CpG-A-Induced Monocyte IFN-γ-Inducible Protein-10 Production Is Regulated by Plasmacytoid Dendritic Cell-Derived IFN-α

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Abstract
Unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (ODN) are known for inducing a Th1 cytokine/chemokine environment, but the mechanisms regulating this have been unclear. Recent studies have defined two classes of CpG ODN, CpG-A ODN that induce plasmacytoid dendritic cells (pDC) to secrete very high levels of IFN-α, and CpG-B ODN that induce only low levels of IFN-α production, but strongly activate B cells. We now demonstrate that a CpG-A ODN directly activates pDC secretion of IFN-α and other soluble factors that secondarily induce purified monocytes to secrete high levels of the Th1-promoting chemokine IFN-γ-inducible protein-10 (IP-10). Cell contact between the monocytes and pDC is not required for this interaction. IFN-α is necessary, but only partially sufficient, for this indirect CpG-induced monocyte IP-10 production. Although CpG ODN induce human PBMC to make only very slight amounts of IFN-γ, we find that these low concentrations synergize with IFN-α for inducing monocyte production of IP-10. These studies provide a better understanding of the mechanisms through which CpG ODN create a Th1-like environment.