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* Cooperative Research Centre for Chronic Inflammatory Diseases and Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, and
School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia
Bacterial CpG-containing (CpG) DNA promotes survival of murine macrophages and triggers production of proinflammatory mediators. The CpG DNA-induced inflammatory response is mediated via TLR9, whereas a recent study reported that activation of the Akt prosurvival pathway occurs via DNA-dependent protein kinase (DNA-PK) and independently of TLR9. We show, in this study, that Akt activation and survival of murine bone marrow-derived macrophages (BMM) triggered by CpG-containing phosphodiester oligodeoxynucleotides or CpG-containing phosphorothioate oligodeoxynucleotides was completely dependent on TLR9. In addition, survival triggered by CpG-containing phosphodiester oligodeoxynucleotides was not compromised in BMM from SCID mice that express a catalytically inactive form of DNA-PK. CpG DNA-induced survival of BMM was inhibited by the PI3K inhibitor, LY294002, but not by the MEK1/2 inhibitor, PD98059. The effect of LY294002 was specific to survival, because treatment of BMM with LY294002 affected CpG DNA-induced TNF-
production only modestly. Therefore, CpG DNA activates macrophage survival via TLR9 and the PI3K-Akt pathway and independently of DNA-PK and MEK-ERK.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Health and Medical Research Council of Australia (ID 301211 and ID 301210).
2 Address correspondence and reprint requests to Dr. Matthew J. Sweet, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, Queensland, 4072, Australia. E-mail address: m.sweet{at}imb.uq.edu.au
3 Abbreviations used in this paper: DC, dendritic cell; DNA-PK, DNA-dependent protein kinase; PO-ODN, phosphodiester oligodeoxynucleotide; PS-ODN, phosphorothioate oligodeoxynucleotide; BMM, bone marrow-derived macrophage; AO-1, activating oligonucleotide-1; NAO-1, nonactivating oligonucleotide-1; EC DNA, Escherichia coli genomic DNA.
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