Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation.
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.
Section of Retroviral Immunology, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Ken J
KJ
Ishii
Fumihiko
F
Takeshita
Ihsan
I
Gursel
Mayda
M
Gursel
Jacqueline
J
Conover
Andre
A
Nussenzweig
Dennis M
DM
Klinman
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018899:CpG Islands / Q000235:genetics / Q000276:immunology*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology; D051217:Toll-Like Receptor 9; D014162:Transfection; D000077191:Wortmannin
D000730:Androstadienes; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D051217:Toll-Like Receptor 9; D000077191:Wortmannin; C408982:CPG-oligonucleotide; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; C497263:PRKDC protein, human