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 cells. 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 translocation of nuclear factor-kappa B, accumulate tumor necrosis factor (TNF)-alpha mRNA and release large amounts of TNF-alpha. In vivo these events culminate in acute cytokine-release syndrome which includes systemic but transient accumulation of TNF-alpha. D-Galactosamine (DGalN)-sensitized mice succumb to lethal toxic shock due to macrophage-derived 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 bacterial DNA with acute release of pro-inflammatory cytokines may point out an important and as yet unappreciated sensing mechanism for foreign DNA.
Sparwasser
T
T
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Germany.
Miethke
T
T
Lipford
G
G
Erdmann
A
A
Häcker
H
H
Heeg
K
K
Wagner
H
H
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001482:Base Composition / Q000276:immunology; D004269:DNA, Bacterial / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D004357:Drug Synergism; D005688:Galactosamine / Q000276:immunology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
D004269:DNA, Bacterial; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine