CpG-Induced IFNγ 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, IFNγ-deficiency or anti-IFNγ pretreatment reduced CpG-expanded IL-18 responses to LPS by 67 and 83%, respectively. Mice pretreated with either IFNγ 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 IFNγ 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 IFNγ-dependent and IFNγ-sufficient mechanism in vivo that is optimally triggered by LPS.