the prostaglandin I2 receptor IP protects against respiratory syncytial virus-induced illness.","volume-title":"J. Virol.","year":"2004"},{"key":"2025032603213570100_R17","first-page":"252","article-title":"Viral-associated exacerbations of asthma and COPD.","volume-title":"Curr. Opin. Pharmacol.","year":"2007"},{"key":"2025032603213570100_R18","first-page":"535","article-title":"Inhaled corticosteroids in chronic obstructive pulmonary disease.","volume-title":"Proc. Am. Thor. Soc.","year":"2007"},{"key":"2025032603213570100_R19","first-page":"488","article-title":"The interplay between the glucocorticoid receptor and nuclear factor-\u03baB or activator protein-1: molecular mechanisms for gene repression.","volume-title":"Endocr. Rev.","year":"2003"},{"key":"2025032603213570100_R20","first-page":"201","article-title":"Long-acting \u03b22-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airway epithelial and smooth muscle cells.","volume-title":"Mol. Pharmacol.","year":"2008"},{"key":"2025032603213570100_R21","first-page":"799","article-title":"Separating transrepression and transactivation: A distressing divorce for the glucocorticoid receptor?.","volume-title":"Mol. Pharmacol.","year":"2007"},{"key":"2025032603213570100_R22","first-page":"25765","article-title":"Role of dual specificity phosphatases in biological responses to glucocorticoids.","volume-title":"J. Biol. Chem.","year":"2008"},{"key":"2025032603213570100_R23","first-page":"79","article-title":"Anti-inflammatory functions of glucocorticoid-induced genes.","volume-title":"Mol. Cell. Endocrinol.","year":"2007"},{"key":"2025032603213570100_R24","first-page":"1723","article-title":"The coupling of multiple signal transduction pathways with steroid response mechanisms.","volume-title":"Endocrinology","year":"1994"},{"key":"2025032603213570100_R25","first-page":"449","article-title":"Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells.","volume-title":"Am. Rev. Respir. Dis.","year":"1989"},{"key":"2025032603213570100_R26","first-page":"4042","article-title":"Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E release.","volume-title":"Eur. J. Biochem.","year":"2004"},{"key":"2025032603213570100_R27","first-page":"335","article-title":"RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists.","volume-title":"Br. J. Pharmacol.","year":"2006"},{"key":"2025032603213570100_R28","first-page":"833","article-title":"Adenovirus-mediated delivery and expression of a cAMP-dependent protein kinase inhibitor gene to BEAS-2B epithelial cells abolishes the anti-inflammatory effects of rolipram, salbutamol and prostaglandin E2: a comparison with H-89.","volume-title":"J. Pharmacol. Exp. Ther.","year":"2004"},{"key":"2025032603213570100_R29","first-page":"6640","article-title":"Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662.","volume-title":"Biochemistry","year":"2002"},{"key":"2025032603213570100_R30","first-page":"1275","article-title":"Kinetic and empirical analysis of dose-response curves illustrated with a cardiac example.","volume-title":"Life Sci.","year":"1978"},{"key":"2025032603213570100_R31","first-page":"479","article-title":"Taprostene sodium.","volume-title":"Cardiovasc. Drug Rev.","year":"1993"},{"key":"2025032603213570100_R32","first-page":"1081","article-title":"Effects of topical corticosteroids on inflammatory mediator-induced eicosanoid release by human airway epithelial cells.","volume-title":"J. Allergy. Clin. Immunol.","year":"1999"},{"key":"2025032603213570100_R33","first-page":"597","article-title":"International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology.","volume-title":"Pharmacol. Rev.","year":"2003"},{"key":"2025032603213570100_R34","first-page":"17","article-title":"Focus on prostacyclin and its novel mimetics.","volume-title":"Trends Pharmacol. Sci.","year":"1996"},{"key":"2025032603213570100_R35","first-page":"423","article-title":"Agonists can discriminate between cloned human and mouse prostacyclin receptors.","volume-title":"Prostaglandins Leukot. Essent. Fatty Acids","year":"2004"},{"key":"2025032603213570100_R36","first-page":"821","article-title":"IP-receptor-dependent activation of PPAR\u03b3 by stable prostacyclin analogues.","volume-title":"Biochem. Biophys. Res. Commun.","year":"2007"},{"key":"2025032603213570100_R37","first-page":"29603","article-title":"Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ.","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2025032603213570100_R38","first-page":"115","article-title":"The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells.","volume-title":"J. Allergy Clin. Immunol.","year":"2007"},{"key":"2025032603213570100_R39","first-page":"1811","article-title":"p57Kip2, a glucocorticoid-induced inhibitor of cell cycle progression in HeLa cells.","volume-title":"Mol. Endocrinol.","year":"1999"},{"key":"2025032603213570100_R40","first-page":"7366","article-title":"Corticosteroid inhibition of growth-related oncogene protein-\u03b1 via mitogen-activated kinase phosphatase-1 in airway smooth muscle cells.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032603213570100_R41","first-page":"285","article-title":"The use of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs.","volume-title":"Biochim. Biophys. Acta.","year":"2000"},{"key":"2025032603213570100_R42","volume-title":"Prostacyclin and Its Receptors","year":"2000"},{"key":"2025032603213570100_R43","first-page":"104","article-title":"Prostanoid receptor antagonists: development and therapeutic applications.","volume-title":"Br. J. Pharmacol.","year":"2009"},{"key":"2025032603213570100_R44","first-page":"359","article-title":"Identification of a functional glucocorticoid response element in the promoter of the cyclin-dependent kinase inhibitor p57Kip2.","volume-title":"J. Mol. Endocrinol.","year":"2003"},{"key":"2025032603213570100_R45","first-page":"2515","article-title":"Chromatin immunoprecipitation scanning identifies glucocorticoid receptor binding regions in the proximal promoter of a ubiquitously expressed glucocorticoid target gene in brain.","volume-title":"J. Neurochem.","year":"2008"},{"key":"2025032603213570100_R46","first-page":"2645","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease.","volume-title":"N. Engl. J. Med.","year":"2004"},{"key":"2025032603213570100_R47","first-page":"48092","article-title":"p57KIP2 modulates stress-activated signaling by inhibiting c-Jun NH2-terminal kinase\/stress-activated protein Kinase.","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2025032603213570100_R48","first-page":"e94","article-title":"Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor.","volume-title":"PLoS. Genet.","year":"2007"},{"key":"2025032603213570100_R49","first-page":"913","article-title":"3\u2032,5\u2032-Cyclic adenosine monophosphate response element-binding protein and CCAAT enhancer-binding protein are dispensable for insulin inhibition of phosphoenolpyruvate carboxykinase transcription and for its synergistic induction by protein kinase A and glucocorticoids.","volume-title":"Mol. Endocrinol.","year":"2005"},{"key":"2025032603213570100_R50","first-page":"457","article-title":"Identification of a cAMP response element within the glucose-6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells.","volume-title":"Biochem. J.","year":"1999"},{"key":"2025032603213570100_R51","first-page":"513","article-title":"The glucose-6-phosphatase system.","volume-title":"Biochem. J.","year":"2002"},{"key":"2025032603213570100_R52","first-page":"1005","article-title":"Ligand-independent activation of the glucocorticoid receptor by \u03b22-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells.","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2025032603213570100_R53","first-page":"704","article-title":"Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy.","volume-title":"Am. J. Respir. Crit Care Med.","year":"2005"},{"key":"2025032603213570100_R54","first-page":"323","article-title":"Biochemical interaction between effects of beclomethasone dipropionate and salbutamol or formoterol in sputum cells from mild to moderate asthmatics.","volume-title":"Allergy","year":"2005"},{"key":"2025032603213570100_R55","first-page":"1293","article-title":"Interaction between glucocorticoids and \u03b22 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling.","volume-title":"Lancet","year":"2002"},{"key":"2025032603213570100_R56","first-page":"1451","article-title":"Modulation of glucocorticoid receptor function by protein kinase A.","volume-title":"Mol. Endocrinol.","year":"1992"},{"key":"2025032603213570100_R57","first-page":"158","article-title":"Modulation of glucocorticoid receptor activity by cyclic nucleotides and its implications on the regulation of human skin fibroblast growth and protein synthesis.","volume-title":"Biochim. Biophys. Acta","year":"1984"},{"key":"2025032603213570100_R58","first-page":"5346","article-title":"Glucocorticoids and protein kinase A coordinately modulate transcription factor recruitment at a glucocorticoid-responsive unit.","volume-title":"Mol. Cell. Biol.","year":"1995"},{"key":"2025032603213570100_R59","first-page":"8720","article-title":"8-Bromo-cyclic AMP induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein.","volume-title":"Mol. Cel.l Biol.","year":"2000"},{"key":"2025032603213570100_R60","first-page":"4336","article-title":"Recruitment of coactivator glucocorticoid receptor interacting protein 1 to an estrogen receptor transcription complex is regulated by the 3\u2032,5\u2032-cyclic adenosine 5\u2032-monophosphate-dependent protein kinase.","volume-title":"Endocrinology","year":"2008"},{"key":"2025032603213570100_R61","first-page":"49120","article-title":"cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1.","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2025032603213570100_R62","first-page":"183","article-title":"Immunology of asthma and chronic obstructive pulmonary disease.","volume-title":"Nat. Rev. Immunol.","year":"2008"},{"key":"2025032603213570100_R63","first-page":"90","article-title":"Do chronic inhaled steroids alone or in combination with a bronchodilator prolong life in chronic obstructive pulmonary disease patients?.","volume-title":"Curr. Opin. Pulm. Med.","year":"2007"},{"key":"2025032603213570100_R64","first-page":"808","article-title":"Pulmonary vascular involvement in COPD.","volume-title":"Chest","year":"2008"},{"key":"2025032603213570100_R65","first-page":"1371","article-title":"Pulmonary hypertension in COPD.","volume-title":"Eur. Respir. J.","year":"2008"},{"key":"2025032603213570100_R66","first-page":"109","article-title":"Clinical and morphologic correlations in chronic airway obstruction.","volume-title":"Aspen. Emphysema. Conf.","year":"1968"},{"key":"2025032603213570100_R67","first-page":"21","article-title":"Soluble P-selectin as a marker of platelet hyperactivity in patients with chronic obstructive pulmonary disease.","volume-title":"J. Investig. Med.","year":"2000"},{"key":"2025032603213570100_R68","first-page":"9","article-title":"Platelet hyperfunction in patients with chronic airways obstruction.","volume-title":"Eur. J. Respir. Dis.","year":"1985"},{"key":"2025032603213570100_R69","first-page":"676","article-title":"Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke.","volume-title":"Am. J. Respir. Crit Care Med.","year":"2007"},{"key":"2025032603213570100_R70","first-page":"1794","article-title":"Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study Group.","volume-title":"Am. J. Respir. Crit Care Med.","year":"1997"},{"key":"2025032603213570100_R71","first-page":"518","article-title":"Aerosolized iloprost induces a mild but sustained inhibition of platelet aggregation.","volume-title":"Eur. Respir. J.","year":"2002"},{"key":"2025032603213570100_R72","first-page":"1477","article-title":"Survival in primary pulmonary hypertension: the impact of epoprostenol therapy.","volume-title":"Circulation","year":"2002"},{"key":"2025032603213570100_R73","first-page":"867","article-title":"Prostanoid receptors involved in the relaxation of human bronchial preparations.","volume-title":"Br. J. Pharmacol.","year":"1999"},{"key":"2025032603213570100_R74","first-page":"625","article-title":"Dosing considerations in the use of intravenous prostanoids in pulmonary arterial hypertension: an experience-based review.","volume-title":"Am. Heart J.","year":"2009"},{"key":"2025032603213570100_R75","first-page":"1181","article-title":"2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug.","volume-title":"J. Pharmacol. Exp. 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