Immunobiology of Bacterial CpG-DNA pp 41-58
Macrophage Activation by Immunostimulatory DNA
Activation of macrophages/dendritic cells appears to be of crucial importance in vivo in immunostimulation by foreign DNA. Immune cell activation by bacterial DNA was first observed using mixed spleen cell cultures (Shimada et al. 1986; Yamamoto et al. 1992) and B cells (Messina et al. 1991), and the role of unmethylated CpG motifs in this activation was elucidated in B cells (Krieg et al. 1995). This work showed that oligonucleotides containing an unmethylated CG dinucleotide in a certain sequence context (ACGT but not CCGG) could mimic the activity of bacterial DNA. A combination of methylation of the vertebrate genome and suppression of the frequency of activating sequences may prevent immune activation by self DNA. In mixed spleen cell culture, bacterial DNA or stimulatory oligonucleotides (here termed “CpG DNA”) promote production of a range of cytokines, including interferons-α/β and -γ (IFN-α/β, IFN-γ), interleukins-6 and -12 (IL-6, IL-12) and tumour necrosis factor-α (TNF-α). A role for macrophages in this activation was suggested by the finding that the production of IFN-γ by the non-adherent fraction of spleen cells was dependent on IL-12 and TNF-α production by the adherent fraction (Halpern et al. 1996). Direct activation of macrophages by bacterial DNA and oligonucleotides was first shown by activation of nuclear factor (NF)-ĸB and induction of TNF-α mRNA and human immunodeficiency virus (HIV)-1 long terminal repeat (LTR) promoter activity (Stacey et al. 1996).
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