Published online before print March 21, 2006
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Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland
1Correspondence: Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail: mari.strengell{at}ktl.fi
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(IFN-) and interleukin (IL)-21, which have important immunoregulatory functions. Here, we have analyzed the effect of IL-21 and IFN- on lipopolysaccharide (LPS)-induced maturation and cytokine production of human monocyte-derived DCs. IL-21 and IFN- receptor genes were expressed in high levels in immature DCs. Pretreatment of immature DCs with IL-21 inhibited LPS-stimulated DC maturation and expression of CD86 and human leukocyte antigen class II (HLAII). IL-21 pretreatment also dramatically reduced LPS-stimulated production of tumor necrosis factor 
, IL-12, CC chemokine ligand 5 (CCL5), and CXC chemokine ligand 10 (CXCL10) but not that of CXCL8. In contrast, IFN- had a positive feedback effect on immature DCs, and it enhanced LPS-induced DC maturation and the production of cytokines. IL-21 weakly induced the expression Toll-like receptor 4 (TLR4) and translation initiation region (TIR) domain-containing adaptor protein (TIRAP) genes, whereas the expression of TIR domain-containing adaptor-inducing IFN-ß (TRIF), myeloid differentiation (MyD88) 88 factor, or TRIF-related adaptor molecule (TRAM) genes remained unchanged. However, IL-21 strongly stimulated the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3 genes. SOCS are known to suppress DC functions and interfere with TLR4 signaling. Our results demonstrate that IL-21, a cytokine produced by activated T cells, can directly inhibit the activation and cytokine production of myeloid DCs, providing a negative feedback loop between DCs and T lymphocytes.
Key Words: human • cell activation • cytokines
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Interleukin-21 (IL-21) is a T cell-derived cytokine that has many immunoregulatory functions. T cell activation via the T cell receptor (TCR) or stimulation with phorbol myristate acetate and ionomycin leads to a rapid and robust IL-21 gene expression. IL-21 production appears to be limited to CD4+ T cells, and it has been reported that IL-21 is expressed selectively by T helper cell type 2 (Th2) cells [6
]. Nuclear factor of activated T cell (NFAT) c2 transcription factor enhances IL-21 gene expression, whereas T-bet appears to repress it [7
]. The functional IL-21 receptor (IL-21R) is composed of an IL-21-specific component and the common chain (c) subunit [8
9
10
]. IL-21 signals via its receptor complex to Janus tyrosine kinase 1 (Jak1) and Jak3, which in turn activate signal transducer and activator of transcription 1 (Stat1), Stat3, and Stat4 [9
10
11
12
]. IL-21R is expressed on B cells, natural killer (NK) cells, and CD4+ and CD8+ T cells [13
]. Depending on costimulatory signals, IL-21 may enhance and inhibit B cell proliferation [14
, 15
]. It also regulates immunoglobulin (Ig) gene expression and stimulates the production of IgG1 [16
, 17
]. IL-21 stimulates T and NK cell activation/proliferation and cytotoxicity. IL-21 also up-regulates IL-12R and IL-18R genes and synergistically with IL-15 and/or IL-18, enhances interferon- (IFN-) production in human NK and T cells [11
, 12
]. It is thus evident that IL-21 has an important role in B, NK, and T cell biology.
Myeloid DCs have also been shown to express IL-21R [18 ], but the effects of IL-21 on DC functions have remained much less studied. However, in murine bone marrow-derived DCs (BM-DCs), IL-21 inhibits DC differentiation and maturation [18 ]. In addition, DCs differentiated in the presence of IL-21 were not able to induce T cell responses [19 ], which is a typical feature for immature DCs. At present, there is no information about the role of IL-21 in human DC maturation and functions.
To characterize cytokine-mediated cross-talk between DCs and activated T cells, we have studied the biological effects of important T cell cytokines, IL-21 and IFN-, on human monocyte-derived DCs. We observed that the expression of IL-21R and IFN-R genes is high in immature DCs. Pretreatment of DC with IL-21 inhibited lipopolysaccharide (LPS)-induced expression of CD86 and human leukocyte antigen (HLA) class II. In addition, LPS-induced tumor necrosis factor (TNF-), IL-12, CC chemokine ligand 5 (CCL5), and CXC chemokine ligand 10 (CXCL10) production was clearly reduced in IL-21-pretreated cells. IFN- pretreatment, instead, had mainly DC stimulatory- and cytokine-inducing effects. It is interesting that LPS-induced CXCL8 production was not affected by IL-21 or IFN- pretreatment. The expression of TLR4 or TLR-associated adaptor genes was not reduced by IL-21 in DCs. However, Northern blot analysis of IL-21-stimulated DC revealed that IL-21 induced the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, which could account for the inhibitory effects of IL-21 on DC functions.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cytokines
Highly purified human leukocyte IFN- was provided by Dr. Hannele Tölö (Finnish Red Cross Blood Transfusion Service). rhIL-21 was provided by Dr. Don Foster (Zymogenetics, Seattle, WA). The cytokine concentrations used were 10 IU/ml for IFN- and 10 ng/ml for IL-21 unless otherwise indicated.
Flow cytometric analysis
DCs were treated with IL-21 (10 ng/ml) or IFN- (10 IU/ml) for 18 h, and LPS was used to stimulate the cells in different concentrations (0.1–100 ng/ml). Control cells were left without cytokine or LPS stimulation. The cells were harvested after 24 h and fixed with 1% paraformaldehyde. Fixed cells were stained with fluorescein isothiocyanate-conjugated anti-HLA-DR or phycoerythrin-conjugated anti-CD86 (Caltag Laboratories, Burlingame, CA) antibodies and analyzed with FACScan using CellQuest software (Becton Dickinson).
Northern blotting
The cells were stimulated with IL-21 or IFN- for different times as indicated in the figure legends. Total cellular RNA was isolated with RNeasy Midi kit (Qiagen, Valencia, CA). The samples containing equal amounts of RNA (10 µg) were size-fractionated on a 1.0% formaldehyde-agarose gel, transferred to a nylon membrane (Hybond, Amersham, Buckinghamshire, UK), and hybridized with IL-21R [22
], IFN-R1, IFN-R2 (kindly provided by Dr. Sergei Kotenko, New Jersey Medical School, Newark, NJ), TLR4 [23
], myeloid differentiation factor 88 (MyD88) [24
], translation initiation region (TIR) domain-containing adaptor protein (TIRAP), TIR domain-containing adaptor-inducing IFN-ß (TRIF), TRIF-related adaptor molecule (TRAM) [25
], SOCS-1, SOCS-2, SOCS-3, and cytokine-inducible Src homology 2 protein (CIS) probes (kindly provided by Dr. Douglas Hilton, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia). Ethidium bromide staining of ribosomal RNA bands was used to ensure equal RNA loading. The probes were labeled with (-32P) deoxy-adenosine 5'-triphosphate (3000 Ci/mmol, Amersham) using a random-primed DNA labeling kit (Boehringer Mannheim, Mannheim, Germany). The membranes were hybridized using UltraHyb hybridization buffer (Ambion, Autin, TX). The membranes were washed three times at 42°C and once at 60°C in 1x saline sodium citrate/0.1% sodium dodecyl sulfate for 30 min each time. The membranes were exposed to Kodak AR X-Omat films at –70°C using intensifying screens. The results were quantitated using Kodak Digital Science 1D image analysis software. The intensities of the bands in Northern blot films were determined and normalized by ß-actin. Relative mRNA levels were obtained by comparing normalized intensities to 1 h control sample intensity.
Cytokine enzyme-liniked immunosorbent assays (ELISAs)
Cell culture supernatants were collected from the experiments described above in a fluorescein-activated cell sorter analysis section. ELISAs for detecting TNF-, CCL5, CXCL8, and CXCL10 levels were performed using antibodies and ELISA standards from PharMingen (San Diego, CA) or R&D Biosystems. IL-12 p70 determinations were carried out with an IL-12 Elipair kit (BioSite, Täby, Sweden).
Statistical analysis
Data are presented as mean value ± SD. Data were analyzed for statistical significance using Student’s t-test. P values <0.05 were considered statistically significant.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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on DCs, we first determined whether IL-21R or IFN-R were expressed during macrophage or DC differentiation. It is surprising that we observed a dramatic difference in IL-21R expression between macrophages and DCs. Although 1-day monocytes were virtually devoid of IL-21R mRNA expression, 3-day- and especially 7-day-differentiated DCs expressed IL-21R mRNA in high levels. Instead, the expression IL-21R mRNA occurred at low levels in cells committed to macrophage differentiation (Day 3) or in mature macrophages (Day 7; Fig. 1
). In contrast, creceptor chain expression was at high level in monocytes but was reduced to a lower basal level in differentiating macrophages and DCs (Days 3 and 7; Fig. 1
) The mRNA expression of IFN-R chains, IFN-R1 and IFN-R2, was readily detectable in macrophages and DCs, although the expression level was somewhat higher in DCs (Fig. 1)
.
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Figure 1. Expression of IL-21R and IFN-R during macrophage or DC differentiation. Monocytes (Mo) from four individual donors were differentiated to macrophages (Mø) with GM-CSF (10 ng/ml) or to DCs with a combination of GM-CSF (10 ng/ml) + IL-4 (20 ng/ml). Cells were collected at various times during differentiation and pooled, and total cellular RNA was isolated. Equal amounts of RNA (10 µg) were separated on 1% agarose gels, and Northern blotting with IL-21R, c, IFN-R1, and IFN-R2 cDNA probes were carried out. Ethidium bromide staining was used to control equal sample loading.
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) in DCs. First, we characterized the effect of these cytokines on the expression of DC cell surface molecules CD86 and HLA class II, whose expression is enhanced during DC maturation. Immature DCs were left untreated or pretreated with IL-21 or IFN- for 18 h followed by stimulation with different doses of LPS for 24 h. In unprimed cells, LPS enhanced the expression of CD86 and HLA class II in a dose-dependent manner (Fig. 2
). IL-21 pretreatment significantly inhibited LPS-induced (doses of 1–100 ng/ml) up-regulation of CD86 expression, whereas IFN- priming had a stimulatory effect on LPS-induced CD86 expression (Fig. 2)
. It is interesting that IL-21 and IFN- priming resulted in reduced LPS-induced expression of HLA class II, especially in high LPS doses (Fig. 2)
.
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Figure 2. The effect of IL-21 or IFN- pretreatment on LPS-induced DC maturation. DCs from four individual blood donors were pretreated with IL-21 (10 ng/ml) or IFN- (100 IU/ml) for 18 h followed by stimulation of the cells with different doses of LPS as indicated in the figure. Twenty-four hours after LPS stimulation, cells were collected and pooled two in one. The cells were fixed and stained with anti-CD86 and anti-HLA class II (DR)-specific antibodies. Values represent the mean (+1 SD unit) fluorescent intensities of the two pooled samples. Results from one representative experiment out of three are shown. Statistical differences between the groups were calculated with Student’s t-test. Significant differences between the groups are shown: *, P < 0.05. n.s., Not significant.
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, IL-12, CCL5, and CXCL10 but not that of CXCL8 pretreatment affected the ability of DC to produce cytokines. We concentrated on analyzing the production of proinflammatory cytokines TNF-, IL-12, CCL5, CXCL8, and CXCL10, which regulate DC maturation (TNF-), a Th1 response (IL-12), and T cell traffic (CCL5, CXCL8, and CXCL10). DCs were left untreated or pretreated with IL-21 or IFN- followed by stimulation with different doses of LPS. The cell culture supernatants were collected, and TNF-, IL-12, CCL5, CXCL8, and CXCL10 levels were determined by ELISA. LPS stimulation induced the production of all studied cytokines in nonpretreated cells. This induction of TNF-, IL-12, CCL5, and CXCL10 was inhibited significantly by IL-21 pretreatment and was detectable with all doses of LPS used (Fig. 3
). In the case of the highest LPS dose (100 ng/ml), IL-21 pretreatment inhibited cytokine production from 50% (TNF-) to 80% (IL-12). IFN- pretreatment, instead, enhanced LPS-induced cytokine production more than two- to fourfold, depending on the cytokine analyzed (Fig. 3)
. In contrast, CXCL8 induction by LPS was not affected by IL-21 or IFN- pretreatment. It is interesting that IL-21 and IFN- stimulation alone enhanced CXCL8 production in immature DC (Fig. 3)
.
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Figure 3. The effect of IL-21 or IFN- pretreatment on LPS-induced DC cytokine production. DCs were pretreated with IL-21 (10 ng/ml; solid bars) or IFN- (10 IU/ml; hatched bars) for 18 h and stimulated with different doses of LPS for 24 h. Cell culture supernatants were collected, and cytokine levels for TNF-, IL-12, CCL5, CXCL10, and CXCL8 were determined by ELISA. The results are the means (+1 SD unit) of four individual blood donors. Statistical differences between the groups were calculated with Student’s t-test. Significant differences between untreated and cytokine-pretreated and LPS-stimulated cell culture supernatants are shown: *, P < 0.05; **, P < 0.01. Results from one representative experiment out of three are shown.
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Figure 4. Expression of TLR4 and TLR adaptor molecules in IL-21-stimulated DCs, which from four different blood donors, were left untreated or stimulated with IL-21 (10 ng/ml). Cells were collected at different times after stimulation, total cellular RNA was isolated, and Northern blot analyses (10 µg each RNA) were carried out with TLR4, TRIF, MyD88, TRAM, and TIRAP cDNA probes (A). The results were quantitated by determing the intensities of the bands. Intensities were normalized by ß-actin. Relative mRNA levels, compared with 1 h control, are shown (B).
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, followed by isolation of total cellular RNA and Northern blot analysis of SOCS mRNA expression. SOCS-1 and SOCS-3 mRNA expression was found to be induced at 3 h after IL-21 stimulation, and the expression of both of these mRNAs remained at elevated levels up to 24 h (Fig. 5A
). In IL-21-stimulated DCs, the expression of SOCS-2 and CIS mRNAs remained unchanged (results not shown). The relative induction of SOCS-1 and SOCS-3 mRNAs was, at most, 20- and tenfold, respectively (Fig. 5B)
. As IFN- is known to induce SOCS-1 expression [28
, 29
], we wanted to compare the level of IL-21-induced SOCS gene expression with that induced by IFN-. Although the SOCS-1 gene was induced equally well by IL-21 and IFN-, SOCS-3 mRNA expression was induced threefold higher by IFN- as compared with that of IL-21 (Fig. 5A
and 5B)
.
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Figure 5. Analysis of SOCS mRNA expression in IL-21- or IFN--stimulated DCs, which from four individual donors, were stimulated with IL-21 (10 ng/ml) or IFN- (10 IU/ml) for different periods of times. Total cellular RNA was isolated from pooled cells and separated on 1% agarose gels (10 µg each RNA), and Northern blot analyses with SOCS-1 and SOCS-3 cDNA probes were carried out (A). The Northern blot analyses were quantitated and normalized by ß-actin, and relative mRNA levels (compared with 3 h control) are shown.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, whose production is triggered via the TCR, are produced during the intimate contact of T cells with DCs occurring during antigen presentation. However, these cytokines are likely to be produced in different occasions, as IL-21 is mainly produced by Th2 and IFN-, by Th1 CD4+ cells [6
, 30
]. DCs are also expected to be responsive to these T cell-derived cytokines, as they express IL-21R and IFN-R [18
, 31
]. Among APCs of myeloid origin, IL-21R expression appeared to be restricted to GM-CSF + IL-4-differentiated DCs, as they readily expressed IL-21R mRNA, and macrophages were almost completely devoid of its expression (Fig. 1)
. Conversely, c-receptor chain, which is essential for IL-21 signaling [9
, 10
], was expressed at basal level in macrophages and in DCs. As expected, IFN-R1 and IFN-R2 were expressed in both APC types.
In vitro murine BM cells can be differentiated into myeloid DCs with GM-CSF stimulation. Murine BM cells, which were differentiated into DCs in the presence of GM-CSF and IL-21 (IL-21DCs), remained in a more immature state as compared with cells that were differentiated with GM-CSF only. These cells also failed to mature in response to LPS stimulation, and antigen-specific T cell proliferation did not take place [18
, 19
]. IL-21 was also able to inhibit LPS-induced maturation and cytokine production in DCs, which were already differentiated [18
]. The data strongly suggest that in the murine system, IL-21 is able to modify DC development and inhibit the activation of DCs. Our data, conversely, suggest that human DCs appear to behave differently from their murine counterparts. Standard stimulatory cytokine combination for differentiating human monocytes to DCs is GM-CSF + IL-4, and with GM-CSF alone, macrophages are obtained. In the presence of GM-CSF + IL-21, monocytes did not differentiate to DCs or macrophages (data not shown). We did, however, find out that similarly to murine DCs, IL-21 pretreatment clearly and efficiently inhibited LPS-induced DC maturation and cytokine production in human immature DCs. In this respect, the biological effect of IL-21 on immature DCs was similar in mouse and man. It is noteworthy that DC pretreatment with IL-21 inhibited the production of proinflammatory cytokines TNF- and IL-12 as well as chemokines CCL5 and CXCL10 in response to LPS stimulation. The inhibition of IL-12 and CXCL10 production by IL-21 deserves a special notion, as these cytokines regulate the polarization and chemoattraction of Th1 T cells, respectively. It is likely that by inhibiting the production of Th1 cytokines/chemokines in DCs, IL-21 confines Th1 immune response and may even shift the immunological balance toward a Th2 response. Conversely, the inhibitory effect of IL-21 seems to be specific in the sense that IL-21 pretreatment did not affect the production of CXCL8 in DC. Thus, chemotactic effects of CXCL8 on neutrophils and T cells are not reduced by IL-21. On the contrary, priming of DCs with IFN-, which is the product of activated NK, CD8+, and Th1 CD4+ T cells, strongly enhanced LPS-stimulated cytokine production. This, on its part, suggests that IFN- provides a strong feedback signal between DCs and IFN--producing CD8+ and Th1 CD4+ T cells to favor a Th1 response. IL-21-mediated, negative feedback and IFN--mediated, positive feedback signals were likely to occur at the transcriptional level, as the mRNA expression of an immediate early cytokine gene, TNF- was clearly reduced in IL-21-pretreated cells and enhanced in IFN--pretreated cells after LPS stimulation (data not shown).
To reveal the molecular basis of IL-21-mediated inhibitory effects on DC functions, we analyzed the mRNA expression of TLR4 and its downstream signaling components [32
] in response to IL-21 stimulation. In these experiments, we failed to obtain a plausible explanation for the inhibitory effects of IL-21, i.e., that the expression of TLR4 or its downstream adaptor genes would be reduced in IL-21-stimulated DCs. Indeed, the gene expression of TLR4 was rather increased than decreased by IL-21, but the differences were probably not biologically significant, as the variation in mRNA levels in control samples were quite big. Quantitation of Northern blot analysis revealed only two- to threefold increases in TLR4 and TIRAP expression in IL-21-stimulated cells as compared with controls. IFN- did not enhance TLR4 mRNA expression in our model (data not shown), although it has been reported that IFN- up-regulates TLR4 gene expression at least in endothelial cells and peripheral blood mononuclear cells [33
, 34
]. We also analyzed NF-
B binding to the promoter regions of CCL5, CXCL8, and CXCL10 genes but failed to see any reduction in LPS-induced NF-B activation in IL-21-pretreated cells (data not shown). This suggests that down-regulation of cytokine production in IL-21-primed cells is likely to be mediated by other signal transduction pathways apart from NF-B. This is further supported by the observation that CXCL8 production, which is regulated mainly by NF-B [35
, 36
], was not affected by IL-21 pretreatment.
The SOCS family of inhibitors has recently received a lot of attention, also in connection with DCs. APCs obtained from SOCS-1-deficient mice are hyper-responsive to LPS and produce large amounts of proinflammatory cytokines [37 , 38 ]. SOCS-1 appears to suppress DC maturation and functions and prevents the development of systemic autoimmunity [39 40 41 ]. SOCS-1 has also been shown to inhibit TLR4 signaling directly [26 , 42 ]. We observed that IL-21 enhanced the expression of SOCS-1 and SOCS-3 genes, which may serve as one potential mechanism of IL-21-mediated DC immunosuppression. SOCS mRNA induction by IL-21 was rapid, suggesting that SOCS-1 and SOCS-3 are likely to be regulated directly by IL-21-activated Stats. As IL-21 was not able to significantly induce TLR4 or its downstream signaling molecules, the inhibitory effects of SOCS-1 and SOCS-3 could be effective in LPS signaling.
In the present work, we have demonstrated that IL-21 functions as an inhibitory cytokine in human monocyte-derived DCs. The production of LPS-induced proinflammatory cytokines, especially those directing immunity toward a Th1 response, was clearly inhibited. It appears that IL-21 is a pleiotropic cytokine that has significant cell type-specific, biological effects in various leukocyte types. Detailed analysis of the biological effects of IL-21 in the human system is also a prerequisite for the future development of IL-21 as a therapeutic agent.
Received September 9, 2005; revised January 20, 2006; accepted February 9, 2006.
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