Selective prostacyclin receptor agonism augments glucocorticoid-induced gene expression in human bronchial epithelial cells.
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 p57(kip2)) 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.
Wilson
Sylvia M
SM
Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Shen
Pamela
P
Rider
Christopher F
CF
Traves
Suzanne L
SL
Proud
David
D
Newton
Robert
R
Giembycz
Mark A
MA
D000813:Anilides / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D005822:Genetic Vectors / Q000276:immunology / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology; D020218:Response Elements / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001572:Benzofurans; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; D009841:Oligonucleotides; D047495:PPAR gamma; D011422:Propionates; D034741:RNA, Small Interfering; C515593:RO3244794; D044006:Receptors, Epoprostenol; C015482:protein kinase modulator; D005576:Colforsin; C039188:taprostene; D003907:Dexamethasone; D011464:Epoprostenol; D000242:Cyclic AMP