Sester David P, Brion Kristian, Trieu Angela, Goodridge Helen S, Roberts Tara L, Dunn Jasmyn, Hume David A, Stacey Katryn J, Sweet Matthew J
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.
J Immunol. 2006 Oct 1;177(7):4473-80. doi: 10.4049/jimmunol.177.7.4473.
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.
含细菌CpG的（CpG）DNA可促进小鼠巨噬细胞的存活并触发促炎介质的产生。CpG DNA诱导的炎症反应是通过TLR9介导的，而最近一项研究报道，Akt促存活途径的激活是通过DNA依赖性蛋白激酶（DNA-PK）发生的，且不依赖于TLR9。在本研究中，我们发现，含CpG的磷酸二酯寡脱氧核苷酸或含CpG的硫代磷酸酯寡脱氧核苷酸触发的小鼠骨髓来源巨噬细胞（BMM）的Akt激活和存活完全依赖于TLR9。此外，含CpG的磷酸二酯寡脱氧核苷酸触发的存活，在表达无催化活性形式DNA-PK的SCID小鼠的BMM中并未受损。CpG DNA诱导的BMM存活受到PI3K抑制剂LY294002的抑制，但不受MEK1/2抑制剂PD98059的抑制。LY294002的作用对存活具有特异性，因为用LY294002处理BMM仅适度影响CpG DNA诱导的TNF-α产生。因此，CpG DNA通过TLR9和PI3K-Akt途径激活巨噬细胞存活，且不依赖于DNA-PK和MEK-ERK。
