title: Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway.
abstract: Antimicrobial human neutrophil peptides (HNPs) play a pivotal role in innate host defense against a broad spectrum of prokaryotic pathogens. In addition, HNPs modulate cellular immune responses by producing the chemokine interleukin-8 (IL-8) in myeloid and epithelial cells and by exerting chemotaxis to T cells, immature dendritic cells, and monocytes. However, the mechanisms by which HNPs modulate the immune responses in the eukaryotic cells remain unclear. We demonstrated that, as with adenosine triphosphate (ATP) and uridine diphosphate (UDP), HNP stimulation of human lung epithelial cells selectively induced IL-8 production in 10 pro- and anti-inflammatory cytokines examined. HNP-induced IL-8 release was inhibited by treatment with the nucleotide receptor antagonists suramin and reactive blue. Transfection of lung epithelial cells with antisense oligonucleotides targeting specific purinergic P2Y receptors revealed that the P2Y6 (ligand of UDP) signaling pathway plays a predominant role in mediating HNP-induced IL-8 production.
authors.affiliation: Department of Anaesthesia, St Michael's Hospital, Rm 7-007, Queen Wing, 30 Bond St, Toronto, Ontario M5B 1W8, Canada.
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Khine
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Del Sorbo
authors.forename: Rosanna
authors.initials: R
authors.lastname: Vaschetto
authors.forename: Stefanos
authors.initials: S
authors.lastname: Voglis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tullis
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
mesh_terms: D001483:Base Sequence; D002470:Cell Survival; D002634:Chemotaxis, Leukocyte; D003550:Cystic Fibrosis / Q000097:blood; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000097:blood*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D009504:Neutrophils / Q000502:physiology*; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
chemical_list: D016209:Interleukin-8; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D007770:L-Lactate Dehydrogenase