Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation.

Date

2002-07-15

Author

Ishii, KJ
Takeshita, F
Gursel, I
Gürsel, Mayda
Conover, J
Nussenzweig, A
Klinman, DM

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Unmethylated CpG motifs present in bacterial DNA stimulate a strong innate immune response. There is evidence that DNA-dependent protein kinase (DNA-PK) mediates CpG signaling. Specifically, wortmannin (an inhibitor of phosphatidylinositol 3 kinase [PI3]-kinases including DNA-PK) interferes with CpG-dependent cell activation, and DNA-PK knockout (KO) mice fail to respond to CpG stimulation. Current studies establish that wortmannin actually inhibits the uptake and colocalization of CpG DNA with toll-like receptor (TLR)-9 in endocytic vesicles, thereby preventing CpG-induced activation of the NF-kappaB signaling cascade. We find that DNA-PK is not involved in this process, since three strains of DNA-PK KO mice responded normally to CpG DNA. These results support a model in which CpG signaling is mediated through TLR-9 but not DNA-PK, and suggest that wortmannin-sensitive member(s) of the PI3-kinase family play a critical role in shuttling CpG DNA to TLR-9.

Subject Keywords

Immunology, Immunology and Allergy

URI

https://hdl.handle.net/11511/40266

Journal

The Journal of experimental medicine

DOI

https://doi.org/10.1084/jem.20020773

Collections

Department of Biology, Article

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Cutting edge: Role of toll-like receptor 9 in CpG DNA-induced activation of human cells Takeshita, F; Leifer, CA; Gursel, I; Ishii, KJ; Takeshita, S; Gürsel, Mayda; Klinman, DM (The American Association of Immunologists, 2001-10-01) Unmethylated CpG motifs present in bacterial DNA stimulate a rapid and robust innate immune response. Human cell lines and PBMC that recognize CpG DNA express membrane-bound human Toll-like receptor 9 (hTLR9). Cells that are not responsive to CpG DNA become responsive when transfected with hTLR9. Expression of hTLR9 dramatically increases uptake of CpG (but not control) DNA into endocytic vesicles. Upon cell stimulation, hTLR9 and CpG DNA are found in the same endocytic vesicles. Cells expressing hTLR9 are ...
Effect of suppressive DNA on CpG-induced immune activation. Yamada, H; Gursel, I; Takeshita, F; Conover, J; Ishii, KJ; Gürsel, Mayda; Takeshita, S; Klinman, DM (The American Association of Immunologists, 2002-11-15) Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs stimulate a strong innate immune response. This stimulation can be abrogated by either removing the CpG DNA or adding inhibitory/suppressive motifs. Suppression is dominant over stimulation and is specific for CpG-induced immune responses (having no effect on LPS- or Con A-induced activation). Individual cells noncompetitively internalize both stimulatory and suppressive ODN. Studies using ODN composed of both stimula...
CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection. Verthelyi, D; Gürsel, Mayda; Kenney, RT; Lifson, JD; Liu, S; Mican, J; Klinman, DM (The American Association of Immunologists, 2003-05-01) Oligodeoxynucleotides containing CpG motifs (CpG ODNs) mimic microbial DNA and activate effectors of the innate immune response, which limits the spread of pathogens and promotes an adaptive immune response. CpG ODNs have been shown to protect mice from infection with intracellular pathogens. Unfortunately, CpG motifs that optimally stimulate humans are only weakly active in mice, mandating the use of nonhuman primates to monitor the activity and safety of "human" CpG ODNs in vivo. This study demonstrates t...
Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. Gursel, I; Gürsel, Mayda; Yamada, H; Ishii, KJ; Takeshita, F; Klinman, DM (The American Association of Immunologists, 2003-08-01) Bacterial DNA contains immunostimulatory CpG motifs that trigger an innate immune response capable of promoting host survival following infectious challenge. Yet CpG-driven immune activation may also have deleterious consequences, ranging from autoimmune disease to death. We find that repetitive elements present at high frequency in mammalian telomeres, but rare in bacteria, down-regulate CpG-induced immune activation. Suppressive activity correlates with the ability of telomeric TTAGGG repeats to form G-te...
CpG RNA: identification of novel single-stranded RNA that stimulates human CD14+CD11c+ monocytes. Sugiyama, T; Gürsel, Mayda; Takeshita, F; Coban, C; Conover, J; Kaisho, T; Akira, S; Klinman, DM; Ishii, KJ (The American Association of Immunologists, 2005-02-15) 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 ...

Citation Formats

K. Ishii et al., “Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation.,” The Journal of experimental medicine, pp. 269–74, 2002, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/40266.