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CpG RNA: Identification of Novel Single-Stranded RNA That Stimulates Human CD14⁺CD11c⁺ Monocytes

Takahiro Sugiyama^*,, Mayda Gursel^*, Fumihiko Takeshita, Cevayir Coban^,¶, Jacqueline Conover^*, Tsuneyasu Kaisho, Shizuo Akira^,¶, Dennis M. Klinman^* and Ken J. Ishii^1,*,,¶

^* Section of Retroviral Immunology, Division of Viral Products, Center for Biologics, Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Yokahama, Japan; Department of Molecular Biodefense Research, School of Medicine, Yokohama City University, Yokohama, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka University, Osaka, Japan; and ^¶ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Synthetic immunostimulatory nucleic acids such as CpG DNA are being harnessed therapeutically as vaccine adjuvants, anticancer or antiallergic agents. Efforts to identify nucleic acid-based agents capable of more specifically modulating the immune system are being developed. The current study identifies a novel class of single-stranded oligoribonucleotides (ORN) containing unmethylated CpG motifs and a poly(G) run at the 3' end (CpG ORN) that directly stimulate human CD14⁺CD11c⁺ monocytes but not dendritic cells or B cells. CpG ORN activate NF-B and p38 MAPK, resulting in IL-6 and IL-12 production and costimulatory molecule up-regulation but not IFN. Methylation of cytosine at the 5' portion in core CpG motif abrogates such activation. TLR3, 7, 8, or 9 alone did not confer response to CpG ORN, in contrast to previously reported respective nucleic acid ligands. These data suggest that CpG ORN represent a novel class of synthetic immunostimulatory nucleic acids with distinct target cells, receptors, and functions from that of previously known immunomodulatory nucleic acids.

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