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Published online before print February 13, 2004
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Department of Microbiology, National Public Health Institute, Helsinki, Finland
1 Correspondence: Department of Microbiology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail: ville.veckman{at}ktl.fi
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: gram-positive bacteria • IL-2 • IL-23 • IL-27
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The type of maturation stimulus as well as cytokines and chemokines produced by the DCs dictates whether adaptive immune response is directed toward T helper cell type 1 (Th1), Th2, or tolerance. Interleukin (IL)-12 is an important Th1 skewing cytokine, which is composed of p35 and p40 subunits. Recently, two new IL-12 cytokine family members have been described. IL-23 is a heterodimer of p19 and p40 subunits, and it induces the proliferation of memory T cells [3 ]. IL-27 consists of p28 and EBI3 subunits, and it induces the proliferation of naïve T cells [4 ]. Currently, little data exist about the ability of bacteria to induce the expression of IL-23 or IL-27. Another key cytokine of the adaptive immune response is IL-2, which induces the proliferation of T and natural killer (NK) cells. Previously, it has been thought that IL-2 is only produced by lymphocytes. However, recent reports indicate that DCs are also able to produce IL-2 in response to microbial stimulation [5 , 6 ].
Streptococcus pyogenes or group A streptococcus is a human pathogen causing, e.g., erysipelas, myositis, and skin infections [7 ]. S. pyogenes produces several exoenzymes and exotoxins, which promote the pathogenesis of the bacteria [8 ]. Some of the streptococcal exotoxins are potent superantigens that induce spontaneous T cell activation, which can lead to streptococcal toxic shock syndrome [7 ]. We and others have reported that S. pyogenes induces Th1-type immune response in monocytes, macrophages, and streptococci-infected tissues [9 10 11 ].
Lactobacillus rhamnosus GG is a nonpathogenic lactic acid bacterium, which is widely used in various probiotic products. There is in vitro and in vivo evidence that probiotic bacteria, especially L. rhamnosus, have immunostimulatory effects. In vivo effects include reduced susceptibility to atopy or allergy after administration of probiotic products [12 , 13 ]. In addition, it has been shown that probiotic bacteria reduce inflammatory responses in milk-hypersensitive subjects [14 ]. The reduced susceptibility to atopy and allergy could result from the ability of probiotic bacteria to modulate immune response from Th2 to Th1 [13 ]. Despite these findings, the molecular mechanisms behind the immunostimulatory effects of probiotic bacteria have been poorly characterized. As DCs have a major role in regulating innate and adaptive immune responses, the proposed immunostimulatory effects of probiotic bacteria could result from an interplay between DCs and the bacteria. Currently, there are only few published observations about the interactions between lactic acid bacteria and DCs [15 , 16 ].
In the present work, we have compared the ability of two Gram-positive bacteria, pathogenic S. pyogenes and nonpathogenic L. rhamnosus, to induce DC maturation, which was characterized by analyzing the expression of DC costimulatory molecules, cytokine, and chemokine production and DC endocytotic activity in response to bacterial stimulation. Our results indicate that S. pyogenes is a more potent stimulator of DC maturation than L. rhamnosus. Although S. pyogenes induced a Th1-type response, stimulation of DCs with L. rhamnosus resulted in a weak cytokine and chemokine response and only moderate expression of costimulatory molecules.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DC purification
Monocytes were purified from freshly collected, leukocyte-rich buffy coats obtained from healthy blood donors (Finnish Red Cross Blood Transfusion Service, Helsinki). Human peripheral blood mononuclear cells were isolated by a density gradient centrifugation over Ficoll-Paque gradient (Amersham-Pharmacia Biotech, Uppsala, Sweden) as described previously [19
]. Mononuclear cells were collected, and monocytes were further purified by centrifugation over Percoll gradient (Amersham-Pharmacia Biotech). Percoll gradients of 34%, 47.5%, and 60% (v/v) were made by mixing Percoll with RPMI-1640 medium (Sigma Chemical Co., St. Louis, MO) supplemented with 0.6 µg/ml penicillin, 60 µg/ml streptomycin, 2 mM L-glutamine, 20 mM HEPES, and 10% fetal calf serum (FCS; Integro BV, Dieren, The Netherlands). Mononuclear cells were suspended to 34% Percoll solution, and the three Percoll layers were mixed. Cells were centrifuged at 1700 g for 35 min, and the top layer containing monocytes was collected. Next, cells were washed twice with serum-free RPMI-1640 medium with supplements as above, and the remaining T or B cells were depleted by using anti-CD3 and anti-CD19 magnetic beads (Dynal, Oslo, Norway). After beading, cells were washed once with RPMI-1640 medium and counted. Monocytes were allowed to adhere to plastic six-well plates (Falcon, Becton Dickinson, Franklin Lakes, NJ) for 1 h at 37°C in RPMI-1640 medium without FCS (2.5x106 cells/well). After incubation, nonadherent cells were removed, and the wells were washed with phosphate-buffered saline (PBS). Monocytes were allowed to differentiate to immature DCs for 6 days in RPMI 1640 with the same supplements as mentioned plus 10% FCS, 10 ng/ml recombinant human (rh) granulocyte macrophage-colony stimulating factor (Leucomax, Schering-Plough, Innishannon, Ireland), and 20 ng/ml rhIL-4 (R&D Biosystems, Abingdon, UK). Fresh media (1 ml/well) was added every 2 days. Cultured cells were CD1asemi, CD14–, CD80low, CD83–, and CD86semi, and they showed a typical DC morphology (data not shown).
Stimulation experiments
To minimize inter-individual variation, all experiments were performed with cells obtained from three to four donors. Stimulation experiments were conducted in RPMI-1640 medium containing 10% FCS. The optimal stimulation dose of S. pyogenes and L. rhamnosus was determined to be 5:1 bacteria:DC ratio (see Fig. 1
). In certain experiments, bacteria were heat-inactivated by boiling for 15 min. After stimulation, cells and cell-culture supernatants were collected and pooled. Cells were used for isolation of total cellular RNA or for flow cytometric analysis [fluorescein-activated cell sorter (FACS)]. Supernatants were stored at –20°C and used for cytokine and chemokine quantification by enzyme-linked immunosorbent assay (ELISA).
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-32P]deoxy-adenosine 5'-triphosphate (3000 Ci/mmol; Amersham-Pharmacia Biotech) using a random-primed DNA-labeling kit. Hybridizations were performed in Ultrahyb buffer (Ambion, Austin, TX). After hybridization, membranes were washed three times with 1x saline sodium citrate/0.1% sodium dodecyl sulfate at 42°C for 30 min and once at 65°C for 30 min. Membranes were exposed to Kodak X-Omat AR films (Eastman Kodak, Rochester, NY) at –70°C with intensifying screens.
Cytokine- and chemokine-specific ELISAs
Cytokine and chemokine levels from cell-culture supernatants were analyzed by the sandwich-ELISA method as described previously [10
]. Tumor necrosis factor (TNF-), chemokine ligand 5 (CCL5)/regulated on activation, normal T expressed and secreted, CXC ligand 9 (CXCL9)/monokine induced by interferon-
(IFN-), and CXCL10/IFN-inducible protein 10 levels were determined with antibody pairs and standards obtained from BD PharMingen (San Diego, CA). IL-2, CCL19/macrophage-inflammatory protein-3ß (MIP-3ß), and CCL20/MIP-3 levels were determined with a Duoset kit (R&D Biosystems) and IL-12 p70 levels with an IL-12 Elipair kit (BioSite, Täby, Sweden).
Flow cytometry (FACS)
For FACS analysis, the cells from three to four blood donors were pooled after stimulation experiments. Cells were washed once with cold PBS, and nonspecific binding of antibodies was prevented by incubating cells with 2% FCS in PBS for 15 min. The expression of costimulatory molecules was analyzed by staining DCs with fluorescein isothiocyanate (FITC)-conjugated anti-CD80, anti-CD83, and anti-CD86 antibodies (Caltag Laboratories, Burlingame, CA). Respective FITC-conjugated mouse isotype controls were used. Cells were stained on ice for 35 min, washed twice with PBS + 2% FCS, and fixed with 3% paraformaldehyde for 15 min. Next, the cells were washed and suspended into PBS + 2% FCS. Cells were analyzed with FACScan using Cellquest software (Becton Dickinson).
FITC–dextran uptake
DC endocytotic activity was analyzed by a FITC–dextran uptake method [25
]. After stimulation, DCs were incubated for 2 h with 1 mg/ml FITC–dextran FD-40S (Sigma Chemical Co.). Next, DCs were collected, washed three times with PBS, and fixed with 3% paraformaldehyde for 15 min. FITC–dextran uptake was analyzed by flow cytometry as described above.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Streptococci- and Lactobacilli-induced cytokine and chemokine production
DC maturation is accompanied by the production of TNF-, CCL19, and CCL20 [1
, 2
]. Furthermore, the two latter chemokines characterize DC maturation stage, as CCL20 and CCL19 are produced by DCs at early and at late maturation stages, respectively. We were also interested in the ability of Gram-positive bacteria to induce the production of IL-2, IL-12, CXCL9, and CXCL10, the key factors involved in proliferation, polarization, and chemotaxis of Th1 cells [26
, 27
]. To characterize the kinetics of bacteria-induced cytokine and chemokine production, DCs were stimulated with L. rhamnosus or S. pyogenes at a 5:1 bacteria:DC ratio. Cell-culture supernatants were collected at different time-points, and cytokine and chemokine levels were determined by ELISA.
In S. pyogenes-stimulated DCs, TNF-, IL-2, CXCL10, and CCL20 production was detectable at 6 h, and IL-12, CCL5, CCL19, and CXCL9 production was measurable at 12 h after stimulation (Fig. 2
). The production of all the cytokines and chemokines analyzed increased toward 24 h. In contrast to S. pyogenes, L. rhamnosus stimulation resulted in a detectable production of only TNF- and CCL20 (Fig. 2)
. Moreover, L. rhamnosus-induced production of these cytokines and chemokines was very low compared with S. pyogenes-stimulated DCs.
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Stimulation of DCs with S. pyogenes resulted in enhanced mRNA expression of CD83 and CCL20 genes at 6 h after stimulation, and CD80, CD86, and CCL19 mRNA expression was enhanced after 12 h stimulation (Fig. 3 ). The mRNA expression of costimulatory molecules and of CCL20 remained elevated up to 48 h, whereas CCL19 mRNA expression peaked at 24 h and was down-regulated at 48 h.
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Bacteria-induced mRNA expression of IL-2, IL-12, IL-23, and IL-27
Recent reports indicate that DCs are able to produce several important T cell-modulating cytokines. These include IL-2, IL-12, and the two novel IL-12 cytokine family members IL-23 and IL-27 [3
4
5
]. Currently, there are no data concerning the ability of Gram-positive bacteria to induce the production of IL-2, IL-23, or IL-27 in human monocyte-derived DCs. Thus, we performed a Northern blot analysis.
Stimulation of DCs with S. pyogenes resulted in enhanced IL-2 mRNA expression already after 3 h stimulation (Fig. 4A ). S. pyogenes-induced IL-2 mRNA expression peaked at 6 and 12 h and was down-regulated at 24 h. No IL-2 mRNA expression was detected in unstimulated or L. rhamnosus-stimulated DCs.
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Effect of heat inactivation on bacteria-induced DC maturation
Our results showed a difference between live, nonpathogenic L. rhamnosus and pathogenic S. pyogenes in their ability to induce DC maturation. To analyze whether these differences were related to metabolic activity of the bacterium, i.e., to the production of extracellular compounds as has been shown for S. pyogenes [7
, 8
], we performed experiments with heat-inactivated bacteria and studied their effect on DC maturation. DCs were stimulated with live or heat-inactivated L. rhamnosus or S. pyogenes at a 5:1 bacteria:DC ratio for 24 h. After stimulation, the expression of costimulatory molecules, cytokine, and chemokine production and the degree of DC endocytosis were analyzed.
L. rhamnosus-induced expressions of CD83 and CD86 were reduced by 62% and 33% by heat inactivation, respectively. The corresponding figures for S. pyogenes were 67% and 56% (Fig. 5A ). L. rhamnosus- or S. pyogenes-induced increase in CD80 expression was low (Figs. 1 and 5A) , but heat inactivation of bacteria completely prevented this enhanced CD80 expression (Fig. 5A) .
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, IL-2, IL-12, CCL5, CXCL9, and CXCL10 were reduced in response to heat-inactivated S. pyogenes. The amounts produced in response to heat-inactivated S. pyogenes were similar to those induced by live L. rhamnosus (Fig. 5B)
.
After antigen uptake, the endocytotic capacity of DCs gradually decreases [2
]. Thus, the degree of endocytotic activity can be considered as a marker for DC maturation. To analyze the effect of L. rhamnosus or S. pyogenes stimulation on DC endocytosis, DCs were stimulated with live or heat-inactivated bacteria for 24 h. After stimulation, DCs were incubated with FITC–dextran for 2 h, washed, and analyzed by flow cytometry. Stimulation of DCs with live or heat-inactivated L. rhamnosus reduced DC endocytosis by 20% compared with unstimulated, immature DCs (Fig. 5C)
. When DCs were stimulated with live S. pyogenes, DC endocytosis was 
55% lower than in unstimulated DCs. Heat-inactivated S. pyogenes reduced DC endocytosis by 40%. The difference in DC endocytosis between live and heat-inactivated S. pyogenes was, however, not statistically significant.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, IL-2, IL-12, CCL5, CCL19, CCL20, CXCL9, and CXCL10. S. pyogenes also induced the mRNA expression of the recently identified cytokines IL-23 and IL-27. In contrast to S. pyogenes, interaction of L. rhamnosus with DCs resulted in only a moderate up-regulation of costimulatory molecules and a very low production of TNF- and CCL20. S. pyogenes stimulation induced a rapid and strong IL-2 production at mRNA and protein level. Transient IL-2 production has previously been described in murine DCs stimulated with Escherichia coli, yeast, or microbial components [5 , 6 ]. DC-produced IL-2 has been shown to be important in enhancing T cell proliferation [5 ], and it has been speculated that DC-derived IL-2 could play a role in activating NK cells in the early phases of immune response [28 ]. Our results show that in addition to murine DCs, human monocyte-derived DCs are able to produce IL-2 in response to Gram-positive bacteria. However, significant differences between different bacterial species exist, as in contrast to S. pyogenes, no IL-2 was detected at mRNA or protein level in L. rhamnosus-stimulated DCs. The difference in the ability of S. pyogenes and L. rhamnosus to induce IL-2 production could result from a different ability to induce the activation of transcription factors. IL-2 gene expression has been studied thoroughly in T cells, where nuclear factor of activated T cells (NFAT) and activator protein-1 (AP-1) transcription factors have been shown to be crucial for IL-2 gene expression [29 , 30 ]. As Cyclosporin A, a selective NFAT inhibitor, reduces IL-2 expression in DCs (ref. [6 ] and data not shown), it is likely that NFAT transcription factors, most likely in concert with AP-1, regulate IL-2 gene expression in DCs as well. However, further studies are required to characterize the regulation of IL-2 production in DCs.
IL-12 has long been known to be an important cytokine in skewing T cell differentiation toward Th1 type. Recently, two other IL-12-related cytokines, designated IL-23 and IL-27, were described. The biological roles of IL-12, IL-23, and IL-27 are distinct but overlapping. IL-27 induces the proliferation of naïve T cells, and IL-23 has been shown to activate memory T cells [3 , 4 ]. It is currently known that human and murine DCs produce IL-23 and IL-27 in response to lipopolysaccharide challenge [3 , 4 ]. However, no data on the ability of Gram-positive bacteria to induce IL-23 or IL-27 exist. As in the case of IL-2 production, we found that only S. pyogenes was able to induce efficient mRNA expression of IL-12, IL-23, and IL-27 subunits in human monocyte-derived DCs. From the mRNA expression data, it could be interpreted that IL-12 and IL-27 are produced relatively early during S. pyogenes infection, and IL-23 is produced at later phases. Our results suggest that S. pyogenes-stimulated DCs may efficiently activate naïve and memory T cells. S. pyogenes was also able to induce CXCL9 and CXCL10 production in DCs. These chemokines attract NK cells and Th1-polarized T cells, as both of these cell types express the chemokine receptor CXCR3 [27 , 31 , 32 ]. Thus, S. pyogenes-infected DCs are likely to recruit these cell types to the site of inflammation. As S. pyogenes-stimulated DCs also produce IL-2, IL-12, IL-23, and IL-27, it could be speculated that in vivo, these DCs create a cytokine milieu that polarizes adaptive immune response toward Th1 type.
We have previously shown that stimulation of human mononuclear cells or macrophages with L. rhamnosus results in efficient cytokine and chemokine response. In these cells, L. rhamnosus induces the production of TNF-, IL-12, IL-18, IFN-/ß, and Th1-attracting chemokines CCL2 and CXCL10 [10
, 11
, 33
]. As an indication of L. rhamnosus-induced DC maturation, we detected some enhancement of CD83 and CD86 expression and reduction of DC endocytosis. However, the L. rhamnosus-induced cytokine and chemokine response in DCs was low. Only TNF- and CCL20 were detected, and the production levels were significantly lower than in S. pyogenes-stimulated DCs. These results are in line with recent observations by Christensen et al. and Braat et al. [15
, 16
]. In addition, we observed that L. rhamnosus was unable to induce the expression of IL-2, IL-12, IL-23, or IL-27. This most likely decreases the potency of L. rhamnosus-stimulated DCs to activate and polarize T cells.
Heat inactivation almost completely abolished the S. pyogenes-induced cytokine and chemokine production. The difference between live and heat-inactivated bacteria in the ability to induce expression of DC costimulatory molecules was less dramatic. Moreover, the endocytotic activity of DCs was similarly reduced in response to live and heat-inactivated bacteria. Thus, live and heat-inactivated bacteria induced functional maturation of DCs but showed different ability to induce cytokine and chemokine gene expression. These results indicate that the metabolic activity of bacteria, at least in the case of S. pyogenes, may be required for efficient cytokine and chemokine production. One possibility is that heat inactivation prevents the production of streptococcal factors such as exoenzymes or exotoxins, which could play a role in enhancing DC activation. However, further experiments are required to clarify this observation. Another possibility is that the distinct responses between live and heat-inactivated bacteria resulted from heat-induced modification of bacterial cell structures. This could affect the ability of DCs to recognize bacteria by their pattern-recognition molecules and thus, the efficiency by which transcriptional pathways are activated in DCs.
In the present study, we have shown that human monocyte-derived DCs distinguish between nonpathogenic and pathogenic Gram-positive bacteria and respond to them differently. Stimulation of DCs with L. rhamnosus leads to a moderate increase in the expression of cell-surface costimulatory molecules and to a weak cytokine and chemokine response. In contrast, S. pyogenes strongly induced DC maturation accompanied by high Th1-type cytokine and chemokine production. These different DC responses most likely result in the development of distinct adaptive immune responses as well.
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ACKNOWLEDGEMENTS |
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Received October 8, 2003; revised December 23, 2003; accepted January 8, 2004.
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