Moreover, the potent immunologic activation by unmethylated CpG motifs suggests that the vertebrate immune system uses these unique bDNA characteristics to trigger innate immune defenses against infection by microorganisms.Įndotoxin is one of the primary mediators of inflammation released by Gram-negative organisms and appears to be an important cause of environmentally induced airway disease. Thus, in addition to the potential adjuvant effects of oligonucleotides containing CpG motifs ( 12, 13, 14, 15, 16, 17), these agents are particularly effective in substantially modifying a Th2 cytokine-driven inflammatory response, making it more Th1-like ( 18). However, oligonucleotides containing CpG motifs also stimulate the production and secretion of IL-10 ( 4, 5), a potent immunosuppressive cytokine ( 11). Further evaluation of the immunologic response to CpG-containing oligonucleotides indicates that these specific motifs stimulate a Th1-like inflammatory response dominated by the release of IL-12 and IFN-γ ( 2). DNA containing unmethylated CpG motifs results in B cell proliferation and in the release of IL-6 and IL-10 ( 2, 3, 4, 5), NK cell activation, secretion of IFN-γ ( 2, 6, 7, 8), and monocyte activation with elevated production of TNF-α and IL-12 ( 9, 10). CpG motifs appear to be underrepresented in vertebrate genomes when present, they are more likely to be methylated. Unmethylated CpG motifs are ∼20-fold more common in bDNA than in vertebrate DNA. Recently, we have found that bacterial DNA (bDNA) 3 and certain oligonucleotides containing unmethylated CpG dinucleotides have stimulatory effects on murine and human lymphocytes in vitro and murine lymphocytes in vivo when compared with the effects of eukaryotic DNA or methylated oligonucleotides that are nonstimulatory ( 1). These findings indicate that CpG-containing oligonucleotides or bDNA are protected against LPS-induced cellular airway inflammation through an IL-12-dependent pathway, and that the pulmonary cytokine and cellular changes appear to be regulated independently. In contrast, CpG DNA did not protect mice with a disrupted IL-12 gene against the LPS-induced cellular influx, even though CpG DNA reduced the release of TNF-α and macrophage inflammatory protein-2 in the lung. The protective effect of CpG oligonucleotides was observed in mice with either a disrupted IL-10 or IFN-γ gene, but release of cytokines in the lung was increased, especially in the mice lacking IFN-γ. bDNA resulted in a similar immunoprotective effect, and methylation of the CpG motifs abolished the protective effect of CpG oligonucleotides. The immunoprotective effect of CpG-containing oligonucleotides was dose-dependent and was most pronounced in mice pretreated between 2 and 4 h before the inhalation challenge, corresponding to the peak levels of serum cytokines. treatment with CpG oligonucleotides resulted in higher systemic concentrations of polymorphonuclear leukocytes, IL-10, and IL-12, but significantly reduced the concentration of total cells, polymorphonuclear leukocytes, TNF-α, and macrophage inflammatory protein-2 in the lavage fluid following LPS inhalation. Compared with non-CpG oligonucleotides, i.v. bacterial DNA (bDNA) or oligonucleotides with or without CpG motifs, exposed these mice to LPS by inhalation, and measured the inflammatory response systemically and in the lung immediately following LPS inhalation. To determine whether the systemic immune activation by CpG DNA could alter airway inflammation, we pretreated mice with either i.v.
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