title: Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin-8 and leukotriene B4 receptors.
abstract: Neutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B4 (LTB4 ) constitute key mediators by binding to the surface receptors CXCR1/2 and BLT1, respectively. Oligonucleotides (ODN) containing CpG motifs mediate potent immunomodulatory effects through binding to Toll-like receptor 9. So far, knowledge on how ODN can affect neutrophil migration during inflammation is lacking. This study demonstrates that several novel CpG ODN significantly down-regulate the surface expression of CXCR1/2 and BLT1. In addition, the ODN significantly blocked IL-8-induced and LTB4 -induced neutrophil migration in vitro, as well as leucocyte migration in vivo demonstrated in mice by intravital microscopy and in a model of airway inflammation. The down-regulation of CXCR1 is rapid, occurring 15 min after ODN stimulation, and can be mediated through an endosomally independent mechanism. Inhibition of the IL-8 and LTB4 pathways may provide new opportunities of therapeutic intervention using ODN to reduce neutrophil infiltration during inflammation.
authors.affiliation: InDex Pharmaceuticals AB, Stockholm, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Admyre
authors.forename: Lars-Göran
authors.initials: LG
authors.lastname: Axelsson
authors.forename: Oliver
authors.initials: O
authors.lastname: von Stein
authors.forename: Arezou
authors.initials: A
authors.lastname: Zargari
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D018899:CpG Islands / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D056747:Immunomodulation; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D009841:Oligonucleotides / Q000494:pharmacology*; D010047:Ovalbumin; D023062:Receptors, Interleukin-8A / Q000096:biosynthesis*; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D009841:Oligonucleotides; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D018102:Receptors, Leukotriene B4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin
keywords: chemotaxis; inflammation; neutrophils; oligonucleotide
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