title: [Enrichment of extracellular DNA from the cultivation medium of human peripheral blood mononuclears with genomic CpG rich fragments results in increased cell production of IL-6 and TNF-a via activation of the NF-kB signaling pathway].
abstract: Previously, it was found that blood plasma extracellular DNA (ecDNA) of patients with rheumatoid arthritis (RA) is enriched with CpG-rich genomic DNA fragments, which contain TLR9 ligands (Veiko et al., 2006). In this study we have demonstrated that ecDNA of a RA patient and model fragments added to a cultivation medium of peripheral blood mononuclear cells (PBMC) of healthy donors stimulate expression of genes for the TLR9-MyD88-NF-kB signaling pathway; this leads to a significant increase in concentrations of the proinflammatory cytokines IL-6 and TNF-a in the cultivation medium. Human genomic DNA non-enriched with the CpG sequences did not stimulate IL-6 and TNF-a synthesis in PBMC. A scheme explaining the potential role ecDNA in the induction and maintenance of increased levels of the proinflammatory cytokines under conditions damaging the human cells has been proposed.
authors.affiliation: Nasonova Research Institute of Rheumatology, Moscow, Russia.
authors.forename: A I
authors.initials: AI
authors.lastname: Speranskii
authors.affiliation: Research Centre of Medical Genetics (RCMG), Moscow, Russia.
authors.forename: S V
authors.initials: SV
authors.lastname: Kostyuk
authors.affiliation: Moscow Regional Research Institute of Obstetrics and Gynecology, Moscow, Russia.
authors.forename: E A
authors.initials: EA
authors.lastname: Kalashnikova
authors.affiliation: Research Centre of Medical Genetics (RCMG), Moscow, Russia.
authors.forename: N N
authors.initials: NN
authors.lastname: Veiko
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D018899:CpG Islands; D004247:DNA / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D004247:DNA
keywords: NF-kB; TLR9; rheumatoid arthritis (RA)