The Journal of Experimental Medicine
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Published online 8 July 2002 doi:10.1084/jem.20020773
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© Rockefeller University Press, 0022-1007/2002/7/269/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 2, July 15, 2002 269-274

Brief Definitive Report

Potential Role of Phosphatidylinositol 3 Kinase, rather than DNA-dependent Protein Kinase, in CpG DNA–induced Immune Activation

Ken J. Ishii1, Fumihiko Takeshita1, Ihsan Gursel1, Mayda Gursel1, Jacqueline Conover1, Andre Nussenzweig2 and Dennis M. Klinman1

1 Section of Retroviral Immunology, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration
2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Dennis M. Klinman, Bldg. 29A, Rm. 3D10, CBER/FDA, Bethesda, MD 20892. Phone: 301-827-1707; Fax: 301-496-1810; E-mail: klinman{at}cber.fda.gov

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-{kappa}B 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.

Key Words: toll-like receptors • wortmannin • dendritic cells • innate immunity • cytokines


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