Bacterial DNA induces NK cells to produce IFN-gamma in vivo and increases the toxicity of lipopolysaccharides.
Microbial products released during bacterial infection induce cytokine-mediated inflammatory responses that can be protective, but excessive release of inflammatory cytokines may promote development of the sepsis syndrome. We examined the ability of bacterial DNA to induce in vivo cytokine release and to potentiate the toxicity of LPS. Intravenous treatment of mice with Escherichia coli (EC) DNA, but not calf thymus (CT) DNA, induced a rapid (within 4 h) dose-dependent increase in serum IFN-gamma and splenic IFN-gamma-forming cells. Over 90% of splenic IFN-gamma-producing cells were identified by surface phenotype as NK cells. Mice also mounted an IFN-gamma response following challenge with 20-base oligonucleotide that contained an internal CG motif (but did not respond to a control oligonucleotide). Treatment of mice with EC DNA followed by a sublethal LPS challenge resulted in a 3-fold increase in the peak serum level of TNF-alpha and a 10-fold increase in the peak level of IL-6 compared with mice that received CT DNA followed by LPS. Mice treated with EC DNA followed by LPS showed 75% mortality, compared with no deaths in mice treated with CT DNA followed by LPS. EC DNA/LPS treatment of mice with disrupted IFN-gamma genes resulted in a 5% mortality while 59% of similarly treated +/+ mice died. Thus, bacterial DNA induces in vivo release of IFN-gamma which, in turn, is associated with an increase in LPS-induced TNF-alpha and IL-6 release, and with increased sensitivity to the toxic effects of LPS.
Cowdery
J S
JS
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Chace
J H
JH
Yi
A K
AK
Krieg
A M
AM
D000818:Animals; D001483:Base Sequence; D004269:DNA, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D004357:Drug Synergism; D007371:Interferon-gamma / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004269:DNA, Bacterial; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma