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Cutting Edge: CpG DNA Inhibits Dendritic Cell Apoptosis by Up-Regulating Cellular Inhibitor of Apoptosis Proteins Through the Phosphatidylinositide-3'-OH Kinase Pathway¹

Division of Molecular and Life Sciences, National Laboratory of DNA Medicine, Pohang University of Science and Technology, Pohang, Korea

	Abstract

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CpG DNA has been recognized as a powerful stimulant of dendritic cells (DCs). In this study, we demonstrate that CpG DNA inhibits spontaneous apoptosis of DCs. CpG DNA up-regulated cellular inhibitor of apoptosis proteins (cIAPs) as well as Bcl-2 and Bcl-x_L, but down-regulated active caspase-3. Although CpG DNA activated p38 mitogen-activated protein kinase, extracellular signal-related kinase, and phosphatidylinositide-3'-OH kinase (PI3K), only the blocking of PI3K inhibited the CpG DNA-induced DC survival. Moreover, while the expression of Bcl-2 and Bcl-x_L depends on both PI3K and p38 mitogen-activated protein kinase, the up-regulation of cIAPs and the down-regulation of active caspase-3 by CpG DNA require PI3K activation, suggesting PI3K-dependent up-regulation of cIAPs in the antiapoptotic activity of CpG DNA in DCs. This study indicates that CpG DNA provides a survival signal to DCs, which might be one of mechanisms by which bacterial DNA stimulates and maintains the innate immune responses.

	Introduction

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Dendritic cells (DCs)³ are the principal APCs and play a pivotal role in the initiation of immune responses. Upon Ag exposure, DCs undergo a maturation process and then become specialized in Ag presentation and competent to activate naive T cells (1). Thus, the modulation of DC maturation and survival is critical for the initiation and maintenance of immune responses. Despite the importance of DCs in the immune system, the molecular mechanisms involved in DC apoptosis and survival are still poorly understood. Several factors have been demonstrated to contribute to DC survival. T cell-derived signals such as CD40 ligand, TNF-, and TNF-related activation-induced cytokine were shown to inhibit apoptosis of DCs (2). Furthermore, LPS, one of the pathogen-related products, promotes DC activation and survival (3, 4).

Over the past several years, it has been noticed that bacterial DNA containing unmethylated CpG motifs (CpG DNA) is immunologically active and provides "danger signals" to alert a host immune system (5, 6). CpG DNA or synthetic CpG oligodeoxynucleotides (ODNs) are able to stimulate DCs to become activated and maturated into professional APCs (7, 8). To determine whether bacterial DNA plays a role in the DC survival, we tried to investigate the effects of CpG DNA on the apoptosis of mouse splenic DCs. In this study, we demonstrate that CpG DNA inhibits spontaneous apoptosis of DCs by up-regulating the cellular inhibitor of apoptosis proteins (cIAPs), with a concomitant down-regulation of active caspse-3. Moreover, phosphatidylinositide-3'-OH kinase (PI3K) plays an important role in the cIAP-dependent antiapoptotic activity of CpG DNA.

	Materials and Methods

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Mice and ODNs

Six- to 8-wk-old female BALB/c mice were purchased from Japan SLC (Shizuoka, Japan). Endotoxin-free phosphorothioate-stabilized CpG ODN and its control GpC ODN were purchased from GenoTech (Taejon, Korea).

Abs and inhibitors

Anti-mouse Bcl-2, Bcl-x_L, cIAP1, and cIAP2 Abs were purchased form Santa Cruz Biotechnology (Santa Cruz, CA). Abs to phospho- and total p38, phospho- and total extracellular signal-related kinase (ERK), and phospho- and total Akt were purchased from New England Biolabs (Beverly, MA). The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (SB), MAP/ERK kinase inhibitor PD98059 (PD), and PI3K inhibitor LY294002 (LY) were purchased from Calbiochem (La Jolla, CA) and dissolved in DMSO.

Preparation of DC

Splenic DCs were prepared by using Percoll (Sigma-Aldrich, St. Louis, MO) gradient as previously described (9), and shown as 60–65% CD11c⁺, 5–10% CD11b⁺, 15–20% B220⁺, 10–15% CD3⁺, and 80–90% I-A^d+. CD11c⁺ DCs (>95%) from splenocytes were positively selected by a magnetic cell sorting with a mini-MACS column (Miltenyi Biotec, Auburn, CA) according to the manufacturer’s protocol.

Flow cytometry and evaluation of apoptosis

DCs were incubated with 1 µM CpG ODN or 10 µg/ml LPS for 48 h and harvested. Cells were stained with FITC-conjugated annexin V (BD PharMingen, San Diego, CA) and propidium iodide (PI; Sigma-Aldrich), and cell death was assessed by flow cytometry. For intracellular staining, cells were permeabilized using Cytofix/Cytoperm Plus kit (BD PharMingen) according to the manufacturer’s instructions.

Western blot analysis

DCs (2 x 10⁷) were incubated with 1 µM CpG and harvested at indicated time points. A total of 50 µg of cell extracts from each sample was resolved on a 10% SDS-PAGE and transferred onto nitrocellulose membranes. After blocking of membrane in 5% skim milk, the blots were probed with specific Abs and visualized with the appropriate HRP-conjugated secondary Abs (Southern Biotechnology Associates, Birmingham, AL) and an ECL detection system (Pierce, Rockford, IL).

	Results

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CpG DNA inhibits spontaneous apoptosis of DCs

Consistent with previous reports (2, 3, 4), DCs underwent spontaneous apoptosis in a 48-h culture (Fig. 1A), which was inhibited by the addition of LPS as a positive control. Interestingly, DC apoptosis was significantly inhibited by the addition of CpG DNA, but not that of GpC DNA, indicating a CpG motif-specific antiapoptotic effect. The population of cells which is thought to be already dead or in the late stage of apoptosis was significantly decreased by treatment with CpG DNA, as identified by being stained with both annexin V and PI (Fig. 1A). In addition, the apoptotic DCs containing subdiploid DNA were significantly reduced by CpG DNA (data not shown). On day 7, 35% of DCs were still viable in the presence of CpG DNA, whereas after 4 days, only 10% were viable when CpG DNA was absent (Fig. 1B). To determine the soluble factors induced by CpG DNA which might provide survival signals to DCs, we added the supernatants from DCs treated with CpG DNA for 4 or 8 h followed by further incubation without CpG DNA for 44 or 40 h, respectively. Any inhibitory effect on DC apoptosis was observed in this condition (data not shown), suggesting that CpG DNA directly provides survival signals to DCs.

View larger version (67K): [in this window] [in a new window]   FIGURE 1. Inhibition of spontaneous apoptosis of DCs by CpG DNA. A, DCs were incubated with 1 µM CpG DNA or GpC DNA, or 10 µg/ml LPS for 48 h. B, The kinetics of DC survival induced by CpG DNA was assessed. Apoptotic cell death was analyzed by staining with annexin V and PI. Single-positive cells for annexin V are considered as an early apoptotic population. The experiments were reproduced more than five times with similar results.

It has been reported that CpG DNA activates p38 MAPK, c-Jun NH₂-terminal kinase, and NF-B in professional APCs, and that these pathways are important for cytokine production mediated by CpG DNA (10, 11). However, ERK activation by CpG DNA is observed in macrophages, but not in DCs (12). To understand the mechanisms underlying the enhancement of DC survival by CpG DNA, we investigated the role of classical MAP kinase pathways such as the p38 MAPK and ERK by using specific inhibitors. CpG DNA or LPS appeared to induce phosphorylation of p38 MAPK (Fig. 2). Although the p38 inhibitor SB reduced CpG DNA-mediated IL-12 production in DCs (Fig. 3A), it did not affect CpG DNA-induced DC survival (Fig. 3B). Like LPS, CpG DNA significantly phosphorylated both ERK1 and ERK2 in DCs (Fig. 2), which is inconsistent with the previous report that CpG DNA did not induce the phosphorylation of ERK in bone marrow-derived DCs (12). This discrepancy might be due to the different cell types, such as spleen- and bone marrow-derived DCs. However, the MAP/ERK kinase inhibitor PD was not shown to inhibit either IL-12 production or cell survival induced by CpG DNA (Fig. 3). It was reported that PI3K and its downstream products are involved in the survival of many cell types, and that Akt is the target of receptor tyrosine kinases that signal via PI3K (13). Accordingly, we also addressed whether the activation of PI3K is involved in CpG DNA-mediated signaling pathways in DCs. As shown in Fig. 2, CpG DNA induced phosphorylation of Akt in DCs, implying the activation of PI3K by CpG DNA. Moreover, inhibition of this pathway with PI3K inhibitor LY suppressed DC survival as well as IL-12 production in a dose-dependent manner (Fig. 3). It is unlikely that the decrease of IL-12 production was caused by the cell death, because IL-12 production was also inhibited by LY even at an early time point (8 h), when the cell survival was not affected. Another PI3K inhibitor, wortmannin, also inhibited CpG DNA-induced DC survival (data not shown). The activation of p38 MAPK, ERK, and PI3K is CpG motif specific, because GpC DNA was unable to phosphorylate any of these kinases. In addition, GpC DNA did not induce the IL-12 production (Fig. 3A) as well as the up-regulation of CD80 and CD86 (data not shown). These results indicate that CpG DNA-mediated DC survival requires activation of PI3K, but not p38 MAPK or ERK.

View larger version (91K): [in this window] [in a new window]   FIGURE 2. Activation of p38 MAPK, ERK, and PI3K by CpG DNA in DCs. DCs were stimulated 1 µM CpG DNA or GpC DNA, or 10 µg/ml LPS for indicated time points. The kinase activity was determined by Western blots of cell extracts using Abs specific for phosphorylated forms of p38 MAPK, ERK, or Akt. Membranes were stripped and reprobed with Abs for total forms of p38 MAPK, ERK, or Akt to show the equal loading of protein samples. The numbers indicated were the relative ratios (%) of each phospho-form to its total form. Representative data of three independent experiments are shown.

View larger version (33K): [in this window] [in a new window]   FIGURE 3. Inhibition of CpG DNA-induced DC survival by blocking the PI3K, but not p38 MAPK or ERK. DCs were preincubated with indicated concentrations (µM) of p38 MAPK inhibitor SB, ERK inhibitor PD, or PI3K inhibitor LY for 30 min, and then stimulated with 1 µM CpG DNA. A, After 48 h, IL-12 production was determined by ELISA. B, Cell death was assessed by staining with annexin V and PI. Each bar indicates the mean value ± SEM from four independent experiments.

To understand the molecular mechanisms by which CpG DNA promotes DC survival, we first determined the expression of Bcl-2 and Bcl-x_L, negative regulators of apoptosis (14). The basal expression of Bcl-2 and Bcl-x_L (Fig. 4A, 0 h) was slightly decreased in untreated DCs at 48 h. However, treatment of CpG DNA significantly increased the expression of both molecules. In addition, the expression of cIAP1 and cIAP2, known to be potent inhibitors of caspase-3 and -7 (15), was increased in CpG DNA-treated DCs. Control GpC DNA did not increase the expression of cIAP1, cIAP2, Bcl-2, and Bcl-x_L. Moreover, DCs treated with CpG DNA significantly decreased the level of active caspase-3, when compared with untreated DCs (Fig. 4B). Next, we examined the involvement of these antiapoptotic molecules in the PI3K-dependent DC survival. The PI3K inhibitor LY significantly suppressed the expression of Bcl-2 and Bcl-x_L induced by CpG DNA (Fig. 4C). It is worth noting that the p38 MAPK inhibitor SB, which did not inhibit CpG DNA-mediated DC survival, also reduced the expression of Bcl-2 and Bcl-x_L. These results suggest that Bcl-2 family members are not critical for CpG DNA-mediated DC survival. Interestingly, the expression of cIAPs is inhibited only in the presence of LY, indicating the important role of cIAPs in PI3K-dependent DC survival. Moreover, only LY significantly inhibited the down-regulation of active caspase-3 by CpG DNA (Fig. 4D). Taken together, these results suggest that CpG DNA induces DC survival by up-regulation of cIAPs and by down-regulation of active caspase-3 through PI3K pathway.

View larger version (59K): [in this window] [in a new window]   FIGURE 4. The role of kinase activity in the expression of Bcl-2, Bcl-xL, and cIAPs, as well as the down-regulation of active caspase-3 induced by CpG DNA. DCs were incubated with 1 µM CpG DNA for 48 h in the presence or absence of 25 µM LY, 10 µM SB, or 50 µM PD. The expression of Bcl-2, Bcl-xL cIAP1, and cIAP2 was determined by Western blot analysis (A and C). The numbers indicated were the relative expression (%) of each molecule to actin. The level of active caspase-3 was analyzed by intracellular staining using specific Abs for active caspase-3 (17–22 kDa) (B and D). Representative data of three independent experiments are shown (A–C), and each bar indicates the mean value ± SEM from three independent experiments (D).

	Discussion

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It has been known that the p38 MAPK pathway is activated by CpG DNA, which is crucial for CpG DNA-induced cytokine production (10, 11). However, the p38 MAPK inhibitor had no effect on the antiapoptotic activity of CpG DNA, suggesting that different signaling pathways regulate CpG DNA-induced DC activation and survival. Although our data show that CpG DNA induces phosphorylation of ERK in DCs, this pathway appeared not to be involved in either activation or survival of DCs. In contrast, CpG DNA induces activation of PI3K, and inhibition of this pathway significantly reduces cell survival as well as IL-12 production in DCs, indicating that PI3K activation might be a crucial pathway for CpG DNA-induced DC activation and survival. It was demonstrated that the PI3K pathway was important in the survival of LPS-stimulated human DCs (4). In addition, LPS appeared to induce the phosphorylation of Akt in murine peritoneal macrophages (our unpublished observation). However, the present study suggested that LPS failed to activate the PI3K pathway, because LPS did not induce the phosphorylation of Akt in murine DCs. This discrepancy might be due to either the difference between human and mouse system or the different cell types.

PI3K and its downstream target, Akt, have been shown to play an important role in promoting cell survival (13). It was reported that PI3K mediates the survival signal via phosphorylation of Bad by Akt (17). The phosphorylated Bad then dissociates from Bcl-2/Bcl-x_L, moving into the cytosol in a complex with 14-3-3 protein, where it is unable to promote apoptosis (14). However, it is unlikely that PI3K-dependent DC survival occurs through the Akt/Bad pathway for the following reasons. First, the phosphorylation of Akt and Bad also decreased in the presence of p38 MAPK or ERK inhibitor, as well as in the presence of PI3K inhibitor (data not shown). Second, Bcl-2 family members are not critical for CpG DNA-mediated DC survival, because cell survival is still sustained even when the expression of Bcl-2 and Bcl-x_L is significantly reduced through the specific inhibition of p38 MAPK. Another possible mechanism by which CpG DNA induces DC survival by PI3K-dependent up-regulation of cIAPs is through the activation of NF-B. It was reported that CpG DNA activates DNA-dependent protein kinase, a member of PI3K-like family, which is required for NF-B activation (18). In addition, NF-B activation was reported to increase the expression of cIAP1 and cIAP2 (19). Therefore, PI3K-dependent up-regulation of cIAPs by CpG DNA might be mediated via NF-B activation (Fig. 5). When we tested NF-B inhibitors such as N-a-tosyl-L-phenylalanine chloromethyl ketone and pyrrolidine dithiocarbamate, both untreated and CpG DNA-treated DCs were almost dead even at a low concentration (5 µM) (data not shown). It is possible that nonspecific toxic effect of these inhibitors induces cell death, or NF-B activation is ultimately required for cell survival, as previously discussed (20).

View larger version (37K): [in this window] [in a new window]   FIGURE 5. A proposed mechanism for the CpG DNA-induced DC survival. CpG DNA activates PI3K that induces the expression of cIAP1 and cIAP2, which may inhibit the activation of caspase-3 leading to promote DC survival. IL-12 production by CpG DNA depends on p38 MAPK and PI3K pathways, but not ERK, while DC survival requires PI3K activation, but not p38 MAPK or ERK, suggesting that DC activation and survival might be mediated by different signaling pathways. It is possible that the up-regulation of cIAP1 and cIAP2 is mediated via NF-B activation, which might be induced by PI3K activation.

	Acknowledgments

 
We thank Sang Chun Lee for animal care and Dr. Yoe-Sik Bae and Youndong Kim for helpful discussions.

	Footnotes

 
¹ This work was supported by a grant from the Genexine Company and a National Research Laboratory Grant from the Korea Institute of Science and Technology Evaluation and Planning (2000-N-NL-01-C-202).

² Address correspondence and reprint requests to Dr. Young Chul Sung, Division of Molecular and Life Sciences, National Laboratory of DNA Medicine, Pohang University of Science and Technology, San 31, Hyoja-dong, Nam-ku, Pohang 790-784, Korea. E-mail address: ycsung{at}postech.ac.kr

³ Abbreviations used in this paper: DC, dendritic cell; ODN, oligodeoxynucleotide; cIAP, cellular inhibitor of apoptosis protein; PI3K, phosphatidylinositide-3'-OH kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinase; PI, propidium iodide; SB, SB203580; PD, PD98059; LY, LY294002; TLR, Toll-like receptor.

Received for publication August 23, 2001. Accepted for publication November 8, 2001.

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