title: Effects of phosphodiester and phosphorothioate ODN2216 on leukotriene synthesis in human neutrophils and neutrophil apoptosis.
abstract: Polymorphonuclear leukocytes (PMNLs, neutrophils) play a major role in the initiation and resolution of the inflammatory response, and neutrophil apoptosis is a critical step in resolving inflammation. We examined the effects of oligodeoxynucleotide (ODN) species with different numbers of phosphodiester and phosphorothioate bonds on leukotriene synthesis in PMNLs and on neutrophil apoptosis. Our modifications were based on the well-known ODN2216 molecule (Krug et al., 2001). Treatment of cultured human neutrophils with ODN2216 accelerated apoptosis except in the case of a species with only phosphodiester bonds. The ODNs with poly(g) (phosphorothioate) sequences at both ends and a phosphodiester inner core had maximal effects on leukotriene synthesis in neutrophils and inhibited formation of 5-lipoxygenase metabolites. Addition of phosphodiester and phosphorothioate ODNs to PMNLs produced distinct effects on superoxide and nitric oxide formation: phosphorothioate-containing ODNs concomitantly stimulated production of nitric oxide and superoxide, which may rapidly combine to generate peroxynitrite. Altogether, our results describe strong activation of neutrophil's cellular responses by phosphorothioate ODN2216. We propose that phosphorothioate modification of ODNs represents a potential mechanism of PMNL activation.
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow 119234, Russia.
authors.forename: Galina M
authors.initials: GM
authors.lastname: Viryasova
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow 119234, Russia.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Golenkina
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow 119234, Russia.
authors.forename: Svetlana I
authors.initials: SI
authors.lastname: Galkina
authors.affiliation: FGBU Hematology Research Centre, Russia Federation Ministry of Public Health, Moscow 125167, Russia.
authors.forename: Tatjana V
authors.initials: TV
authors.lastname: Gaponova
authors.affiliation: Gamaleya Research Institute of Epidemiology and Microbiology, Moscow 123098, Russia.
authors.forename: Yulia M
authors.initials: YM
authors.lastname: Romanova
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow 119234, Russia. Electronic address: sudina@genebee.msu.ru.
authors.forename: Galina F
authors.initials: GF
authors.lastname: Sud'ina
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology; D054735:Phosphorothioate Oligonucleotides / Q000737:chemistry / Q000494:pharmacology
chemical_list: C408982:CPG-oligonucleotide; D015289:Leukotrienes; D009838:Oligodeoxyribonucleotides; D054735:Phosphorothioate Oligonucleotides
keywords: 5-Lipoxygenase; Apoptosis; Neutrophil; Oligodeoxynucleotide