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

Ken J Ishii; Fumihiko Takeshita; Ihsan Gursel; Mayda Gursel; Jacqueline Conover; Andre Nussenzweig; Dennis M Klinman

doi:10.1084/jem.20020773

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

J Exp Med. 2002 Jul 15;196(2):269-74. doi: 10.1084/jem.20020773.

Authors

Ken J Ishii¹, Fumihiko Takeshita, Ihsan Gursel, Mayda Gursel, Jacqueline Conover, Andre Nussenzweig, Dennis M Klinman

Affiliation

¹ Section of Retroviral Immunology, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.

Abstract

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Androstadienes / pharmacology
Animals
Base Sequence
Cell Line
CpG Islands / genetics
CpG Islands / immunology*
DNA-Activated Protein Kinase
DNA-Binding Proteins / immunology
Dendritic Cells / drug effects
Dendritic Cells / immunology
Female
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Immunological
Nuclear Proteins
Oligodeoxyribonucleotides / genetics
Oligodeoxyribonucleotides / immunology*
Oligodeoxyribonucleotides / pharmacology
Phosphatidylinositol 3-Kinases / metabolism*
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Receptors, Cell Surface / immunology
Toll-Like Receptor 9
Transfection
Wortmannin

Substances

Androstadienes
CPG-oligonucleotide
DNA-Binding Proteins
Nuclear Proteins
Oligodeoxyribonucleotides
Receptors, Cell Surface
TLR9 protein, human
Tlr9 protein, mouse
Toll-Like Receptor 9
DNA-Activated Protein Kinase
PRKDC protein, human
Protein Serine-Threonine Kinases
Wortmannin