Bacterial DNA-induced NK cell IFN-gamma production is dependent on macrophage secretion of IL-12.
Bacterial DNA (bDNA) activates B cells and macrophages and can augment inflammatory responses by inducing release of proinflammatory cytokines. We found that bDNA stimulation of mouse spleen cells induced NK cell IFN-gamma production that was dependent upon the presence of unmethylated CpG motifs, and oligonucleotides with internal CpG motifs could also induce splenocytes to secrete IFN-gamma. The bDNA-induced IFN-gamma response was strictly macrophages dependent. While splenocytes from SCID mice secreted IFN-gamma in response to bDNA, depletion of macrophages eliminated this response. Additionally, purified NK cells did not respond to bDNA; however, addition of macrophages restored the NK cell IFN-gamma response. Coculture of NK cells with preactivated macrophages further increased bDNA-induced NK cell IFN-gamma production. Anti-IL-12 or IL-10 inhibited bDNA-induced IFN-gamma response. Treatment of purified macrophages with bDNA resulted in IL-12 secretion accompanied by an increase in IL-12 p40 mRNA level. Although isolated NK cells did not make IFN-gamma in response to bDNA, NK cells costimulated with IL-12 gained the ability to respond to bDNA. These experiments show that bDNA induces macrophage IL-12 production which, in turn, stimulates NK cell IFN-gamma production. Macrophage-derived IL-12 renders NK cells responsive to bDNA permitting an even greater IFN-gamma response to bDNA.
Chace
J H
JH
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Hooker
N A
NA
Mildenstein
K L
KL
Krieg
A M
AM
Cowdery
J S
JS
D000818:Animals; D004269:DNA, Bacterial / Q000494:pharmacology*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology
D004269:DNA, Bacterial; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma