Effects of a hexameric deoxyriboguanosine run conjugation into CpG oligodeoxynucleotides on their immunostimulatory potentials.
CpG oligodeoxynucleotides (ODNs) are promising immunomodulatory agents for treating human diseases and vaccine development. Phosphodiester CpG ODNs were demonstrated to have poor immunostimulatory potentials for cytokine production. However, the conjugation of consecutive deoxyriboguanosine residues, called a dG run, at the 3' terminus of phosphodiester CpG ODNs significantly enhanced TNF-alpha and IL-12 production from mouse splenic dendritic cells (DCs). The optimal induction of cytokine production was achieved by the addition of a hexameric dG (dG6) run. In contrast, the existence of a dG6 run either at the 5' terminus of phosphodiester CpG ODNs or at the 3' terminus of phosphorothioate CpG ODNs diminished CpG-mediated cytokine induction, suggesting that the effects of a dG run depend on its location and the chemical property of the ODN backbone, respectively. In addition, we provided the evidence that the conjugation of a dG6 run caused the structural transformation of CpG ODNs, which facilitates their targeting into mouse APCs such as splenic DCs, B cells, and peritoneal macrophages with a scavenger receptor type A ligand specificity. Among primary APCs, DCs were the most potent for CpG ODN-mediated IL-12 production. Furthermore, we demonstrated that the conjugation of a dG6 run into the 3' terminus of phosphodiester CpG ODNs was crucial for their ability to generate Th1 immunity in vivo. Thus, the conjugation of a dG6 run into phosphodiester CpG ODNs would be an alternative way to optimize their immunostimulatory potentials in vitro and in vivo.
Lee
S W
SW
Department of Life Science, Center for Biofunctional Molecules, Pohang University of Science and Technology, Korea.
Song
M K
MK
Baek
K H
KH
Park
Y
Y
Kim
J K
JK
Lee
C H
CH
Cheong
H K
HK
Cheong
C
C
Sung
Y C
YC
D020413:3' Untranslated Regions / Q000276:immunology; D020121:5' Untranslated Regions / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003849:Deoxyguanosine / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007111:Immunity, Cellular; D007279:Injections, Subcutaneous; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000276:Adjuvants, Immunologic; D016207:Cytokines; D008024:Ligands; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D003849:Deoxyguanosine