MACROPHAGES SENSE PATHOGENS VIA DNA MOTIFS - INDUCTION OF TUMOR NECROSIS FACTOR-ALPHA-MEDIATED SHOCK

Cell surface components of pathogens, such as lipopolysaccharide (LPS) , are an important signal for receptor-mediated activation of immune c ells. Here we demonstrate that DNA of gram-positive and gram-negative bacteria or certain synthetic oligonucleotides displaying unmethylated CpG-motifs can trigger macrophages in vitro to induce nuclear translo cation of nuclear factor-kappa B, accumulate tumor necrosis factor (TN F)-kappa mRNA and release large amounts of TNF-kappa. In vivo these ev ents culminate in acute cytokine-release syndrome which includes syste mic but transient accumulation of TNF-alpha. D-Galactosamine (D-GalN)- sensitized mice succumb to lethal toxic shock due to macrophage-derive d TNF-alpha resulting in fulminant apoptosis of liver cells. LPS and a specific oligonucleotide synergized in vivo as measured by TNF-alpha- release, suggesting that macrophages integrate the respective signals. The ability of macrophages to discriminate and to respond to bacteria l DNA with acute release of proinflammatory cytokines may point out an important and as yet unappreciated sensing mechanism for foreign DNA.