title: CpG DNA activates survival in murine macrophages through TLR9 and the phosphatidylinositol 3-kinase-Akt pathway.
abstract: 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-alpha production only modestly. Therefore, CpG DNA activates macrophage survival via TLR9 and the PI3K-Akt pathway and independently of DNA-PK and MEK-ERK.
authors.affiliation: Cooperative Research Centre for Chronic Inflammatory Diseases and Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Sester
authors.forename: Kristian
authors.initials: K
authors.lastname: Brion
authors.forename: Angela
authors.initials: A
authors.lastname: Trieu
authors.forename: Helen S
authors.initials: HS
authors.lastname: Goodridge
authors.forename: Tara L
authors.initials: TL
authors.lastname: Roberts
authors.forename: Jasmyn
authors.initials: J
authors.lastname: Dunn
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D018899:CpG Islands / Q000502:physiology*; D004247:DNA; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015151:Immunoblotting; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt