Selective prostacyclin receptor agonism augments glucocorticoid-induced gene expression in human bronchial epithelial cells.

Abstract

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.

• Authors: Sylvia M Wilson, Pamela Shen, Christopher F Rider, Suzanne L Traves, David Proud, Robert Newton, Mark A Giembycz
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 10 Pg. 6788-99 (Nov 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19880449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-chloro-5-nitrobenzanilide
• Anilides
• Anti-Inflammatory Agents, Non-Steroidal
• Benzofurans
• Glucocorticoids
• Intracellular Signaling Peptides and Proteins
• Oligonucleotides
• PPAR gamma
• Propionates
• RNA, Small Interfering
• RO3244794
• Receptors, Epoprostenol
• protein kinase modulator
• Colforsin
• taprostene
• Dexamethasone
• Epoprostenol
• Cyclic AMP

Topics

• Anilides (pharmacology)
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Benzofurans (pharmacology)
• Bronchi (drug effects, immunology)
• Cell Survival (drug effects, immunology)
• Cells, Cultured
• Colforsin (pharmacology)
• Cyclic AMP (agonists, immunology, metabolism)
• Dexamethasone (pharmacology)
• Epoprostenol (analogs & derivatives, pharmacology)
• Gene Expression (drug effects)
• Genetic Vectors (immunology, metabolism)
• Glucocorticoids (pharmacology)
• Humans
• Intracellular Signaling Peptides and Proteins (immunology, metabolism)
• Oligonucleotides (pharmacology)
• PPAR gamma (antagonists & inhibitors, immunology, metabolism)
• Propionates (pharmacology)
• RNA, Small Interfering (immunology, metabolism)
• Receptors, Epoprostenol (agonists, antagonists & inhibitors, metabolism)
• Respiratory Mucosa (drug effects, immunology)
• Response Elements (drug effects, immunology)
• Transcriptional Activation (drug effects, immunology)