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Biomed Pharmacother. 2019 Apr;112:108657. doi: 10.1016/j.biopha.2019.108657. Epub 2019 Feb 21.

Immunostimulatory activity of Y-shaped DNA nanostructures mediated through the activation of TLR9.

Author information

1
BK21plus team, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
2
School of Chemical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
3
BK21plus team, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea. Electronic address: joolee@catholic.ac.kr.

Abstract

Immunostimulatory oligodeoxynucleotides (DNAs) have been widely studied in pharmaceutical and biomedical research fields for applications in cancer immunotherapy and vaccination. Toll-like receptors (TLRs) are critical for the instruction and orchestration of the host immune system composed of innate and adaptive immunity. In particular, TLR9 responds to DNAs with unmethylated deoxycytosine-deoxyguanosine (CpG) motifs, thereby inducing the activation of innate immune cells, such as dendritic cells, and consequently, adaptive immune cells. In this study, we developed two kinds of Y-shaped double-stranded DNA nanostructures (Y-DNAs), including a single unit composed of three DNA strands (YS-DNA) and a ligated multiunit complex formed by crosslinking each YS-DNA (YL-DNA), and investigated whether they have immunostimulatory activity in innate immune cells. YS-DNA and YL-DNA induced the production of immune cytokines such as IL-12 and TNF-α and the expression of costimulatory molecules such as CD80 and CD86 in primary mouse dendritic cells and macrophage cells (RAW264.7 cells). A Coprecipitation study demonstrated that YL-DNA was directly associated with TLR9. The induction of immune cytokines by YS-DNA and YL-DNA was abolished in TLR9-deficient primary mouse dendritic cells. The results demonstrated that Y-DNAs induced the activation of dendritic cells and macrophages mediated by the activation of TLR9, as shown by the expression of immune cytokines and costimulatory molecules. The results suggest that Y-DNA nanostructures provide a beneficial strategy for immunotherapy by modulating the immune system.

KEYWORDS:

Immunostimulatory DNA; Nanostructures; Pattern recognition receptor; Toll-like receptor

PMID:
30798119
DOI:
10.1016/j.biopha.2019.108657
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