CpG-B oligodeoxynucleotides inhibit Toll-like receptor-dependent and -independent induction of type I IFN in dendritic cells (136.10)

Abstract

Abstract CpG oligodeoxynucleotides (ODNs) signal through TLR9 to induce type-I IFN (IFNαβ) in dendritic cells. CpG-A ODNs are more efficacious than CpG-B ODNs for induction of IFNαβ. Because IFNαβ may contribute to autoimmunity, it is important to identify mechanisms to inhibit induction of IFNαβ. In our studies, CpG-B ODN inhibited induction of IFNαβ by CpG-A ODN, while induction of TNFα and IL-12p40 by CpG-A ODN was not affected. CpG-B inhibition of IFNαβ was observed in Flt3L-induced murine DCs, purified murine mDCs and pDCs, and human PBMCs. CpG-B ODN inhibited induction of IFNαβ by agonists of multiple receptors, including MyD88-dependent TLRs and MyD88-independent receptors. CpG-B ODN did not inhibit the IFNαβ positive feedback loop “second wave” IFNαβ, since IFNαβ-induced expression of IFNαβ mRNA was unaffected, and CpG-B inhibition of IFNαβ was manifested in IFNαβR-/- DCs, which lack the positive feedback mechanism. Rather, CpG-B ODN inhibited early “first-wave” IFNα4 and IFNβ. Chromatin immunoprecipitation revealed that association of IRF1 with the IFNα4 and IFNβ promoters was induced by CpG-A ODN but not CpG-B ODN. Moreover, CpG-A-induced association of IRF1 with these promoters was inhibited by CpG-B ODN. Our studies demonstrate a novel mechanism of transcriptional regulation of first-wave IFNαβ that selectively inhibits induction of IFNαβ downstream of multiple receptors and may provide targets for future therapeutic inhibition of IFNαβ expression in vivo.