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J. Biol. Chem., Vol. 281, Issue 50, 38200-38207, December 15, 2006

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CpG-B Oligodeoxynucleotide Promotes Cell Survival via Up-regulation of Hsp70 to Increase Bcl-x_L and to Decrease Apoptosis-inducing Factor Translocation^*

Cheng-Chin Kuo, Shu-Mei Liang^¶1, and Chi-Ming Liang^||2

From the Agricultural Biotechnology Research Center, the Genomics Research Center, and the ^||Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan and the ^¶Graduate Institute of Biotechnology, National Chung-Hsing University, Taichung City 402, Taiwan

Unmethylated CpG oligodeoxynucleotides (ODNs) activate immune responses in a TLR9-dependent manner. In this study, stimulation of mouse macrophages with CpG-B ODN increased cellular Hsp70 expression and prevented apoptosis induced by serum starvation or staurosporine treatment. CpG-B ODN-induced Hsp70 expression depended on TLR9, MyD88, and phosphatidylinositol 3-kinase. Inhibition of Hsp70 synthesis by an inhibitor (quercetin) or antisense hsp70 attenuated not only Hsp70 expression but also the anti-apoptotic capacity of CpG-B ODN. Ectopic expression of Hsp70 rescued the inhibitory effect of quercetin on CpG-B ODN-induced anti-apoptosis. Additional experiments demonstrated that quercetin and anti-sense hsp70 modulated CpG-B ODN-induced anti-apoptosis via a caspase-3-independent pathway by down-regulating the survival gene bcl-x_L and by increasing translocation of apoptosis-inducing factor. These findings suggest that CpG-B ODN may up-regulate Hsp70 via a TLR9/MyD88/phosphatidylinositol 3-kinase pathway to increase Bcl-x_L and to decrease apoptosis-inducing factor nuclear translocation, resulting in anti-apoptosis.

Received for publication, June 7, 2006 , and in revised form, September 26, 2006.

^* This work was supported by Grant AS 912BC3PP from Academia Sinica and Grant NSC93-2317-B-001-03 from the National Science Council of Taiwan. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

¹ To whom correspondence may be addressed: Agricultural Biotechnology Research Center, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan. Tel.: 886-2-2785-5696 (ext. 8010); Fax: 886-2-2651-5120; E-mail: smyang{at}gate.sinica.edu.tw. ² To whom correspondence may be addressed: Inst. of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan. Tel: 886-2-2651-8030; Fax: 886-2-2651-8049; E-mail: cmliang{at}gate.sinica.edu.tw.

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