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(Journal of Leukocyte Biology. 2002;71:289-294.)
© 2002 by Society for Leukocyte Biology

Cyclosporin A inhibition of macrophage colony-stimulating factor (M-CSF) production by activated human T lymphocytes

Stéphanie Frétier*, Arnaud Besse{dagger}, Adriana Delwail*, Martine Garcia*, Franck Morel*, Valérie Leprivey-Lorgeot{ddagger}, John Wijdenes§, Vincent Praloran{dagger} and Jean-Claude Lecron*

* Laboratoire Cytokines, FRE 2224, IFR FR 59, IBMIG, Université de Poitiers, Cedex, France;
{dagger} Laboratoire Universitaire d’Hématologie, EA 482, Université de Bordeaux 2, France;
{ddagger} Laboratoire de Physiologie, Faculté de Médecine, Université de Limoges, Cedex, France; and
§ Laboratoire Diaclone, BP 1985, Besançon, France

Correspondence: J. C. Lecron, Laboratoire Cytokines, FRE 2224, IFR FR 59, IBMIG, Université de Poitiers, 40, avenue du Recteur Pineau, 86022 Poitiers, Cedex, France. E-mail: Jean-Claude.Lecron{at}univ-poitiers.fr


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ABSTRACT
 
M-CSF is a pleiotropic cytokine involved in the survival, proliferation, and differentiation of cells of the monocyte/macrophage lineage. M-CSF is produced by numerous cells including CD3-activated T cells. M-CSF serum levels are increased during acute graft rejection. We tested the in vitro production of M-CSF, GM-CSF, IL-2, and IL-4 by T-cell clones costimulated by CD3 and accessory activation pathways and the effects of cyclosporin A and methylprednisolone. The nine clones studied and CD4+ cells purified from peripheral blood mononuclear cells (PBMC) spontaneously produced low levels of M-CSF, which PMA and CD3 mAb strongly enhanced. In contrast to IL-2, CD28 mAb did not further enhance this production. CsA inhibited M-CSF production by clones and purified CD4 T cells. Addition of IL-2, anti IL-2, or anti CD25 mAb to the cultures demonstrated that CsA down-regulated M-CSF synthesis by activated T cells through its inhibition of IL-2 synthesis. These results could help to better understand the complex mechanisms of acute graft rejection and immunosuppression.

Key Words: immunosuppression • graft-versus-host • TNF-{alpha} • PMA


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INTRODUCTION
 
The glycoprotein macrophage colony-stimulating factor (M-CSF or CSF-1) is a hematopoietic growth factor required for the survival, proliferation, and differentiation of cells of the monocyte/macrophage lineage [1 , 2 ]. M-CSF was shown later to participate in the immunological defenses, bone metabolism, lipoprotein clearance, fertility, and pregnancy, demonstrating that it is a pleiotropic cytokine (reviewed in refs. [3 , 4 ]). M-CSF is produced spontaneously, or after stimulation, by numerous cell types such as endothelial cells, fibroblasts, monocytes-macrophages, or bone marrow-derived stromal cells [3 ]. Activated normal B cells and spontaneously outgrown Epstein-Barr virus (EBV)-B cell lines [5 ], as well as activated T cells [6 ], also produce M-CSF. Previously, we demonstrated that activation of normal T cells by phorbol 12-myristate 13-acetate (PMA) and the A23187 calcium ionophore, cytokines [tumor necrosis factor {alpha} (TNF-{alpha}), interleukin (IL)-1{alpha}] or anti-CD3 monoclonal antibodies (mAb), and IL-2 induced the production of M-CSF [6 , 7 ]. A unique gene located on the short arm of chromosome 1 [8 ] encodes M-CSF. Multiple alternative mRNA splicing and complex co- and/or posttranslational glycosylations together with proteolysis of M-CSF from the cell surface generate soluble and membrane-associated mature isoforms of M-CSF (reviewed in refs. [9 , 10 ]). M-CSF binds to a specific cell-surface tyrosine kinase receptor (CSF-1-R or M-CSF-R), which is the product of the c-fms protooncogene [11 ]. Because T cells do not express this receptor, the M-CSF that they produce acts locally or by humoral route on other cells, such as monocytes, participating in the regulation of the inflammatory and immune response [11 ].

The binding of the T-cell receptor leads to signal transduction when it is associated with costimulatory signals provided by cytokines and/or cell-cell interactions [12 13 14 ]. It induces T-cell activation, proliferation, and various functions, such as cytokine synthesis. CD28, a constitutive T-cell surface glycoprotein [15 16 17 18 ], constitutes an important accessory pathway for T-cell activation and survival. Its natural ligands, B7-1 (CD80) and B7-2 (CD86), are two monomeric transmembrane glycoproteins expressed by the antigen-presenting cells [16 , 19 ]. In addition to the signals provided by the activation of the CD2 or CD3 pathways, anti-CD28 mAb induces a long-lasting and monocyte-independent T-cell proliferation [12 ]. This proliferation is associated with the induction of a prolonged secretion of high levels of cytokines, such as IL-1{alpha}, IL-2, TNF-{alpha}, and M-CSF [17 , 19 , 20 ]. The accessory molecules modulate the pattern of cytokines produced in response to these different signals. Conversely, cytokine production can be down-regulated by immunosuppressors. Cyclosporin A (CsA), an immunosuppressive drug used in treating rejection of allogeneic transplants, inhibits cytokine synthesis, in particular IL-2 [21 ]. Methylprednisolone (MP), another immunosuppressor, inhibits IL-6 synthesis [22 ]. We demonstrated several years ago that serum and tissue levels of M-CSF were increased during an acute graft-versus-host (GVH) reaction model in mice [23 ] and recently that high serum levels of M-CSF accompanied the onset of kidney graft-rejection episodes in humans [24 ].

This work was focused on the production of M-CSF by activated CD4 and CD8 T-cell clones and CD4+ lymphocytes purified from peripheral blood mononuclear cells (PBMC) and on the mechanisms of inhibition of this secretion by the immunosuppressors CsA and MP.


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MATERIALS AND METHODS
 
T-cell clones and culture conditions
The cloned CD4+ T-cell lines SP-B21, TA 20.6, TA 23.6 [25 ], and the EBV-lymphoblastoid cell line JY used in this study were kindly provided by Dr. H. Yssel (INSERM U454, Montpellier, France). The cloned CD4+ T-cell lines AB14 and AO22 and the cloned CD8+ T-cell lines AO15, AO23, NN82, and NN84 were obtained in the laboratory as described by Spits et al. [26 ]. T-cell clones (2x105 cells/ml) were stimulated every 2 weeks by 0.1 µg/ml purified phytohemagglutinin (PHA; Murex, Châtillon, France) on a feeder cell mixture consisting of 106 irradiated (50 GY), allogenic PBMC and 105 irradiated (50 GY) JY cells per ml in Yssel’s medium [27 ] supplemented with 1% fetal calf serum (FCS; Sigma Chemical Co., Saint Quentin Fallavier, France) and were seeded in 24-well plates (Nunc, Paisley, Scotland). Three to 4 days after PHA stimulation and every 2 days until days 10–12, the T-cell clones were split and further expanded in Yssel’s medium containing 10 ng/ml rIL-2 (Eurocetus, Amsterdam, The Netherlands). The JY cell line was cultured in RPMI-1640 medium (Gibco BRL, Cergy Pontoise, France) supplemented with 10% FCS. All cells were cultured at 37°C in a humidified atmosphere of 6% CO2. T-cell clones were collected for cytokine assays 10–12 days after stimulation with PHA and feeder cells.

Purification of CD4+ T cells from PBMC
PBMC from normal donors were prepared by centrifugation of heparinized blood on Ficoll-Hypaque (Nycomed, Oslo, Norway). CD4+ T lymphocytes were isolated with magnetic anti-CD4 microbeads (Miltenyi Biotec, Paris, France) using a magnetic cell sorter (VarioMacs, Miltenyi Biotec), according to the manufacturer’s instructions. The lymphocyte fraction was enriched up to 98% of CD4+ T cells as assessed by flow cytometry.

T-cell stimulations
T cells were washed and incubated (106 T cells) during 24 h in 24-well plates containing 1 ml Yssel’s medium with different combinations of antibodies and/or PMA (1 ng/ml). The antibodies used were anti-CD3 (10 µg/ml; OKT3, purified from ascite), anti-CD25 mAb (15 µg/ml; gift of Dr. Y. Jacques, INSERM U463, Nantes, France), anti-IL-2 mAb (0.2, 2, 20 µg/ml B-G5; Diaclone, Besançon, France), anti-CD28 L293 (1 µg/ml; a gift of Dr. L. Lanier, DNAX Research Institute, Palo Alto, CA), and the combination of anti-CD2 D66 and X11 mAb (2 µg/ml; gift of Pr. A. Bernard, INSERM U243, Nice, France). Cultures were realized with or without MP (10-5 M; Sigma Chemical Co.) or CsA (5 µg/ml or concentrations indicated in legends; Sandoz, Basel, Switzerland). Culture supernatants were centrifuged (400 g, 5 min, 20°C), aliquoted, and stored at -20°C until cytokine measurements.

Cytokines measurements
Concentrations of IL-2 (sensitivity: 44 pg/ml) and M-CSF (sensitivity: 5 IU/ml) were measured by specific enzyme-linked immunosorbent assay (ELISA), as described previously [28 , 29 ]. IL-4 (sensitivity: 31 pg/ml; Biosource, Fleurus, Belgium) and granulocyte-macrophage colony-stimulating factor (GM-CSF; sensitivity: 4 pg/ml; Endogen, Montluçon, France) measurements were performed as indicated by the manufacturers’ instructions.


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RESULTS
 
Production of M-CSF by T-cell clones
The low spontaneous production of M-CSF (16–70 IU/ml) by the five CD4+ and four CD8+ T-cell clones was not modified by anti-CD28 mAb stimulation alone (Fig. 1 ). PMA, anti-CD3 mAb, anti-CD2 mAb, and PHA significantly increased this basal synthesis. The combination of PMA with anti-CD3 or anti-CD2 mAb further increased the M-CSF production in comparison with either of these agents alone. Although anti-CD28 mAb was ineffective on the anti-CD3 mAb- or PMA/anti-CD3 mAb-induced M-CSF secretion, its effect was greater than additive when added to PMA (Fig. 1 and Table 1 ). In contrast, the addition of anti-CD28 mAb to PMA/anti-CD3 mAb strongly enhanced IL-2 production, as evidenced for the SP-B21 clone in Table 1 . Production of M-CSF by CD4+ T-cell clones stimulated with PMA/anti-CD3 mAb or PMA/anti-CD3/anti-CD28 mAb stimulations appears more important than in CD8+ clones. In addition (Fig. 2 ), the kinetic analysis of induced production of several cytokines showed that it peaked earlier for IL-2 (6 h) than for IL-4, GM-CSF, and M-CSF (72–96 h).



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  		Figure 1. Production of M-CSF by CD4+ and CD8+ T-cell clones. The CD4+ ({blacksquare}) (SP-B21, 20.6, 23.6, AO22, and AB14) and CD8+ ({circ}) T-cell clones (NN82, NN84, AO23, and AO15) were stimulated for 24 h with a combination of PHA, PMA with anti-CD2 or anti-CD3 mAb, and/or anti-CD28 mAb. M-CSF levels were measured by ELISA.


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  		Table 1. Effects of CsA and MP on the Production of Cytokines by SP-B21 and Purified CD4+ T Cells



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  		Figure 2. Kinetics of cytokine production by the CD4+ T-cell clone SP-B21. Cells were stimulated with a combination of PMA and anti-CD3 mAb. Cytokine levels were measured in the culture supernatants by ELISA. Mean ± SE of three experiments.

Effect of CsA and MP on the production of M-CSF, IL-2, IL-4, and GM-CSF by SP-B21 T-cell clones and CD4+-purified T cells
CsA strongly inhibits (up to sevenfold) the production of IL-2, IL-4, and GM-CSF by SP-B21 T cells (activated by PMA/anti-CD3 mAb and PMA/anti-CD3/anti-CD28 mAb) and by purified CD4+ cells (activated by PMA/anti-CD3 mAb), whereas its inhibition of M-CSF production is lower (three- to sixfold; Table 1 ). This CsA inhibition of the production of IL-2 and M-CSF by SP-B21 cells or CD4+-purified T cells (Fig. 3a and b) is dose-dependent. By contrast, in the same conditions of stimulation, MP was a weak inhibitor of the production of IL-2, IL-4, GM-CSF, and M-CSF (Table 1) .



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  		Figure 3. Inhibition by CsA of M-CSF (•) and IL-2 ({blacksquare}) production by SP-B21 (a) or purified CD4+ T cells (b). T cells were stimulated with PMA and anti-CD3 mAb, with increasing concentrations of CsA. M-CSF and IL-2 levels were measured by specific ELISA. Mean ± SE of three experiments.

Mechanism of the CsA-induced M-CSF inhibition
We hypothesized that the inhibition of the M-CSF production could be indirect and linked to the decrease of IL-2 production by T-cell clones. Addition of exogenous IL-2 to PMA/anti-CD3 mAb-stimulated T-cell clones in the presence of CsA partially restored the production of M-CSF, whereas it did not restore the GM-CSF and IL-4 production, also inhibited by CsA. The addition of IL-2 was also ineffective to reverse the MP-induced inhibition of M-CSF, IL-4, or GM-CSF production or to enhance the spontaneous or induced M-CSF production (Fig. 4 ).



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  		Figure 4. Effect of anti-CD25 mAb and IL-2 on the production of M-CSF, IL-4, and GM-CSF by SP-B21. Cells were stimulated or not with PMA and anti-CD3 mAb, with or without IL-2 (50 ng/ml) or anti-CD25 mAb (15 µg/ml). Cytokine levels were measured by ELISA. Mean ± SE of three experiments.

Finally, addition of anti-CD25 (Fig. 4) - as well as anti-IL-2 (Fig. 5 )-blocking mAb decreased the PMA/anti-CD3 mAb-induced M-CSF production. This is in accordance with our hypothesis that the inhibition of CsA on M-CSF production is mediated indirectly via a decrease of IL-2 production.



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  		Figure 5. Effect of anti-IL2 mAb on the production of M-CSF by SP-B21. Cells were stimulated or not with PMA and anti-CD3 mAb, with or without CsA (5 µg/ml) or anti-IL-2 mAb (0.2, 2, 20 µg/ml). M-CSF levels were measured by ELISA. Mean ± SE of three experiments.


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DISCUSSION
 
Chemical inducers (PMA, PHA, calcium ionophore) or cytokines (IL-1{alpha}, TNF-{alpha}) induced M-CSF production by T cells [6 , 7 ]. Its induction by costimulatory signals, which more closely mimic in vivo interactions, has not been tested. The nine T-cell clones studied constitutively produce low amounts of M-CSF, which PHA, PMA, anti-CD2, or anti-CD3 mAb but not anti-CD28 mAb significantly increased. These results apparently contradicted those of Cerdan et al. [12 ], showing that purified T cells activated by the CD28 pathway display a transient rise of the M-CSF transcripts but remain insensitive to CD2 activation. These discrepancies may be related to the use of blood T cells instead of T-cell clones. More probably, there were discrepancies because the production and release of M-CSF are regulated mainly by posttranscriptional processes [30 31 32 ]. In contrast, the production of IL-2 and GM-CSF was increased by the addition of anti-CD28 mAb to PMA/anti-CD3 mAb stimulation. It suggests that induction of M-CSF production by T cells is associated with a limited number of regulatory mechanisms. As shown previously by Price et al. [10 ] with mouse L929 cells, Western blots of T-cell extracts and supernatants (resting or induced) evidenced several types of M-CSF of similar molecular weight (unpublished results). We suggest that in vivo, the activation of resting T cells strongly enhances their ability to produce soluble and membrane-anchored M-CSF glycoproteins as well as to release the large proteoglycan forms bound to heparansulfates of the extracellular matrix. These three different types of M-CSF display, respectively, endocrine, cell-to-cell, and stroma-to-cells effects. We hypothesize that this enhanced production of the different forms of M-CSF induces the recruitment and activation of monocytes at inflammatory sites. In agreement with this hypothesis, increased M-CSF serum and organ levels have been detected already in a mouse-acute GVH reaction model and during kidney graft-rejection episodes [24 ]. These results could partly explain the rapid and massive macrophage infiltration of the grafted organ that accompanies acute graft rejection [33 , 34 ].

The various combinations of costimulatory molecules that we used induced similar productions of M-CSF by CD4 and CD8 T-cell clones, even if PMA/anti-CD3 mAb or PMA/anti-CD3 mAb/anti-CD28 mAb induced a higher production of M-CSF by CD4+ rather than CD8+ T-cell clones. The low number of clones tested herein does not allow a statistical analysis of these differences.

CD4+ T cells have been classified in different subpopulations characterized by their patterns of cytokine production and functions. The T helper cell type (Th)1 clones produce IL-2, interferon-{gamma} (IFN-{gamma}), and TNF-ß, whereas Th2 clones produce IL-4, IL-5, and IL-10. Both types produce similar amounts of GM-CSF and IL-3. Because we found no correlation between the M-CSF production and those of IL-4 or IL-2 by T-cell clones tested (unpublished results), its production, as for IL-3 or GM-CSF, is probably not linked to a polarized T-cell response.

To investigate a potential down-regulation of the increased M-CSF production during graft-rejection processes, we tested the effect of the two classical immunosuppressive drugs CsA and MP on activated, purified, peripheral CD4+ T cells and T-cell clones. MP inhibits the IL-6 production directly by a large number of cell types [22 ], whereas it weakly inhibits the production of IL-2, IL-4, GM-CSF, and M-CSF by activated T cells. By contrast, CsA strongly inhibits the T-cell production of IL-2, IL-3, and IFN-{gamma}, mainly accounting for its immunosuppressive action [21 , 35 , 36 ]. We showed that CsA strongly inhibits the production of IL-2, IL-4, and GM-CSF by T-cell clones as well as freshly isolated CD4 T cells. We partially contradict the results of Bickel et al. [21 ], showing that CsA inhibited the production of IL-2 but not of GM-CSF by murine T cells, whereas to a lesser extent, CsA also reduced the production of M-CSF, a phenomenon that similarly affects the various isoforms of M-CSF (unpublished results).

Because M-CSF is produced later than IL-2, and its inhibition by CsA is lower than for the other cytokines, we hypothesized that its down-regulation by CsA could be indirectly related to the inhibition of IL-2 production. The partial reversion of CsA inhibition by IL-2 addition and the blocking effect of anti-CD25 (anti-IL-2 receptor) and anti IL-2 mAb on the PMA/anti-CD3-induced M-CSF synthesis confirmed this hypothesis. These data also suggest that the induction of M-CSF synthesis by T cells is independent of the calcineurin/NF-AT pathway, which CsA inhibits strongly and directly [37 ].

It is interesting that the range of concentrations of CsA that inhibits the M-CSF production in vitro in this work was in the same range as those in the serum of patients treated with CsA after renal transplantation [38 ]. Previously, and in this study, we showed [7 ] that activated T lymphocytes produced M-CSF and that acute GVH reaction strongly increased their serum and tissue concentrations [23 ]. Then, the in vivo increase of serum and tissue M-CSF concentrations could be mainly a result of a dramatic T-lymphocyte activation that accompanies the acute GVH reaction. Several studies showed that the extent of infiltration and activation of macrophages in the grafted organs is linked to the rejection processes [3 , 34 , 39 40 41 ]. They could, themselves, be related to the high local concentrations of the proteoglycan forms of M-CSF bound to the stroma. The efficiency of CsA to prevent rejection in transplantation is a result of various well-known effects on T cells, such as the inhibition of IL-2 synthesis [38 ]. It could also be related to the inhibition of M-CSF production by T cells that reduces the graft infiltration by monocytes and the deleterious effects of locally activated macrophages.


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ACKNOWLEDGEMENTS
 
S. F. and A. B. were, respectively, supported by grants from "la Ligue contre le cancer des Deux-Sèvres" and the "Conseil régional du Limousin".


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FOOTNOTES
 
Stéphanie Frétier and Arnaud Besse contributed equally to this work.

Received April 1, 2001; revised September 5, 2001; accepted September 6, 2001.


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 Nephrol Dial TransplantHome page
Y. Le Meur, V. Leprivey-Lorgeot, S. Mons, M. Jose, J. Dantal, B. Lemauff, J.-C. Aldigier, C. Leroux-Robert, and V. Praloran
Serum levels of macrophage-colony stimulating factor (M-CSF): a marker of kidney allograft rejection
Nephrol. Dial. Transplant., July 1, 2004; 19(7): 1862 - 1865.
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