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Originally published online as doi:10.1189/jlb.0906588 on January 8, 2007

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(Journal of Leukocyte Biology. 2007;81:983-989.)
© 2007 by Society for Leukocyte Biology

Lipoteichoic acid and muramyl dipeptide synergistically induce maturation of human dendritic cells and concurrent expression of proinflammatory cytokines

Hye Jin Kim*, Jae Seung Yang{dagger}, Sang Su Woo*, Sun Kyung Kim*, Cheol-Heui Yun{ddagger}, Kack Kyun Kim* and Seung Hyun Han*,{dagger},1

* Department of Oral Microbiology and Immunology and Dental Research Institute, School of Dentistry, and
{ddagger} Graduate School of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; and
{dagger} International Vaccine Institute, SNU Research Park, Seoul, Republic of Korea

1 Correspondence: Department of Oral Microbiology and Immunology and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea. E-mail: shhan-mi{at}snu.ac.kr


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ABSTRACT
 
Maturation is an important process by which dendritic cells (DC) develop the potent antigen-presentation capacity necessary for efficient activation of adaptive immunity. Here, we have investigated the ability of lipoteichoic acid (LTA) and muramyl dipeptide (MDP; the minimal structural unit of peptidoglycan with immunostimulating activity) to induce maturation of human immature DC (iDC), derived from peripheral blood CD14-positive cells, and the production of proinflammatory cytokines. Exposure of iDC to staphylococcal LTA (StLTA) at 1 or 10 µg/ml or MDP at 0.1 or 1 µg/ml alone had little effect on the expression of CD80 and CD83, with a minor increase in expression of CD86, all of which are indicative of cell surface markers for maturation. However, there was a synergistic expression of these molecules when iDC were stimulated with StLTA and MDP together. It is interesting that selective induction of MHC Class II expression was observed during the DC maturation, only when costimulated with LTA plus MDP, and Escherichia coli LPS induced dramatic expression of MHC Classes I and II. Endocytosis assay using Dextran-FITC showed that costimulation with StLTA and MDP attenuated the endocytic capacity of the DC, which is a typical phenomenon of DC maturation. Concomitantly, increased expression of DEC-205, but decreased expression of CD206, was observed under the same costimulating condition. Furthermore, ELISA showed that secretions of TNF-{alpha} and IL-12 p40, but not IL-10, were induced in iDC by the costimulation. These results suggest that StLTA and MDP synergistically induce maturation and activation of human DC.

Key Words: antigen presenting cells • gram-positive bacteria • cell-wall antigens


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INTRODUCTION
 
Dendritic cells (DC) capture and process invading microbes and present their antigens to lymphocytes. Thus, DC are of fundamental importance in the induction of antigen-specific immune responses. In an immature state, DC (iDC) are highly endocytic, enabling them to maximize their capacity to capture antigen [1 ]. In response to danger signals, such as microbial components, or host factors, such as proinflammatory cytokines, DC become mature, resulting in an attenuated ability to capture antigen [2 ]. Also, there is a shift toward presentation of antigenic epitopes and an up-regulation of MHC proteins and costimulatory molecules, including CD80, CD83, and CD86 [3 ]. DEC-205 (CD205) and CD206 expressed on DC are mainly involved in the antigen-uptake process [4 ]. During maturation, DEC-205 is known to be up-regulated [5 ], and CD206 is down-regulated [3 ]. These changes represent functional and molecular indications of DC maturation.

LPS, expressed on the gram-negative bacterial cell wall, has the best-characterized signaling pathway among bacterial components, which trigger DC maturation. LPS stimulates TLR4, resulting in the release of various proinflammatory cytokines [6 ], and is capable of causing sepsis in animal models [7 ]. Gram-positive bacteria express lipoteichoic acid (LTA) rather than LPS on the cell wall. Previous reports suggest that LTA acts as a LPS counterpart in gram-positive bacteria, inducing the activation of the innate immune system [8 ]. Conversely, LTA differs from LPS, as LTA stimulates TLR2 but not TLR4 [9 ]; LTA requires a platelet-activating factor receptor together with TLR2 for the induction of inducible NO synthase (iNOS), while TLR4 activation is sufficient for LPS-induced iNOS induction [10 ]; and LTA is unable to induce multiorgan failure and septic shock in the absence of peptidoglycan (PGN), which is abundant in gram-positive bacteria [11 ]. Therefore, it is critical to investigate immune responses to LTA together with PGN for better understanding inflammatory responses and sepsis induced by gram-positive bacteria.

PGN is a common structural component of the bacterial cell wall, and gram-positive bacteria express more PGN than gram-negative bacteria. Although the role of PGN is important in inducing immune responses to gram-positive bacteria, its signaling pathway is under debate because of improper purification [12 , 13 ]. Initially, PGN was suggested to activate TLR2 [14 , 15 ]. However, it was reported that impurities such as LTA or lipoproteins in the PGN preparation contribute to TLR2 activation, and highly purified PGN does not affect TLR2 [12 ]. Thus, it has been difficult to study the genuine mechanism responsible for gram-positive bacterial sepsis as a result of technical difficulties with PGN purification. Instead, muramyl dipeptide (MDP) has been used in a number of previous studies, as MDP is the common structural unit of PGN expressed in all the bacterial cell wall [16 ]; MDP is the minimal structure that sustains induction of PGN-mediated immune responses [17 ]; MDP is chemically synthesized and thus, unlikely to be contaminated with microbial products containing potent immunomodulating activity [18 ]; and its signaling pathway has been well characterized [16 , 19 ]. In the present study, we investigated the ability of LTA together with MDP to induce the maturation of DC derived from human peripheral blood monocytes by monitoring expression of indicative, costimulatory molecules, endocytic capacity, and secretion of the proinflammatory cytokines TNF-{alpha} and IL-12 and the anti-inflammatory cytokine IL-10.


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MATERIALS AND METHODS
 
Reagents and chemicals
Highly purified, structurally intact LTA was prepared from Staphylococcus aureus [American Type Culture Collection (ATCC), Manassas, VA, USA, ATCC 6538] by butanol extraction, octyl-Sepharose CL-4B, and DEAE-Sepharose column chromatography as described previously [20 ]. MDP was purchased from Sigma Chemical Co. (St. Louis, MO, USA). Antibodies used for flow cytometric analysis were purchased from BD Biosciences (San Diego, CA, USA) unless otherwise stated.

Human monocyte-derived DC
PBMC were obtained by isolating the buffy coat with density gradient centrifugation using Ficoll-Paque Plus (Amersham Bioscience, Brown Deer, WI, USA) from heparinized human blood. Monocytes were isolated from the PBMC using the IMagTM antihuman CD14 antibody, a magnetic bead-based, positive selection kit (BD Bioscience). This procedure routinely resulted in >90% pure, CD14-positive cells, determined by flow cytometry. Monocytes were suspended in RPMI-1640 Glutamax medium, supplemented with 10% FBS, 1 mM sodium pyruvate, 100 U/ml penicillin, and 100 µg/ml streptomycin. To generate iDC, CD14-positive cells were cultured with IL-4 (500 U/ml, R&D Systems, Minneapolis, MN, USA) and GM-CSF (800 U/ml, R&D Systems) for 6 days with changes of media every 3 days. The iDC were stimulated as indicated for 48 h in the presence of IL-4 (500 U/ml) and GM-CSF (800 U/ml).

Dextran-FITC uptake assay
Endocytic activity of DC was measured by the uptake of Dextran (m.w. 40,000) conjugated with FITC (Dextran-FITC, Molecular Probes, Eugene, OR, USA). Briefly, DC were suspended in RPMI 1640 supplemented with 10% FBS and 25 mM HEPES, pH 7.4, and incubated with 1 mg/ml Dextran-FITC for 1 h at 4°C to measure nonspecific binding or at 37°C to measure specific uptake. Cells were then washed extensively with ice-cold PBS, 0.1% BSA, and 0.01% NaN3 and labeled on ice with appropriate antibodies. The actual uptake was determined as the mean fluorescence intensity (MFI) of cells incubated at 37°C minus the MFI of cells incubated at 4°C.

Flow cytometric analysis
For immunophenotypic analysis of stimulated DC, the following mAb were used: PE-conjugated, antihuman CD80 (Clone L307.4), allophycocyanin-conjugated, antihuman CD83 (Clone HB15e), FITC-conjugated, antihuman CD86 [Clone 2331 (FUN-1)], PE-Cy5-conjugated, anti-HLA-A, -B, -C (Clone G46-2.6) for MHC Class I, PE-Cy5-conjugated, anti-HLA-DR (Clone G46-6) for MHC Class II, R-PE-conjugated, antihuman CD206 (Clone 19.2), and FITC-conjugated, antihuman DEC-205 (Clone MG38, eBioscience, San Diego, CA, USA). After staining with antibodies for 20 min on ice, DC were washed, and changes in cell surface marker expression were measured using a FACSCalibur with CellQuest software (BD Biosciences). All flow cytometric data were analyzed by using FlowJo software (Tree Star, San Carlos, CA, USA).

ELISA
iDC were stimulated with various stimuli, as indicated for 48 h in the presence of IL-4 (500 U/ml) and GM-CSF (800 U/ml). The amounts of TNF-{alpha}, IL-12 p40, and IL-10 in the culture supernatant were determined using commercial ELISA kits (DuoSet, R&D Systems), according to the manufacturer’s protocol.


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RESULTS
 
Staphylococcal LTA (StLTA) and MDP synergistically induce DC maturation
It is well known that Escherichia coli LPS induces the maturation of DC and changes in cell surface marker expression, for instance, increasing costimulatory molecules CD80, CD83, and CD86 [3 ]. iDC stimulated with StLTA (1 or 10 µg/ml) or MDP (0.1 or 1 µg/ml) alone showed little or no change in the expression of such markers (Fig. 1 ). However, there was a synergistic expression of these costimulatory molecules when iDC were stimulated with StLTA and MDP together. Indeed, costimulation of iDC with 1 µg/ml MDP and 10 µg/ml StLTA induced expression of CD80, CD83, and CD86 as strongly as the positive control treated with 0.1 µg/ml E. coli LPS. Treatment of the iDC with polymyxin B at 50 µg/ml inhibited the expression of CD80, CD83, and CD86 induced by LPS but not by LTA plus MDP under the same condition (data not shown).


Figure 1
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  		Figure 1. Expression of the costimulatory molecules CD80, CD83, and CD86 on DC stimulated with StLTA and/or MDP. iDC were stimulated with StLTA (1 or 10 µg/ml) and/or MDP (0.1 or 1 µg/ml) for 48 h and analyzed by flow cytometry after staining with antibodies to various costimulatory markers [CD86 (B), CD80 (C), and CD83 (D)]. E. coli LPS as a positive control (A) was used at 0.1 µg/ml. Shaded and open areas indicate expression of the costimulatory receptors on DC before and after stimulation, respectively. MFI is shown in the upper right in each histogram [MFI before stimulation/MFI after stimulation (A) or MFI of the open areas, except MFI of the shaded area in the unstimulated control (B–D)]. This is a representative of four independent experiments with similar results.

Maturation of iDC induced by StLTA and MDP coincides with increased expression of MHC Class II
Expression of MHC molecules on the APC such as DC is essential for T lymphocyte stimulation, as MHC Classes I and II molecules are involved in the presentation of endogenous and exogenous antigens, respectively [21 ]. We examined whether stimulation of iDC with StLTA and MDP influences the expression of MHC molecules. When maturation of DC was induced with LPS, expressions of MHC Classes I and II were increased dramatically (e.g., MFI of MHC Class I was shifted positively from 217 to 575 and MHC Class II, from 173 to 510; Fig. 2 ). However, stimulation with StLTA and MDP together increased MHC Class II but not MHC Class I (Fig. 2) .


Figure 2
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  		Figure 2. Expression of MHC Classes I and II in DC stimulated with MDP and/or StLTA. iDC were stimulated with StLTA (10 µg/ml) and/or MDP (1 µg/ml) for 48 h and analyzed by flow cytometry after staining with anti-MHC Classes I or II antibodies. Shaded and open areas indicate expression of each receptor on DC before and after stimulation, respectively. MFI is shown in the upper left in each histogram (MFI before stimulation/MFI after stimulation). One of the three similar results is shown.

Endocytic activity of DC stimulated with StLTA and MDP
iDC were stimulated with StLTA and/or MDP for 48 h, and their ability to take up Dextran-FITC was assessed. Dextran-FITC uptake by unstimulated iDC at 37°C was significantlyhigher (MFI=51) than the nonspecific control (MFI=11; Fig. 3 ). However, in iDC stimulated with E. coli LPS, there was no difference compared with the nonspecific control. It is intriguing that treatment of DC with MDP and StLTA together induced the maturation of DC and that Dextran-FITC uptake diminished in proportion to the dose of MDP and StLTA (Fig. 3) . It is notable that no decrease in Dextran-FITC uptake was observed when the iDC were treated with MDP or StLTA alone (data not shown).


Figure 3
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  		Figure 3. Dextran-FITC uptake by DC after stimulation with MDP and StLTA. iDC were stimulated with StLTA plus MDP at the indicated concentrations for 48 h and incubated with Dextran-FITC (1 mg/ml) for 1 h at 4°C (shaded area) or 37°C (open area). Dextran-FITC uptake at 37°C was measured using flow cytometry and compared with that at 4°C. MFI is shown in the upper right in each histogram (MFI at 4°C/MFI at 37°C). This result is a representative of three separate experiments.

Expression of DEC-205 increased and CD206 decreased on DC matured by costimulation with StLTA and MDP
DEC-205 and CD206 are related to DC maturation and endocytic activity. During maturation, DEC-205 is known to be up-regulated [5 ], and CD206 is down-regulated [3 ]. Indeed, low expression of DEC-205 was observed in iDC; however, the expression increased markedly after stimulation with MDP and StLTA together (Fig. 4 ). The expression was as strong as when DC were treated with a positive control E. coli LPS, indicating that DEC-205 is an activation-associated antigen. In contrast to DEC-205, the expression of CD206 was decreased after costimulation with StLTA and MDP (Fig. 4) .


Figure 4
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  		Figure 4. Changes in expression of DEC-205 and CD206 on DC stimulated with MDP and/or StLTA. iDC were stimulated with StLTA (10 µg/ml) and/or MDP (1 µg/ml) for 48 h, stained with anti-DEC-205 or anti-CD206 antibodies, and analyzed by flow cytometry. Shaded and open areas indicate expression of DEC-205 (upper panel) and CD206 (lower panel) on DC before and after stimulation, respectively. MFI is shown in the upper right in each histogram (MFI before stimulation/MFI after stimulation). This result is one of the three similar results.

Changes in cytokine production during maturation of DC costimulated with StLTA and MDP
To investigate the profile of cytokine production by DC after stimulation with StLTA and MDP, iDC were stimulated with StLTA and/or MDP, and levels of the proinflammatory cytokines TNF-{alpha} and IL-12 p40 and an anti-inflammatory cytokine IL-10 in the culture supernatant were measured. As shown in Figure 5 , TNF-{alpha} and IL-12 p40 were synergistically induced when DC were stimulated with 10 µg/ml StLTA and 1 µg/ml MDP together. In contrast, no significant changes in IL-10 or IL-12 p70 expression were observed (data not shown).


Figure 5
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  		Figure 5. Production of proinflammatory cytokines by DC stimulated with MDP and/or StLTA. iDC were stimulated with StLTA at 0 (open bar), 1 (hatched bar), or 10 µg/ml (solid bar) and MDP (0, 0.1, or 1 µg/ml) for 48 h, and the culture supernatants were analyzed to determine the concentration of TNF-{alpha} (A) and IL-12 p40 (B) using ELISA. The data shown are representative of three independent experiments with similar results.


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DISCUSSION
 
The incidence of severe inflammation and septic shock caused by gram-positive bacteria has increased markedly for the last few years [22 ]. Thus, it has become more important to clarify the mechanism responsible for the gram-positive bacterial sepsis and to further develop preventives or therapeutics against it. Here, we show that upon exposure to StLTA plus MDP, human monocyte-derived DC express increased levels of the costimulatory molecules CD80, CD83, and CD86 and MHC Class II. Concomitantly, endocytic activity was attenuated at maturation, and the expression of DEC-205 was up-regulated, and CD206 expression was down-regulated. Furthermore, secretion of several proinflammatory cytokines was increased markedly after costimulation with StLTA and MDP, and an anti-inflammatory cytokine was not. Therefore, our data suggest that DC maturation and comparable expression of proinflammatory cytokines are induced synergistically by StLTA plus MDP.

Upon stimulation of DC with LPS, expression of MHC Classes I and II was augmented. In contrast, costimulation of the DC with StLTA and MDP induced expression of MHC Class II but not MHC Class I. This implies that DC maturation by StLTA (a TLR2 ligand) plus MDP [a nucleotide-binding oligomerization domain 2 (NOD2) ligand] and by LPS (a TLR4 ligand) might be regulated by distinct mechanisms. Our results show that stimulation of DC with StLTA plus MDP has great potential to provide a good experimental model when selective up-regulation of MHC Class II is needed. Although cross-presentation has been suggested and demonstrated experimentally [21 ], it is probable that DC matured with gram-positive bacterial cell wall components would be more efficient in the elimination of extracellular pathogens such as S. aureus and Streptococcus pneumoniae, as LTA and MDP preferentially augment the expression of MHC Class II.

When DC maturation is induced by cotreatment with StLTA plus MDP, it was observed that the expression of proinflammatory cytokines TNF-{alpha} and IL-12 p40 was augmented, with no change in the level of the anti-inflammatory cytokine IL-10. Several mechanisms for the maturation of DC by costimulation with StLTA and MDP can be hypothesized. First, StLTA and MDP could induce DC maturation directly via their respective receptors, TLR2 and NOD2, with subsequent activation of signaling pathways sufficient for the initiation of DC maturation. Involvement of the receptors for bacterial antigens has been reported, and mouse DC maturation by LTA is impaired in TLR2-deficient mice [23 ], and LPS activation of human DC is CD14-dependent [24 ]. Second, StLTA plus MDP induces production of proinflammatory cytokines, and these cytokines may then activate their cognate receptors leading to the induction of maturation and attenuation of endocytic activity of DC. Indeed, previous reports show that inflammatory cytokines such as TNF-{alpha}, IL-1ß, and Type I IFNs (IFN-{alpha} or IFN-ß) positively influence the activation of DC indirectly [3 , 25 , 26 ]. However, inflammatory mediators seem to be insufficient for full DC activation, as these are capable of promoting expansion of only CD4+ T cell populations [27 ]. Finally, StLTA plus MDP may induce DC maturation directly at an early stage, concomitantly with the production of proinflammatory cytokines, which subsequently facilitate DC maturation at a later stage.

We found that IL-12 p40, but not IL-12 p70, was detected in the culture supernatants of DC stimulated by StLTA and MDP. It is interesting to speculate why this costimulation induces p40 selectively but not p70, although these two cytokines are structurally similar (p70 is composed of p40 and p35 subunits) [28 ]. In fact, TLR2 stimulation by LTA is likely to favor the induction of Th2 immune responses. TLR2 stimulation failed to induce IL-12 p70 but resulted in induction of the IL-12 p40 homodimer, which potentially inhibits the function of IL-12 p70, thereby inducing Th2 immunity [29 ]. In contrast, it has also been reported that the TLR4 agonist, such as LPS, promoted the Th1-inducing cytokine IL-12 p70 [29 ]. Moreover, NOD stimulation by MDP and its derivatives is likely to have a similar bias toward Th2 immunity [30 ]. Human DC stimulated with PGN fragments, including MDP, MurNAc-L-Ala-D-Glu-L-Lys, or MurNAc-L-Ala-D-isoGln, produce IL-12 p40 but not IL-12 p70 [31 ]. Thus, it would be natural that DC stimulation with LTA and MDP favors the production of IL-12 p40, instead of IL-12 p70, possibly leading to Th2 immune responses. In light of the fact that PGN and LTA are representative cell-wall antigens of gram-positive bacteria with potent immunostimulating activities, our results support the idea that gram-positive bacteria preferentially induce IL-12 p40, not the functionally active form of IL-12 p70, leading to polarization into Th2 immune responses.

Unlike gram-negative bacterial sepsis, the mechanism for the sepsis by gram-positive bacteria has been ambiguous, as gram-positive bacteria do not express LPS, which is identified as the only causative agent of sepsis so far; endotoxin is not always found in serum of patients with septic shock [32 , 33 ]; gram-positive bacteria can cause septic shock without inducing endotoxemia [34 , 35 ]; and LTA, which is the LPS counterpart in gram-positive bacteria, is incapable of causing sepsis in the absence of other stimuli such as PGN [11 ]. Indeed, no sign of sepsis was found in mice given even several hundred micrograms of purified LTA i.p. (unpublished data). Injection (i.v.) of LTA at 3 mg/kg or PGN at 10 mg/kg alone did not cause a significant increase in the plasma levels of IFN-{gamma}, urea, creatine, or transaminases, all of which are indicators of multiorgan failure [36 ]. There is no doubt that LTA and PGN are required for understating host responses to gram-positive bacterial infection.

Although LTA alone is unable to induce symptoms of sepsis, LTA rather than PGN is likely to determine the induction of gram-positive bacterial sepsis. In the presence of PGN from S. aureus or nonvirulent Bacillus subtilis, LTA from sepsis-causing bacteria, S. aureus showed the characteristics of sepsis syndrome, namely, induction of iNOS gene expression and proinflammatory cytokines and multiorgan failure [37 ]. In contrast, LTA from nonvirulent bacteria B. subtilis did not show the aforementioned phenomena in the presence of PGNs regardless of their source strains [37 ]. Therefore, our results, showing that StLTA plus MDP (shared structural unit of most PGNs) synergistically induce DC maturation and concomitant production of proinflammatory cytokines, provide potential clues to understand mechanisms of innate immunity, including inflammatory responses, and sepsis caused by gram-positive bacteria.


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ACKNOWLEDGEMENTS
 
This work was supported by a grant of the Seoul Research and Business Development Program (10548) and by Biogreen 21 program (2005 04 01034696), Rural Development Administration, Republic of Korea.

Received September 25, 2006; revised November 20, 2006; accepted December 4, 2006.


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