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Rheumatology 2001; 40: 185-191
© 2001 British Society for Rheumatology

Non-steroidal anti-oestrogens inhibit the differentiation of synovial macrophages into dendritic cells

J. Komi, M. Möttönen, R. Luukkainen1 and O. Lassila

Turku Graduate School of Biomedical Sciences and Turku Immunology Centre, Department of Medical Microbiology, Turku University, Kiinamyllynkatu 13, 20520 Turku
1 Department of Rheumatology, Satalinna Hospital, Harjavalta, Finland


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Dendritic cells (DC) have been suggested to play an important role in the pathogenesis of rheumatoid arthritis (RA). Agents that inhibit DC differentiation and function may have a therapeutic value in the treatment of RA.

Objective. To examine the effect of the non-steroidal anti-oestrogens toremifene and tamoxifen on the differentiation of synovial fluid (SF) macrophages into DC.

Methods. SF macrophages from patients with RA were cultured with interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF) in the presence or absence of anti-oestrogens. The expression of cell surface markers on SF antigen-presenting cells (APC) was studied by flow cytometry. The capacity of SF APC to stimulate allogeneic T cells was studied using the mixed lymphocyte reaction. The production of tumour necrosis factor-{alpha}, IL-10 and transforming growth factor-ß1 was studied using ELISA.

Results. Anti-oestrogens inhibited the differentiation of SF macrophages into DC and the capacity of SF macrophage-derived DC to stimulate allogeneic T cells.

Conclusions. By inhibiting the differentiation of SF macrophages into DC, non-steroidal anti-oestrogens may have beneficial effects in RA.

KEY WORDS: Toremifene, Tamoxifen, Rheumatoid arthritis, Dendritic cells.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Dendritic cells (DC) are antigen-presenting cells (APC) that differentiate from bone marrow-derived precursors. Owing to their capacity to stimulate naive T cells, DC have a central role in the initiation of immune responses [1] and the regulation of self-tolerance and autoimmunity [2, 3]. The importance of DC in autoimmunity is demonstrated by their ability to transfer autoimmune disease to healthy animals [4, 5]. DC produce high levels of interleukin (IL)-12, the major cytokine responsible for the generation of inflammatory Th1 cells [6–8], which are the predominant Th cell type in various autoimmune diseases, such as rheumatoid arthritis (RA) [9]. Several groups have identified DC in synovial tissue and synovial fluid (SF) from RA patients [10–12]. It has also been reported that 20–45% of synovial non-T mononuclear cells are CD33-positive cells that acquire typical dendritic cell morphology on in vitro culture [12]. These data suggest that DC play an important role in the pathogenesis of RA.

The non-steroidal anti-oestrogen tamoxifen has been reported to have beneficial effects in experimental models of autoimmune diseases, such as collagen-induced arthritis [13], adjuvant-induced arthritis [14] and murine models of systemic lupus erythematosus [15, 16]. Tamoxifen can suppress contact sensitivity skin reactions and inhibit antibody formation in rats [14] and suppress IgG-induced immune synovitis in a rabbit model [17]. In addition, tamoxifen has been shown to improve the clinical symptoms of patients with psoriasis [18], cyclical psoriatic arthritis [19], autoimmune progesterone dermatitis [20, 21] and Riedel's thyroiditis [22]. However, the mechanisms by which tamoxifen mediates its immunosuppressive effects are not clearly understood.

We have shown recently that the anti-oestrogens toremifene and tamoxifen inhibit the differentiation and maturation of human peripheral blood monocyte-derived DC [23]. As DC have been suggested to be involved in the pathogenesis of RA, we have extended our studies in RA and studied the effect of anti-oestrogens on the differentiation of SF macrophages into DC. We show that the non-steroidal anti-oestrogens toremifene and tamoxifen inhibit the differentiation of SF macrophages into DC, as defined by phenotypic cell surface markers and the potential to stimulate allogeneic T cells. These findings may have therapeutic relevance in the treatment of RA.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
SF samples were collected from 13 patients with RA (10 women and three men). The median age of the patients was 63 yr (range 45–79) and the median duration of disease was 12 yr (range 1–29). Twelve patients were treated with disease-modifying anti-rheumatic drugs (corticosteroids and/or non-steroidal anti-inflammatory drugs). RA was determined according to the criteria of the American College of Rheumatology [24]. The study was approved by the ethics committee of Turku University Central Hospital.

Reagents and antibodies
Toremifene and tamoxifen, as the citrate salts, were obtained from Orion-Farmos Corporation (Turku, Finland), diluted in 70% ethanol and stored in 10-2 M stock solution. The highest concentration of ethanol in the final cultures was 0.07%. Purified recombinant human IL-4 and IL-10 were obtained from Schering-Plough Research Institute (Kenilworth, NJ, USA). Recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF) (Leucomax) was purchased from Schering-Plough/Sandoz, and lipopolysaccharide (LPS) (Escherichia coli serotype 0127:B8) from Sigma (St Louis, MO, USA). Phycoerythrin (PE)-conjugated anti-human CD14, CD16, HLA-DR, CD80 and mouse-IgG were purchased from Becton Dickinson (San Jose, CA, USA). PE-conjugated anti-human CD86, fluorescein isothiocyanate (FITC)-conjugated CD32, CD64 and non-conjugated CD1a were purchased from Pharmingen (San Diego, CA, USA). PE-conjugated goat anti-mouse IgG1 was purchased from Southern Biotechnology Associated (Birmingham, AL, USA). Non-conjugated anti-human CD40 (IgG1) was obtained from the Schering-Plough Research Institute. Sp 2/0 (mouse hybridoma culture supernatant) was used as a negative control.

Cell isolation and culture
SF samples from inflamed knee joints were obtained by needle aspiration and placed in heparinized tubes. SF mononuclear cells were isolated by Ficoll–Paque (Pharmacia, Uppsala, Sweden) density gradient centrifugation and incubated on cell culture dishes (Becton Dickinson) for 1 h at 37°C. Non-adherent cells were removed by washing six times with phosphate-buffered saline (PBS) containing 2% fetal calf serum (FCS). The cells (1–2x106/well) were cultured in flat-bottomed 24-well plates (Costar, Cambridge, MA, USA) in Iscove's Modified Dulbecco's Medium (IMDM) (Gibco BRL, Grand Island, NY, USA) supplemented with 10% heat-inactivated FCS (Bioproducts for Science, Indianapolis, IN, USA) and 50 µg/ml gentamycin (Biological Industries, Kibbutz beit Haemek, Israel). IL-4 (100 U/ml)+GM-CSF (50 ng/ml), anti-oestrogens or IL-10 (100 U/ml) were added at the onset of culture. For cytokine measurements, the supernatants were collected after 24 h of cell culture and stored at –70°C until analysed by enzyme-linked immunosorbent assay (ELISA).

Flow cytometry
For immunofluorescence staining, the cells were incubated with PE- or FITC-conjugated monoclonal antibodies (mAbs) or with non-conjugated mAbs for 30 min on ice, followed by incubation with isotype-specific secondary antibody. Before and after each incubation, the cells were washed twice with PBS+2% FCS+0.01% NaN3. The cells were analysed with a FACScan flow cytometer (Becton Dickinson) using CellQuest (Becton Dickinson) software. Data are expressed as mean fluorescence intensity ratios (mean fluorescence intensity with mAb of interest/mean fluorescence intensity with control antibody).

Mixed lymphocyte reaction
SF macrophages were first cultured in the presence of IL-4+GM-CSF with or without anti-oestrogens or IL-10 (100 U/ml) for 3 days. The cells were then irradiated (30 Gy) and co-cultured with 1x105 Ficoll–Paque-isolated allogeneic peripheral blood mononuclear cells for 5 days in U-bottomed 96-well plates (Nunclon, Roskilde, Denmark). To determine the proliferative activity, 1 mCi of [3H]thymidine (Du Pont, Boston, MA, USA) was added to each well 16–18 h before terminating the culture. The cells were harvested onto glass fibre filters (Wallac, Turku, Finland) with a 96-well harvester (Tomtec, Orange, CT, USA). Radioactivity was measured with a 1450 Microbeta Plus liquid scintillation counter (Wallac).

Cytokine measurements
The production of cytokines by SF macrophages was measured by ELISA. The tumour necrosis factor (TNF)-{alpha} ELISA kit was purchased from CLB (Amsterdam, The Netherlands). IL-10 and transforming growth factor (TGF)-ß kits were from R&D Systems (Minneapolis, MN, USA). To detect latent TGF-ß1, the culture supernatant samples were activated with 1 N HCl for 10 min and neutralized by adding 1.2 N NaOH+0.5 HEPES. All ELISAs were performed in duplicate according to the instructions of the manufacturer.

Statistical analysis
The paired Student's t-test was used for statistical analysis.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Anti-oestrogens inhibit the differentiation of SF macrophages into DC
When SF macrophages were cultured in the presence of IL-4+GM-CSF for 3 days, the cells lost CD14 expression and started to express CD1a, a marker for immature DC. The expression of CD40 and the co-stimulatory molecules CD80 and CD86 was also up-regulated, whereas only minor enhancement was observed in HLA-DR expression (Fig. 1Go and Table 1Go). In the presence of toremifene or IL-10, which is known to inhibit the differentiation of SF macrophages into more efficient APC [25], the cells remained CD1a-negative, suggesting that the differentiation of SF macrophages into DC was inhibited. Like IL-10, toremifene also inhibited the up-regulation of CD40 and CD80 during differentiation. On the other hand, toremifene and IL-10 had different effects on CD86 expression. Whereas the up-regulation of CD86 was significantly inhibited by IL-10, toremifene enhanced CD86 expression. IL-10 also inhibited the expression of HLA-DR (P=0.06), whereas no effect on HLA-DR expression was observed in the presence of toremifene (Fig. 1Go and Table 1Go). These data suggested that, although toremifene and IL-10 both inhibit the differentiation of SF macrophages into DC, their effects on the phenotype of SF macrophage-derived DC are different. This was further demonstrated by their distinct effects on the expression of the Fc{gamma} receptors CD16, CD32 and CD64. Whereas toremifene had no effect on the expression of Fc{gamma} receptors in SF macrophages cultured with IL-4+GM-CSF, IL-10 clearly enhanced the expression of CD16 and CD32 and also moderately increased the expression of CD64 (Fig. 2Go). We also compared the effects of two anti-oestrogens (toremifene and tamoxifen) on the phenotype of SF macrophages cultured with IL-4+GM-CSF. As previously shown for peripheral monocyte-derived DC [23], toremifene and tamoxifen had identical effects on the differentiation of SF macrophages into DC (Fig. 3Go). To reveal the functional relevance of the changes in the phenotype of SF macrophages brought about by anti-oestrogens, we studied the ability of SF macrophage-derived DC to activate T cells in allogeneic mixed lymphocyte reaction (MLR). As shown in (Fig. 4Go), both toremifene and IL-10 inhibited the IL-4+GM-CSF-induced enhancement of the capacity of SF macrophages to stimulate allogeneic T cells. Similar effects were observed with tamoxifen (data not shown).



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  		FIG. 1. The effect of toremifene (TOR) and IL-10 on the phenotype of SF macrophages cultured with IL-4+GM-CSF. Adherent SF mononuclear cells were cultured in medium alone (control) or with IL-4+GM-CSF in the presence or absence of toremifene (5 µM) or IL-10 (100 U/ml). After 3 days of culture the cells were stained for various cell surface markers and analysed by flow cytometry. Representative histograms from five individual experiments are shown.

 

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  		TABLE 1. Effects of toremifene and IL-10 on the phenotype of SF macrophages cultured in the presence of IL-4+GM-CSF

 


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  		FIG. 2. The effects of toremifene (TOR) and IL-10 on the expression of Fc{gamma} receptors on SF macrophages cultured with IL-4+GM-CSF. Adherent SF mononuclear cells were cultured in medium alone (control) or with IL-4+GM-CSF in the presence or absence of toremifene (5 µM) or IL-10 (100 U/ml). After 3 days of culture the cells were stained for CD16, CD32 and CD64 and analysed by flow cytometry. Representative histograms and mean fluorescence intensity ratios (see Materials and methods) from three individual experiments are shown.

 


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  		FIG. 3. Toremifene (TOR) and tamoxifen (TAM) have identical effects on the phenotype of SF macrophages cultured with IL-4 + GM-CSF. Adherent SF mononuclear cells were cultured in medium alone (control) or with IL-4 + GM-CSF in the presence or absence of toremifene or tamoxifen (5 mM). After 3 days of culture the cells were stained for various cell surface markers and analysed by flow cytometry. Representative histograms from three individual experiments are shown.

 


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  		FIG. 4. Toremifene (TOR) and IL-10 inhibit the antigen-presenting function of SF macrophages cultured with IL-4 + GM-CSF. Adherent SF mononuclear cells were cultured in medium alone (control) or with IL-4 + GM-CSF in the presence or absence of toremifene (5 mM) or IL-10 (100 U/ml). After 3 days of culture, the cells were washed, irradiated (30 Gy) and counted. 5–20 x 103 cells were then co-cultured with 1 x 105 allogeneic peripheral blood mononuclear cells for 5 days, after which the proliferative activity was measured. The results are expressed as mean ± S.D. c.p.m. of a representative experiment performed in triplicate. Similar results were obtained in two other experiments.

 

Anti-oestrogens inhibit the differentiation of SF macrophages into DC by a mechanism independent of TNF-{alpha}, IL-10 or TGF-ß
Rheumatoid synovium has been shown to be enriched with the macrophage-derived cytokines TNF-{alpha}, IL-10 and TGF-ß, which are known to modulate DC differentiation [11]. Therefore, we wanted to know whether anti-oestrogens inhibit the differentiation of SF macrophage-derived DC by affecting the production of these cytokines. SF macrophages spontaneously produced low amounts of TNF-{alpha} and IL-10, and the production of both cytokines was induced by LPS. Toremifene and tamoxifen did not seem to have any effect on the spontaneous or LPS-induced production of TNF-{alpha} or IL-10, whereas TNF-{alpha} production was clearly inhibited by IL-10 (Table 2Go). Tamoxifen has been shown to enhance the production of the anti-inflammatory cytokine TGF-ß1 [26–28], which has been suggested as one mechanism of immunomodulation by tamoxifen [13]. However, anti-oestrogens and IL-10 were not found to modulate the production of TGF-ß1 by SF macrophages. The presence of latent TGF-ß1 was mainly due to the FCS in the culture medium, suggesting that SF macrophages did not produce significant amounts of TGF-ß1 (Table 2Go). Active TGF-ß1 was not observed in the culture supernatants. Altogether, these data demonstrate that the mechanism by which anti-oestrogens inhibit the differentiation of SF macrophages into DC does not involve modulation of TNF-{alpha}, IL-10 or TGF-ß production.


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  		TABLE 2. Effects of toremifene, tamoxifen and IL-10 on the production of TNF-{alpha}, IL-10 and TGF-ß1 by SF macrophages

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In the present study, the non-steroidal anti-oestrogens toremifene and tamoxifen were found to inhibit the differentiation of SF macrophages into DC. Like IL-10, anti-oestrogens inhibited the up-regulation of CD1a, CD40 and CD80 during differentiation. Furthermore, anti-oestrogens reduced the capacity of SF macrophage-derived cells to stimulate allogeneic T cells in the MLR. Previously, we have shown that anti-oestrogens inhibit the differentiation and function of human peripheral monocyte-derived DC [23]. In that study, peripheral blood monocytes cultured with IL-4+GM-CSF and anti-oestrogens remained CD1a-negative and were functionally impaired in stimulating the proliferation of allogeneic T cells and in producing the biologically active IL-12 p70 heterodimer after CD40 ligation. Anti-oestrogens also partially inhibited the terminal maturation of DC induced by LPS or TNF-{alpha}. Monocytes and immature and mature DC were found to express oestrogen receptors (ER)-{alpha} and ER-ß mRNA, indicating that DC differentiation at all stages can be regulated by the ER. On the other hand, 17ß-oestradiol and the pure ER agonist ICI 182,780, which both bind to the ER with much higher affinity than anti-oestrogens, were not found to affect DC differentiation or to modulate the inhibitory effect of anti-oestrogens, suggesting that anti-oestrogens inhibit DC differentiation by ER-independent mechanisms [23]. Also, synovial macrophages have been shown to express oestrogen receptors [29, 30]. Although the possibility of an ER-mediated mechanism was not addressed in the present study, it is likely that, similarly to the differentiation of peripheral monocyte-derived DC, the differentiation of SF macrophages into DC is also inhibited by ER-independent mechanisms. Other inhibitors of DC differentiation, such as IL-10 and glucocorticoids, are known inhibitors of NF-{kappa}B [31, 32]. However, it is evident that anti-oestrogens inhibit DC differentiation by a mechanism different from that used by IL-10, as demonstrated by the different effects of anti-oestrogens and IL-10 on the expression of Fc{gamma} receptors and the production of TNF-{alpha}. One plausible mechanism involves protein kinase C (PKC), as both toremifene and tamoxifen have been shown to inhibit its function [33, 34]. Differentiation of DC from CD34-positive precursors can be induced by phorbol myristate acetate (PMA), showing the involvement of PKC in the process [35]. As PKC and phorbol esters can activate NF-{kappa}B [36], it is possible that anti-oestrogens inhibit NF-{kappa}B activation by a PKC-mediated mechanism.

As previously shown for peripheral monocyte-derived DC [23], anti-oestrogens clearly up-regulated the expression of CD86 on SF macrophage-derived DC, whereas IL-10 had an opposite effect. Although controversial, it has been suggested that CD80 and CD86 on the APC regulate the development of Th1 and Th2 responses by delivering differential signals to helper T cells [37]. There is evidence that CD80 would preferentially drive the response into the Th1 pathway and CD86 would drive it into the Th2 pathway [38–40]. On the other hand, synovial DC seem to express higher levels of CD86 than CD80 [41], and there is evidence that CD86 is a more important co-stimulatory molecule for many DC than CD80 [42–44]. However, although anti-oestrogen-treated cells expressed higher levels of CD86, they were impaired in stimulating the proliferation of alloreactive T cells. Whether anti-oestrogens modulate the Th1/Th2 balance in rheumatoid synovium remains to be elucidated.

DC have been identified by several groups in synovial tissue and synovial fluid from RA patients [11]. Mature CD33-positive myeloid DC have been found to be enriched three- to fourfold in the synovium of RA patients and to be markedly more efficient stimulators of autologous T cells than peripheral blood DC [12]. The cytokine-rich environment in the inflamed joints may drive locally the differentiation and maturation of DC [10, 11]. Macrophage-derived cytokines, such as TNF-{alpha} and GM-CSF, which induce the differentiation and maturation of DC, as well as IL-13, which can replace IL-4 in driving the differentiation of DC [45], are abundant in the rheumatoid synovium [46–48]. T cells from RA joints have also been shown to express functional CD40L, suggesting that activated T cells in the synovium could promote DC maturation [49]. On the other hand, high levels of the anti-inflammatory cytokines IL-10 and TGF-ß, which inhibit APC function, are also present in the synovium [25, 50, 51]. It is possible that, although anti-inflammatory cytokines are produced in the RA synovium, the local cytokine environment allows the SF macrophages to differentiate into DC, which produce IL-12 and sustain the inflammatory Th1 response in the synovium. Therefore, immunomodulatory agents that have the potential to inhibit the differentiation of SF macrophages into more potent APC may have beneficial effects in the treatment of RA. Clinically, our observations could also be relevant in other autoimmune diseases, such as psoriasis, in which the activation of DC has been shown to play an important role [52]. It is also likely that the beneficial effects of tamoxifen in several models of autoimmune diseases [13–22] are mediated at least partly at the level of APC. We conclude that, by inhibiting the differentiation of DC, anti-oestrogens may have a therapeutic role in the treatment of autoimmune diseases such as RA.


   Acknowledgments
 
We thank Ms Marianne Laine and Ms Anna Hakanen for expert technical assistance. This study was supported by the Academy of Finland, Turku Graduate School of Biomedical Sciences, Turku University Central Hospital special funds and the South-Western Cancer Society of Finland.


   Notes
 
Correspondence to: J. Komi, Turku Immunology Centre, Department of Medical Microbiology, Turku University, Kiinamyllynkatu 13, 20520 Turku, Finland. Back


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 Introduction
 Materials and methods
 Results
 Discussion
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Submitted 19 April 2000; Accepted 2 September 2000


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M. Moghaddami, L. G. Cleland, and G. Mayrhofer
MHC II+ CD45+ cells from synovium-rich tissues of normal rats: phenotype, comparison with macrophage and dendritic cell lineages and differentiation into mature dendritic cells in vitro
Int. Immunol., August 1, 2005; 17(8): 1103 - 1115.
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