当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Evidence for a second receptor for prostacyclin on human airway epithelial cells that mediates inhibition of CXCL9 and CXCL10 release.

Evidence for a second receptor for prostacyclin on human airway epithelial cells that mediates inhibition of CXCL9 and CXCL10 release.

Abstract：

:Herein we provide evidence for the coexpression of two distinct prostacyclin (PGI(2)) receptors (IP) on BEAS-2B human airway epithelial cells. IP receptor heterogeneity initially was suggested by the finding that the rank orders of potency of PGI(2) and three structurally similar analogs [taprostene, iloprost, 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC)] for the inhibition of chemokine (CXCL9 and CXCL10) release and for transcriptional activation/augmentation of cAMP response element and glucocorticoid response element luciferase reporters were distinct. Indeed, PGI(2), taprostene, and iloprost activated both reporters whereas 15-deoxy-TIC was inert. Conversely, 15-deoxy-TIC, PGI(2), and taprostene (but not iloprost) suppressed chemokine release. Further experiments established that iloprost did not antagonize the inhibitory effect taprostene or 15-deoxy-TIC on chemokine output. Likewise, 15-deoxy-TIC failed to antagonize taprostene- and iloprost-induced reporter transactivation. Thus, iloprost- and 15-deoxy-TIC-induced responses were apparently mediated via pharmacologically distinct receptors. In human embryonic kidney 293 cells overexpressing the human recombinant IP receptor receptor, 15-deoxy-TIC was considerably less potent (>10,000-fold) than iloprost and taprostene in promoting cAMP accumulation, yet in BEAS-2B cells, these analogs were equipotent. IP receptor heterogeneity was also supported by the finding that the affinity of the IP receptor antagonist R-3-(4-fluorophenyl)-2-[5-(4-fluorophenyl)-benzofuran-2-yl-methoxycarbonyl-amino] propionic acid (RO3244794) for the receptor mediating inhibition of chemokine release was approximately 10-fold lower than for the receptor mediating both transcriptional outputs. Finally, small interfering RNAs directed against the IP receptor gene, PTGIR, failed to block the suppression of chemokine output induced by taprostene and 15-deoxy-TIC, whereas taprostene- and iloprost-induced transcriptional responses were markedly attenuated. Collectively, these results indicate that PGI(2), taprostene and 15-deoxy-TIC suppress chemokine release from BEAS-2B cells by interacting with a novel IP receptor that we denote here as the "IP(2)" subtype.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Wilson SM,Sheddan NA,Newton R,Giembycz MA

doi

10.1124/mol.110.069674

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

586-95

issue

eissn

0026-895X

issn

1521-0111

pii

mol.110.069674

journal_volume

pub_type

杂志文章

在线工具

Evidence for a second receptor for prostacyclin on human airway epithelial cells that mediates inhibition of CXCL9 and CXCL10 release.