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TISSUE-SPECIFIC STEM CELLS |
aInstitut National de la Santé et de la Recherche Médicale, U 844, Montpellier, France;
bUniversité Montpellier, Unité de Formation et de Recherche de Médecine, Montpellier, France;
cCentre Hospitalier Universitaire Montpellier, Hôpital Lapeyronie, Unité Clinique d'Immuno-Rhumatologie, Montpellier, France
Key Words. Stromal cells • Tolerance/suppression/anergy • Cytokines
Correspondence: Danièle Noël, Ph.D., Institut National de la Santé et de la Recherche Médicale, U 844, Hôpital Saint-Eloi, Bât INM, 80 Avenue Augustin Fliche, F-34091 Montpellier, France. Telephone: 33 (0) 4 99 63 60 26; Fax: 33 (0) 4 99 63 60 20; e-mail: noel{at}montp.inserm.fr
Received on August 31, 2006;
accepted for publication on May 9, 2007.
First published online in STEM CELLS EXPRESS May 17, 2007.
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ABSTRACT |
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Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION |
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The precise mechanisms underlying the immunosuppressive effect of MSC still remain to be clarified. The suppression of proliferation of T cells stimulated by allogeneic lymphocytes, dendritic cells, and mitogen, such as phytohemagglutinin or concanavalin A, has been well documented (for a review, see [7]). Both inhibition via cell contact [8] as well as the activity of soluble factors were shown to be involved in this process [9, 10]. Although controversial results have been reported, more convergent data now suggest that the suppressive activity of MSC is not associated with the secretion of hepatocyte growth factor or transforming growth factor-ß1 [8, 9], and that immune suppression may rely, at least in part, on the generation of CD8+ regulatory T cells [11]. Another mechanism has also been postulated where the immunosuppressive effect of MSC is based on indoleamine 2,3-dioxygenase (IDO) activity, which leads to impaired protein synthesis by depletion of the essential amino acid tryptophan [12]. More recently, it has been reported that MSC inhibit T-cell proliferation through the induction of division arrest tolerance [13]. Another study has shown that MSC altered the cytokine secretion profile of the various cell components of the immune response to induce a more anti-inflammatory or tolerant phenotype, with an increase of interleukin (IL)-10 and IL-4 secretion and a decrease of tumor necrosis factor (TNF)-
and interferon (IFN)-
production [14]. Finally, it has been postulated that MSC may act by suppressing the differentiation of monocytes into mature dendritic cells (DC) impairing the stimulation of T cells [8, 15]. Most of these proposed mechanisms are actually not necessarily exclusive.
We have previously shown that MSC-mediated immune suppression could act via the secretion of a soluble factor induced upon stimulation [11]. The aim of this study was to identify the molecule(s) involved in this process by analyzing the gene expression profile of MSC cocultured with splenocytes using the Atlas Human Cytokine/Receptor Array. We observed that MSC secrete higher levels of IL-6 and vascular endothelial growth factor (VEGF) when cultured in mixed lymphocyte reactions (MLR) and that T-cell activation is partially restored upon anti-IL-6 neutralizing antibody addition to the cultures. Moreover, we report that IL-6 is involved in the reversion of the maturation of DC to a less mature phenotype and in the partial inhibition of bone marrow progenitors to DC. Altogether, our data suggest that IL-6 is involved in the immunoregulatory mechanism mediated by MSC.
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MATERIALS AND METHODS |
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(Invitrogen) supplemented with 10% FCS, 2 mM glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin. Murine primary cells (mMSC) were obtained from bone marrow from DBA1 mice and cultured in DMEM containing FCS, 2 mM glutamine, and 1 ng/ml basic fibroblast growth factor (bFGF) (R&D Systems Inc., Minneapolis, http://www.rndsystems.com). Human primary MSCs (hMSC) were obtained from bone marrow aspirates and expanded at low density in complete MEM supplemented with 1 ng/ml bFGF, as previously described [11]. For macroarray analysis, human MSC were cocultured for 3 days in the presence of splenocytes from DBA1 and BALB/c mice (ratio 1:1:1) in the medium used for MLR (see below). When cultures reached near confluence, cells were detached with 0.05% trypsin and 0.53 mM ethylene diamine tetraacetic acid (EDTA) and subsequently replated at the density of 1,000 cells per cm2. Human peripheral blood mononuclear cells (hPBMC) were isolated from heparinized blood by centrifugation on a Ficoll-Hypaque cushion.
Isolation of Total RNA and cDNA Hybridization
Total RNAs from four separate primary cultures of human MSC and four cocultures of MSC and splenocytes were extracted using the RNeasy mini kit (Qiagen, Hilden, Germany, http://www1.qiagen.com) according to manufacturer's instructions. Radiolabeled cDNA was prepared from each RNA sample with the Atlas array kit (Clontech, Palo Alto, CA, http://www.clontech.com) by a reverse transcription step in the presence of -[32P]dATP. The radiolabeled samples were hybridized to the Human Cytokine/Receptor Atlas Nylon cDNA Expression Array (BD Biosciences, San Diego, http://www.bdbiosciences.com). After stringent washes, membranes were scanned using a PhosphorImager (Amersham Biosciences, Piscataway, NJ, http://www.amersham.com).
Gene Array Analysis
Quantification was performed using the AtlasImage software (BD Biosciences). Data from each array were normalized by the median value to eliminate the variability due to the sample labeling or exposure duration. The normalized median was arbitrarily given the value 150. Analysis was performed using the Cluster and TreeView hierarchical clustering software developed by Eisen et al. [16]. Two filters have been used: one aimed at retaining only genes expressed above the median value and the second retaining genes for which the difference between maximum and minimum values was above twice the median value. Data were log transformed (log base 2) and genes were median centered and clustered by correlation average linkage clustering. The hierarchical clustering was visualized with TreeView.
Mixed Lymphocyte Reaction
MLR were performed using mouse splenocytes obtained as already described [11]. Stimulator splenocytes (107 cells per milliliter) were treated with 50 µg/ml mitomycin C (Sigma) at 37°C for 45 minutes followed by five extensive washes with FCS-containing RPMI 1640 medium (Invitrogen). Responder splenocytes from BALB/c mice and stimulator splenocytes from DBA/1 mice were resuspended in RPMI 1640 medium containing 10% FCS, 2 mM glutamine, 100 U/ml penicillin and 100 µg/ml streptomycin, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 20 mM HEPES, and 5 x 10–5 M 2-mercaptoethanol (Invitrogen). Splenocytes were seeded in triplicates at the concentration of 105 cells per 100 microliters per well in 96-well round bottom plates. In some experiments, responder T lymphocytes were used after purification using the Mouse T-cell Negative Isolation Kit according to the recommendations of the supplier (Dynal, Compiègne, France, http://www.invitrogen.com/dynal). MSC (5 x 104 cells unless otherwise mentioned) were added to the MLR to obtain a 300-µl final volume. The neutralizing BE-8 monoclonal antibody specific for human IL-6 [17] was a kind gift from B. Klein's team (Institut National de la Santé et de la Recherche Médicale U 475, Montpellier) and used at the concentration of 9 µg/ml. When tested, two concentrations (5 and 125 µM) of indomethacin (Sigma) were added to the wells. After 3 days of incubation, 1 µCi/well 3H-thymidine was added overnight, and thymidine incorporation was measured using a ß scintillation counter. The proliferative alloresponse, corresponding to the mean cpm of the allogeneic responder splenocytes, was attributed a 100% value. All experiments were performed in triplicates and repeated at least twice.
Cytokine Quantification by Enzyme-Linked Immunosorbent Assay
Secretion of murine IL-1ß, IL-2, IL-4, IL-6, IL-10, IFN-ß, TNF-, and VEGF was determined in culture supernatants by specific enzyme-linked immunosorbent assays (ELISAs) (BD Biosciences). Prostaglandin E2 (PGE2) was quantified using a specific ELISA (R&D Systems). Human IL-6 produced in cell supernatant was quantified using the human IL-6 ELI-PAIRS kit according to the manufacturer's recommendations (Diaclone, Besan
on, France, http://www.diaclone.com). Quantification was performed at least twice.
Indoleamine 2,3-Dioxygenase Activity Measurement
Human and C3 MSC were stimulated with IFN- (1,000 U/ml) for 48 hours in complete DMEM medium supplemented with L-tryptophan (100 µg/ml). IDO enzyme activity was measured by tryptophan-to-kynurenine conversion with photometric determination of kynurenine concentration in the supernatant as the readout as previously reported [18]. Briefly, 160 µl of cell supernatant was transferred to a 96-well culture plate, and 10 µl of 30% trichloroacetic acid was added for 30 minutes at 50°C. After centrifugation, 100 µl of supernatant was mixed to 100 µl of freshly prepared Ehrlich's solution, and absorbance was read with a microplate reader at 450 nm.
Generation of DC and Coculture with C3
The DC were obtained as previously described [11]. Briefly, DC were obtained from bone marrow progenitors after 6 days in culture with 1,000 U/ml recombinant granulocyte macrophage–colony-stimulating factor and 1,000 U/ml recombinant (r)IL-4 (R&D Systems). The maturation was induced by addition of 1 µg/ml lipopolysaccharides (LPS) (Sigma) for another day. The phenotype of DC was analyzed by flow cytometry using a FACScan cytofluorometer (BD Biosciences). When tested, MSC were added to the mature DC at the ratio 1:1 for 3 other days. Recombinant IL-6 (from 0.1–50 ng/ml) was added to the culture medium either on day 0 and every other day or on day 6. Conditioned supernatants were obtained after 48 hours of culture of C3 MSC, primary mMSC, or NIH-3T3 cells in the presence of murine splenocytes and filtration through a 22-µM porous membrane (BD Biosciences). The anti-IL-6 antibody was used at the concentration of 9 µg/ml. In some experiments, 105 mature DC (mDC) were cultured with 3 x 105 allogeneic T lymphocytes and/or 2 x 105 C3 for 3 other days in six-well plates.
Phenotypic Characterization
For flow cytometry, MSC were harvested by treatment with 0.05% trypsin and 0.53 mM EDTA and resuspended in phosphate-buffered saline containing 0.1% bovine serum albumin and 0.01% sodium azide. Cell aliquots (105 to 5 x 105 cells per 100 microliters) were incubated on ice with conjugated monoclonal antibodies against CD14, CD34, CD44, CD45, CD73, CD90, and CD105 (BD Pharmingen, San Diego, http://www.bdbiosciences.com/index_us.shtml) or conjugated isotypic controls. DC were recovered by centrifugation (300g, 5 minutes). The antibodies specific for DC (fluorescein isothiocyanate-labeled anti-major histocompatibility complex [MHC] class II and phycoerythrin [PE]-labeled anti-CD11c) and costimulatory molecules (PE-labeled anti-CD40, anti-CD80, anti-CD86) were purchased from BD Biosciences. Flow cytometry was performed on a fluorescence-activated cell sorter (FACScan) and data analyzed with the CellQuest software (BD Biosciences).
Statistical Analysis
Statistics were done with Student's t test or a nonparametric Mann-Whitney test to compare data for statistical significance. All data were analyzed by the program Instat (GraphPad, San Diego, http://www.graphpad.com).
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RESULTS |
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were upregulated (Fig. 1A). The secretion of IL-6 by human MSC was confirmed at the protein level, and IL-6 concentration was increased 10-fold when these cells were cultured in the presence of murine splenocytes or hPBMC (Fig. 1B). Similarly, low levels of IL-6 and VEGF were secreted in the culture supernatant of the murine C3 MSC line (Fig. 1C), and these levels were increased by a 10-fold factor in a MLR. To determine whether the cytokines were produced by the MSC or the immune cells present in the culture, we recovered the immune cells and kept the adherent MSC in the culture wells. After thorough washes, cells were independently cultured for another 48 hours. We observed that IL-6 was mainly produced by the C3 cells, since no significant increase was detected in the culture supernatants from splenocytes. In parallel, we found that VEGF was exclusively secreted by the MSC (Fig. 1C). No expression of the IL-2 receptor chain was observed on C3 MSC by fluorescence-activated cell sorting analysis, neither before nor after stimulation with splenocytes (data not shown). These results suggest that, in MLR, the MSC upregulate their secretion of IL-6 no matter what their species of origin, and the C3H10T1/2 cells were thus used for further experiments.
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, IFN-, and IL-2 induced by the coculture with allogeneic splenocytes was repressed when MSC were added. As we previously reported that the inhibition of T-cell proliferation was proportional to the number of MSC added in the well [11], we compared the amounts of secreted cytokines related to the number of MSC (Fig. 2B). Although IFN- levels were high in the MLR, low amounts of IFN- and high levels of IL-6 were detected when 105 C3 MSC were added (Fig. 2C). The decrease of IL-6 and VEGF was proportional to the decreasing number of MSC, whereas, in parallel, the presence of IFN- increased in the culture supernatants. Together, these data show that the secretion of immunostimulatory cytokines is inversely correlated with the presence of MSC as well as with the degree of the inhibition of the T-cell response, in contrast to that of IL-6, the production of which is strongly upregulated.
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increased upon the addition of the anti-IL-6 antibody but to lower levels than those measured in an MLR in the absence of C3 MSC, confirming that the reversion of the T-cell inhibition was only partial (Fig. 3B). The secretion of VEGF was detected only when C3 MSC were present during the MLR and in stable amounts irrespective to the addition of the antibody.
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, which reflects the proliferative activity of the T-cell population, decreased in the MLR with increasing doses of indomethacin and enhanced in the presence of MSC, concomitantly with the reversion of the immunosuppression (Fig. 4B, 4E). Altogether, these data indicate that PGE2 might be involved, at least partly, in the suppressive role mediated by MSC.
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, no IDO activity could be detected in the supernatants of C3 cells cultured for 48 hours in medium alone. Similarly, no IDO activity was measured in the supernatants of the murine MSC line BMC9 or the human MSC-like cells F-Stro1A, whereas it was clearly measured in the supernatants of primary human MSC (data not shown), confirming previous data [12]. Consistent with the absence of IDO activity upon IFN stimulation, no activity was measured when splenocytes were stimulated by concanavalin A or allogeneic splenocytes, although the addition of MSC inhibited the proliferative response. Because C3 MSC do not display any IDO activity in MLR and still are able to inhibit the T-cell response, this enzymatic activity is likely not involved in the suppressive mechanism mediated by MSC, at least in the murine MSC line tested here.
The Immunosuppressive Effect of MSC Is Associated with the Generation of Less Mature Dendritic Cells
Recent data suggest that human MSC may suppress T-cell activation and proliferation by inhibiting differentiation of monocytes into DC and by downregulating the expression of costimulatory molecules on mDC [15]. To determine whether a similar mechanism may occur with the murine counterpart, we first investigated the effect of C3 on the expression of costimulatory molecules on mDC when both cells (ratio 1:1) were cocultured for 3 days. A slight but significant and consistent downregulation of the expression of CD40 and CD86 on MHC class II positive mDC was observed under these experimental conditions in the presence of MSC (94.74 ± 1.27 vs. 78.35 ± 4.99 with MSC and 96.45 ± 2.87 vs. 87.97 ± 1.27 with MSC, respectively). No significant changes in CD14 or CD11c expression were detected (0.78 ± 0.81 vs. 2.17 ± 5.06 with C3 and 59.25 ± 28.59 vs. 50.42 ± 11.83 with C3, respectively). The results suggest that the C3 MSC downregulate the expression of costimulatory molecules on mDC. This downregulation of costimulatory molecules was associated with a less efficient stimulation of lymphocyte proliferation (data not shown).
We then wanted to determine whether IL-6 secreted by MSC may account for the lower levels of costimulatory molecules on mDC. Indeed, in humans, IL-6 has been proposed to inhibit the differentiation of monocytes to DC, rendering them functionally impaired [20, 21]. In the first step, we investigated whether various concentrations of recombinant IL-6 may have an impact on the generation of murine mDC. Indeed, the number of MHC II+/CD11c+ mDC decreases with increasing doses of IL-6 (Fig. 5A, 5B). Because the dose of 50 ng/ml IL-6 was necessary to show a significant reduction of mDC number, we used this concentration in the following experiments. We then tested the addition of rIL-6 on DC generated in vitro from murine bone marrow progenitors, either during the early stages of DC generation or during maturation. To this aim, the cytokine was added on day 0, at the beginning of the culture, or on day 6, where maturation of DC is induced by addition of LPS. As shown in Figure 5C, the addition of IL-6 during the process of maturation did not change the phenotypic profile of DC. On the contrary, when IL-6 was added during the overall period of culture, a significant reduction of the DC markers, CD11c/MHC II, together with the costimulatory molecules CD40, CD80, and CD86 was consistently observed. In parallel, the level of IL-12 secreted by control mDC reached 3,521 pg/ml, whereas it falls down to 839 pg/ml when 50 ng/ml IL-6 was added to the culture. These data suggest that IL-6 interferes with the generation of DC by reducing the expression of costimulatory molecules but has little impact on the decrease of these molecules on mDC.
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In order to determine whether primary MSC may display the same effect on DC generation as C3 MSC, we performed another similar experiment and added NIH-3T3 fibroblasts as control, since these cells are not immunosuppressive. The levels of IL-6 secreted by the primary MSC were shown to be 35.8 ± 5.3 pg/ml in basal conditions and increased by a sevenfold factor in MLR stimulated conditions. As already reported [11], we checked that the conditioned supernatant from activated primary mMSC reduced the proliferation of splenocytes in the MLR (data not shown). In addition, the conditioned supernatant from activated primary mMSC was able to decrease the percentage of CD11c+/MHC II+ DC with little impact on the percentage of costimulatory molecules (Fig. 6B). Surprisingly, control NIH-3T3 display the same effect on DC. Altogether, these results suggest that IL-6 secreted by cells from mesenchymal origin may reduce the number of mDC generated from bone marrow mononuclear cells.
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DISCUSSION |
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By gene expression analysis, we were able to discriminate the MSC samples and to separate the control samples from those that have been cocultured with allogeneic splenocytes suggesting a specific activation profile. Among the RNAs that allowed the discrimination, we found that VEGF and IL-6 were highly upregulated in MSC after stimulation. This is in agreement with recent data reporting the upregulation of VEGF and IL-6 in the supernatants of cocultures of human primary MSC and peripheral blood mononuclear cells [14]. VEGF has been postulated to contribute to immune suppression by blocking the differentiation and/or the emigration of the lymphoid progenitors residing in the bone marrow [22]. We show here that, among the various cell components of the MLR, VEGF is produced uniquely by the MSC, and its secretion is increased in the MLR. As both VEGF and IL-6 levels are upregulated by PGE2 [19], which is also enhanced in the MLR (our data and [14]), we used the PGE2 inhibitor, indomethacin, to discriminate between the respective role of VEGF and IL-6 in immunoregulation. Indeed, the levels of VEGF were not affected by the PGE2 inhibitor, suggesting that VEGF is unlikely involved in the suppressive mechanism. On the contrary, in the presence of PGE2 inhibitor, a partial reversion of the immunosuppressive effect of MSC is associated with a decrease of IL-6 levels. These data are in agreement with the recent study of Aggarwal et al. suggesting that PGE2 plays a key role in the immunoregulation mediated by MSC [14]. Indeed, we propose that IL-6 is an important cytokine playing a role in the immune regulatory mechanism mediated by MSC. First, we show that MSC, among all cell types present in the MLR, were responsible for the increased secretion of IL-6. Second, IL-6 levels were proportional to the number of MSC added in the MLR and inversely correlated with the production of IFN-, IL-2, and TNF-. Third, the production of IL-6 associated to the immune suppression was affected by the PGE2 inhibitor indomethacin, suggesting that PGE2 may act through the increase of IL-6. Finally, the addition of a neutralizing anti-IL-6 antibody partly restored the proliferation of T cells in the MLR. However, because the reversion of immunosuppression was only partial, IL-6 does not account for the overall immunoregulatory effect mediated by the MSC.
The expression and the functional activity of the IDO protein by MSC have been proposed to take part in their immunosuppressive effect [12]. Upon IFN- activation, the enzyme depletes the tryptophan from the cellular environment, resulting in the inhibition of T-cell proliferation due to the lack of this essential amino acid. Although we detected IDO activity in the supernatants of primary human MSC after IFN- induction (data not shown), we were unable to demonstrate the IDO activity among the various MSC lines from murine or human origin used in this study. One possible explanation could be the loss of the enzymatic function during the immortalization process of these cell lines. Indeed, the expression of IDO is confined to a limited range of cell types, and the transcription of the gene has to be stringently controlled to respond to specific inflammatory mediators because IDO would probably be toxic if constitutively active. Our results are in agreement with the study of Tse et al., who excluded the tryptophan depletion in the culture medium of hPBMC as a possible mechanism for T-cell suppression mediated by MSC [9]. Consistently, the consequences of tryptophan deprivation are the induction of T-cell-cycle arrest or the production of toxic metabolites from tryptophan, such as quinolinic acid and 3-hydroxy-anthranillic acid, both of which have been shown to induce apoptosis [23]. However, the role of MSC as possible inducers of T-cell apoptosis has been excluded [9, 10, 14]. Since the C3 cell line used in this study displays an immunosuppressive function but is devoid of IDO activity, we can exclude a major role for IDO in a general suppressive mechanism, although it may participate in the process, at least in human MSC.
The suppressive effect of MSC has also been postulated to act through the modulation of DC differentiation and function either by inhibiting the differentiation of monocytes into DC or by downregulating the costimulatory molecules on mature DC [15]. Consistent with this study, we observed a slight but significant decrease in the percentage of mDC expressing the costimulatory molecules when cultured in the presence of MSC. The downregulation of the costimulatory signals was associated with the decrease of T-cell activation and subsequent proliferation, suggesting that, in our conditions, MSC are likely to reverse the maturation of DC. Furthermore, we show that bone marrow progenitors cultured in the presence of conditioned supernatants from MSC were partly inhibited to differentiate to functional mDC, and this effect was associated, at least in part, with the secretion of IL-6 by the MSC. This cytokine was proven to skew the differentiation of monocytes into DC being functionally impaired [21]. This last study also argues for the immunosuppressive activity of IL-6 via the decreased production of proinflammatory mediators, the inhibition of CCR7 expression on DC, and the inhibition of T-cell proliferation. It was also shown to inhibit the differentiation of monocytes to DC by promoting their differentiation toward macrophages [24]. The demonstration that IL-6 is an essential factor in the molecular control of antigen-presenting cell development was presented in the study of Chomarat et al. [25]. They report that human fibroblasts, on contact with monocytes, release IL-6, which upregulates the expression of macrophage–colony-stimulating factor (M-CSF) receptors at the surface of monocytes. In turn, monocytes consume autocrine M-CSF, leading to the emergence of macrophages at the expense of DC. In our study, we show that MSC, after activation in coculture with immune cells, secrete high levels of IL-6, which interfere with the generation of DC, leading to less mature DC. In our study, the concentration of IL-6 produced by MSC is low as compared with that of rIL-6. The reason for this discrepancy is not fully understood, but we may speculate that, in close contact with the DC in the MLR, MSC will secrete low but continuous levels of IL-6, which will be concentrated at the vicinity of DC and therefore rapidly active. Another possible explanation may be the induction of other suppressive mediators by IL-6, further suggested by a partial reversion of lymphocyte proliferation using specific antibodies. Although we can not exclude that the generation of immature DC might induce the generation of CD8+ T suppressive cells as demonstrated with tolerogenic DC [20, 26], a lack of T-cell activation by less functional immature DC may be the underlying mechanism. This mechanism may occur in vivo in different tissues as suggested by very recent data reporting that a "pre-cDC" precursor population including cells "precommitted" to form conventional DC is present in the spleen [27]. Altogether, these data suggest that, through IL-6 secretion, MSC possibly act by decreasing the percentage of presentation and costimulatory molecules at the surface of DC. As a result, the activation and proliferation of T lymphocytes is reduced in the MLR. This is also supported by the fact that NIH-3T3 fibroblasts were able to decrease the percentage of mDC, although they have no suppressive property but may secrete IL-6 upon activation [28]. Indeed, the effect of IL-6 on DC maturation is certainly one mechanism by which MSC display suppressive activity but probably is not the main mechanism.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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REFERENCES |
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