CpG RNA: identification of novel single-stranded RNA that stimulates human CD14+CD11c+ monocytes.
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-kappaB and p38 MAPK, resulting in IL-6 and IL-12 production and costimulatory molecule up-regulation but not IFNalpha. 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.
Sugiyama
Takahiro
T
Section of Retroviral Immunology, Division of Viral Products, Center for Biologics, Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Gursel
Mayda
M
Takeshita
Fumihiko
F
Coban
Cevayir
C
Conover
Jacqueline
J
Kaisho
Tsuneyasu
T
Akira
Shizuo
S
Klinman
Dennis M
DM
Ishii
Ken J
KJ
D020413:3' Untranslated Regions / Q000737:chemistry / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology*; D039521:CD11c Antigen / Q000096:biosynthesis*; D018899:CpG Islands / Q000276:immunology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D011068:Poly G / Q000737:chemistry / Q000378:metabolism; D012313:RNA / Q000138:chemical synthesis / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020413:3' Untranslated Regions; D000276:Adjuvants, Immunologic; D039521:CD11c Antigen; C408982:CPG-oligonucleotide; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D009843:Oligoribonucleotides; D011068:Poly G; D012313:RNA; D048051:p38 Mitogen-Activated Protein Kinases