ИСТИНА

Polymorphonuclear leukocytes (PMNLs, neutrophils) play a major role in the initiation and resolution of the inflammatory response. Unmethylated cytosine-phosphate-guanosine (CpG) sequences are present in large amounts in the bacterial DNA and are not typical for mammalian DNA. These structures are recognized by the immune system and may cause a specific immune response, for example, by activating TLR9 and increasing production of cytokines. Synthetic CpG-oligonucleotides (CpGODN) in the future may be a component of drugs. We examined the effects of ODN2216 structures, (5’- ggG GGA CGA TCG TCg ggg gg-3 ‘) containing various amounts of phosphodiester and phosphothioate bonds on neutrophil signaling pathways and cellular responses. Leukotriene B4 (LTB4) and 5-HETE are lipid mediators derived from arachidonic acid via the 5-lipoxygenase (5- LOX) pathway, and produced by neutrophils. LTB4 modulates TLR9 expression on human neutrophils and enhances responsiveness to TLR2 and TLR4 ligands. In this study, CpG ODN2216 inhibited leukotriene synthesis. We have demonstrated that ODN with phosphorothioate bonds activate NO synthethis and superoxide production, which can lead to the formation of peroxynitrite (ONOO-). We suggest that reactive oxygen species, NO and peroxynitrite are signaling molecules that regulate the activity of 5-LOX and neutrophil apoptosis. Fully phosphothioate structures have a pronounced effect of inducing apoptosis. By increasing of the phosphodiester bonds content, proapoptotic action of CpG ODN is reduced. We also showed that ODN2216 with phosphorothioate bonds increase the ability of neutrophils to adhere. We propose that phosphorothioate modification of ODNs represents a potential mechanism of PMNL activation.