CpG DNA induces cyclooxygenase-2 expression and prostaglandin production

Unmethylated CpG motifs found in bacterial DNA are potent activators of the innate and acquired immune systems, and rapidly induce the production of p roinflammatory cytokines. We hypothesized that CpG DNA may also elicit the production of prostaglandins (PG), which are central lipid mediators of the immune and inflammatory response. To test our hypothesis, we stimulated mu rine spleen cells and RAW 264.7 murine macrophage cells with CpG DNA and as sessed the effects on the PG synthesis pathway. Compared to control, DNA-co ntaining CpG motifs induced >5-fold increase in PGE(2) production and rapid ly up-regulated cyclooxygenase-2 (COX-2) at both the mRNA and protein level . CpG DNA was an extremely strong inducer of COX-2 as concentrations as low as 3 ng/ml induced COX-2 protein expression. The CpG DNA-induced PGE(2) do wn-regulated the immune response elicited by CpG. Blockade of PGE(2) produc tion with selective COX-2 inhibitors or neutralizing anti-PGE(2) antibody m arkedly enhanced IFN-gamma secretion in vitro from CpG DNA-stimulated splee n cells. Moreover, selective COX-2 inhibition increased CpG DNA-induced IFN -gamma secretion in vivo. Inhibition of COX-2 also increased CpG DNA-induce d lytic activity of NK cells. Taken together, these data indicate that DNA containing CpG motifs is a potent inducer of COX-2 and PGE(2) production. C pG-Induced PG may subsequently down-regulate the immune and inflammatory re sponses elicited by the CpG DNA.