title: P2Y(6) nucleotide receptor mediates monocyte interleukin-8 production in response to UDP or lipopolysaccharide.
abstract: Extracellular nucleotides are autocrine and paracrine cellular mediators that signal through P2 nucleotide receptors. Monocytic cells express several P2Y receptors but the role of these G protein-coupled receptors in monocytes is not known. Here, we present evidence that P2Y(6) regulates chemokine production and release in monocytes. We find that UDP, a selective P2Y(6) agonist, stimulates interleukin (IL)-8 release in human THP-1 monocytic cells whereas other nucleotides are relatively inactive. P2 receptor antagonists or P2Y(6) antisense oligonucleotides inhibit IL-8 release induced by UDP. Furthermore, UDP specifically activated IL-8 production in astrocytoma 1321N1 cells transfected with human P2Y(6). Since lipopolysaccharide has been suggested to activate P2 receptors via nucleotide release, we tested whether IL-8 production stimulated by lipopolysaccharide might result from P2Y(6) activation. P2 antagonists or apyrase, an enzyme which hydrolyzes nucleotides including UDP, inhibit IL-8 production induced by lipopolysaccharide but not by other stimuli. Furthermore, IL-8 gene expression activated by lipopolysaccharide is enhanced by P2Y(6) overexpression and inhibited by P2Y(6) antisense oligonucleotides. Thus, UDP activates IL-8 production via P2Y(6) in monocytic cells. Furthermore, lipopolysaccharide mediates IL-8 production at least in part by autocrine P2Y(6) activation. These findings indicate a novel role for P2Y(6) in innate immune defenses.
authors.affiliation: Gastroenterology Divison, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. mwarny@caregroup.harvard.edu
authors.forename: M
authors.initials: M
authors.lastname: Warny
authors.forename: S
authors.initials: S
authors.lastname: Aboudola
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
authors.forename: J
authors.initials: J
authors.lastname: Sévigny
authors.forename: D
authors.initials: D
authors.lastname: Communi
authors.forename: S P
authors.initials: SP
authors.lastname: Soltoff
authors.forename: C P
authors.initials: CP
authors.lastname: Kelly
mesh_terms: D002460:Cell Line; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D015398:Signal Transduction; D014530:Uridine Diphosphate / Q000494:pharmacology
chemical_list: D016209:Interleukin-8; D008070:Lipopolysaccharides; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate