CpG-induced IFNgamma expands TLR4-specific IL-18 responses in vivo.
Serum IL-18 responses to LPS increase after pretreatment with CpG-containing DNA. Compared to saline-pretreated controls, mice pretreated with CpG for two days produced 20-fold more serum IL-18 when challenged with lipopolysaccharide (LPS). In contrast, IFNgamma-deficiency or anti-IFNgamma pretreatment reduced CpG-expanded IL-18 responses to LPS by 67 and 83%, respectively. Mice pretreated with either IFNgamma or CpG comparably increased LPS-inducible serum IL-18 responses. LPS, compared to challenge with other TLR agonists, was best able to trigger high serum IL-18 levels in CpG-pretreated mice and this response was TLR4-dependent. CpG, compared to pretreatment with other TLR agonists, optimally expanded LPS-induced IL-18 responses that correlated with higher levels of circulating IFNgamma levels prior to LPS challenge. High-level serum IL-18 responses were caspase-1-dependent and P2X7 receptor-independent. We conclude that CpG promotes high-level IL-18 synthesis by an IFNgamma-dependent and IFNgamma-sufficient mechanism in vivo that is optimally triggered by LPS.
Gupta
Sameer
S
Pediatric Pharmacology and Critical Care, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Gould
Meetha P
MP
DeVecchio
Jennifer
J
Canaday
David H
DH
Auletta
Jeffery J
JJ
Heinzel
Frederick P
FP
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020382:Interleukin-18 / Q000097:blood*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*
D003521:Cyclopropanes; D020382:Interleukin-18; D008070:Lipopolysaccharides; C508012:N2-cyclopropylamine-guanosine; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D006151:Guanosine; D007371:Interferon-gamma; D020170:Caspase 1