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IMMUNOBIOLOGY
From the Institute of Hematology and Medical Oncology
"L. e A. Seràgnoli," University of Bologna, Bologna, Italy;
Immunohematology Service, Sant'Orsola Hospital, Bologna, Italy;
Istituto Dermopatico dell' Immacolata IRCCS, Rome, Italy; and
Institute of Biological Chemistry, University of Modena, Modena, Italy.
Exploration of the immunomodulatory activities of the
multifunctional cytokine interleukin-11 (IL-11) has prompted several therapeutic applications. The immunomodulatory effects of IL-11 on
human antigen-presenting cells and on T cells were investigated. IL-11
inhibited IL-12 production by activated CD14+ monocytes,
but not by mature dendritic cells (DCs) stimulated via CD40 ligation.
Moreover, IL-11 did not affect either DC maturation, as demonstrated by
phenotypic analysis and evaluation of cytokine production, or DC
generation from progenitor cells in the presence of specific growth
factors. Molecular analysis demonstrated the expression of IL-11
receptor messenger RNA in highly purified CD14+ monocytes,
CD19+ B cells, CD8+, and CD4+
T cells, and CD4+CD45RA+ naive T
lymphocytes. In keeping with this finding, IL-11 directly prevented Th1
polarization of highly purified CD4+CD45RA+
naive T cells stimulated with anti-CD3/CD28 antibodies, as demonstrated by significant increases of IL-4 and IL-5, by significantly decreased interferon- Interleukin (IL)-11 is a multifunctional
cytokine that was originally isolated from the primate stromal cell
line, PU-34, and later from the human MRC 5 cell line. Biologic
characterization has shown diverse effects on a variety of
hematopoietic and nonhematopoietic cell types (reviewed in reference
1). Due to its ability to stimulate megakaryopoiesis and
thrombopoiesis, IL-11 has been approved in the United States for the
treatment of chemotherapy-induced thrombocytopenia. In addition to
stimulating hematopoietic progenitor cells,2 IL-11 exerts
a strong anti-inflammatory activity in vitro and in vivo. By inhibiting
nuclear translocation of nuclear factor-kB (NF-kB),3 IL-11
reduces production by macrophages of proinflammatory cytokines such as
tumor necrosis factor- Taken together, these studies have revealed that IL-11 exerts a series
of important immunomodulatory effects that can be applied in various
therapeutic contexts. However, the issue as to whether T-cell
polarization is solely due to IL-11-mediated suppression of IL-12 or
whether IL-11 has additional direct effects on
CD4+CD45RA+ naive T cells has yet to be
addressed. The most potent antigen-presenting cells (APCs) involved in
the stimulation of naive CD4+ cells are dendritic cells
(DCs), which induce type I responses by their ability to produce IL-12
on maturation.13 In this study, we investigated the
immunomodulatory effects of IL-11 on monocytes, human monocyte-derived
DCs (Mo-DCs), and T cells. Our results demonstrate that IL-11 regulates
immune responses by at least 2 potent mechanisms of action: it inhibits
IL-12 production by monocytes and exerts a direct effect on
CD4+ Th cell polarization.
Cell sample collection and processing
Generation of DCs in liquid culture
Immunophenotype studies Dual-color immunofluorescence was performed using the following panel of monoclonal antibodies (MoAbs)14,15: phycoerythrin (PE)- or fluorescein isothiocyanate (FITC)-conjugated antihuman CD1a (Pharmingen, San Diego, CA); FITC-conjugated antihuman CD86 (Pharmingen); FITC-BB1/B7 (anti-CD 80; Becton Dickinson); FITC-antihuman HLA-DR (Becton Dickinson); FITC or PE Leu-M3 (anti-CD 14; Becton Dickinson); FITC-Leu-4 (anti-CD3; Becton Dickinson); FITC-Leu-18 (anti-CD45RA; Becton Dickinson); PE-antihuman CD83 (Immunotech, Marseille, France); FITC-antihuman CD40 (Pharmingen); FITC-antihuman Leu-3a (anti-CD4; Becton Dickinson). Negative controls were isotype-matched irrelevant MoAbs (Pharmingen and Becton Dickinson). Cells were incubated in the dark for 30 minutes at 4°C in PBS-1% BSA. After washing, cells were resuspended in PBS and 1% paraformaldehyde and analyzed as reported above.In vitro priming of CD4+CD45RA+ T cells Naive T cells were highly purified from the MNC fraction by MiniMacs high-gradient magnetic separation column (MultiSort isolation kit; Myltenyi Biotec) according to the manufacturer's instructions. Flow cytometric reanalysis of purified cell fractions was performed as reported above. The purity of the enriched populations was always more than 90%. CD4+CD45RA+ T cells were then resuspended in RPMI 1640 containing 5% human AB serum and stimulated with allogeneic mature Mo-DCs (DC/T ratio = 1:10) or with plate-coated anti-CD3 and soluble anti-CD28 MoAbs (both at 1 µg, Immunotech and Pharmingen, respectively) in the presence or absence of recombinant human IL-11 (50 U/mL) or IL-4 (R&D Systems, Minneapolis, MN; 100 U/mL). In neutralization experiments, specific anti-IL-11 antibodies (5 µg/mL; Endogen), anti-IL-4 (10 µg/mL; Endogen), or matched-isotype control Ig were added to the culture. After 6 days of culture, T cells were transferred to uncoated plates in medium containing 30 U/mL recombinant human IL-2 (Proleukin, Chiron, Emeryville, CA). After 7 to 8 days of IL-2 expansion, T cells were treated for cytokine secretion (see below) and for intracellular cytokine staining. Briefly, T lymphocytes were counted and reactivated with IS Cyto Activation Kit, containing phorbol-12-myristate-13-acetate (PMA), ionomycin, and monensin (Immune Source, Los Altos, CA). After 6 hours of incubation at 37°C, cells were washed, fixed in fixation buffer (Immune Source) and permeabilized with permeabilization/wash buffer (Immune Source), following the manufacturer's instructions. T cells were then stained with anti-IL-4-PE and anti-IFN- -FITC
antibodies (Immune Source) and finally analyzed with a flow cytometer.
Assessment of cytokine production To assess the effects of IL-11 on DC cytokine production during maturation, immature Mo-DCs were plated at 5 × 105/mL in RPMI 1640-10% FCS in the presence of 2.5 × 105 irradiated (30 Gy) murine L cells stably transfected with CD40L or untransfected, which served as internal control14 with or without IL-11. Supernatants were collected after 40 hours of coculture and assayed, in serial dilutions, in duplicate, for IL-12 (p75), IL-10, TNF- , and IL-1 (concentration using an enzyme-linked immunosorbent assay [ELISA] kit; R & D Systems). CD14+ cells were
stimulated for 16 hours with IFN- (1000 U/mL) and incubated with LPS
(1 µg/mL; Sigma) in the presence and absence of IL-11 (50 U/mL).
After 24 hours, cells were collected and supernatants were assayed for
IL-12 p75 concentration. IL-11 concentration in the supernatant of DCs
was also determined by an ELISA kit (R & D Systems).
To determine T cell polarization on IL-11 stimulation,
CD4+CD45RA+ naive T lymphocytes were
coincubated with mature Mo-DCs or grown in presence of anti-CD3 and
anti-CD28 MoAbs (see above). At the end of culture, T cells were seeded
in 24-well culture plates at a cell density of
1 × 106/mL in the presence of PMA (10 RNA purification Total cellular RNA was extracted using a modification of the guanidinium-cesium chloride centrifugation technique.16 To avoid a potential genomic DNA contamination of purified RNA, all the samples were digested with RQ1-DNAse for 30 minutes at 37°C by adding 10 U RQ1 (Promega), 40 U RNAsin (Promega), 1 × RQ1 buffer to a final volume of 200 µL. RNA concentration was then evaluated by reading the OD at 260 nm and by loading the samples on a 1% denaturing agarose gel. These quantitative controls are crucial to reverse transcribe the same amount of RNA from the different samples studied.Oligonucleotide primers and probes and complementary DNA fragment labeling Oligonucleotide primers and probes were synthesized with an automated solid-phase DNA synthesizer (Applied Biosystems, Foster City, CA, Model 381A) with the standard fosforamidites chemistry and purified by several extractions with NH4OH, incubated at 56°C for 16 hours and ethanol precipitated or purified by polyacrylamide gel electrophoresis (PAGE). All the synthesized oligomers were previously compared with the gene bank DNAsis (Hitachi, Brisbaine, CA) to avoid homologies with other gene sequences. Furthermore, we synthesized oligonucleotide primers from separate exons for excluding a potential genomic DNA contamination of the RNA samples. The sequences of IL-11 receptor (IL-11R) primer and probe used in this study are 5'-TGGTGTCTGCCTCCTCCCCCTGCC-3' for the direct primer (DP) and 5'-TGTAGGAGTGAGGTAGCGGGTGG-3' for the reverse probe (RP).Oligonucleotide probes and complementary DNA (cDNA) fragments labeling were performed as already reported.16 Reverse transcription-polymerase chain reaction and Southern blotting The reverse transcription-polymerase chain reaction (RT-PCR) reactions were carried out as previously described.16 Briefly, 1 µg total RNA extracted from each sample was reverse transcribed using 400 U M-MLV reverse transcriptase (Gibco, BRL, Gaithersburg, MD) and 1 µg OligoT 15 primer (Boehringer Mannheim, Milan, Italy) for 1 hour at 42°C in 1 × RT buffer in a total volume of 30 µL. The cDNA was then heated at 95°C for 3 minutes and stored at 4°C. The cDNA (1 µL) was subsequently amplified, adding 2.5 U Taq polymerase (Promega), 0.5 µg specific DP and RP in a total volume of 50 µL, in 10 mM Tris 8.3, 50 mM KCl, 1.5 mM MgCl2, 200 µM dNTPS. The amplification was carried out performing 50 cycles using the following conditions: denaturation at 45 seconds starting from the second cycle; annealing at 70°C for 2 minutes; extension at 72°C for 3 minutes. Ten microliters of each sample was then denatured in 0.2 N NaOH, 0.4 M NaCl for 45 minutes, neutralized in 25 mM phosphate buffer, pH 6.5, for 45 minutes and then transferred by electroblotting on a positively charged nylon membrane. Hybridization of the blots with oligonucleotide-labeled probes was then performed. For each experiment the same amount of cDNA was amplified. To check the amount of cDNA in each sample, the 2-microglobulin gene was amplified by
PCR with 35 cycles. A sample without RNA template was used as negative
control to exclude amplified cDNA contamination. In each experiment,
the gel after ethidium bromide staining and the corresponding
autoradiogram after hybridization were examined. The specificity of the
amplification was confirmed by hybridization with an
oligonucleotide probe.
Statistical analysis The results are expressed as the mean ± SD. Where indicated, statistical analysis was performed by means of the nonparametric paired Wilcoxon rank-sum test.
IL-11 does not affect DC generation and maturation Interleukin-11 regulates macrophage effector function by inhibiting the production of several cytokines.4-6 Therefore, we evaluated the possibility that IL-11 could affect other types of APCs such as Mo-DCs. To this end, highly purified circulating CD14+ monocytes were used to generate DCs. In these experiments, 6 to 7 days of culture in presence of GM-CSF and IL-4 induced a cell population with the typical phenotype of immature Mo-DCs: CD1a+, HLA-DR+, CD80+/ ,
CD86+, CD83 (Figure
1A). Addition of IL-11 from either the
beginning of the culture (data not shown) or during the maturation
induced by exposure to LPS, CD40L, or TNF- never modified the
phenotypic profile of mature DCs, as demonstrated by the up-regulation
of CD83, the down-regulation of CD1a, and the coexpression of
costimulatory molecules (Figure 1B). Functionally, DCs generated with
or without IL-11 showed the same potency in stimulating allogeneic
lymphocytes and autologous lymphocytes coincubated in the presence of
soluble proteins such as keyhole lympet hemocyanin or tetanus toxoid
(data not shown).
IL-11 inhibits IL-12 production by activated monocytes but not DCs To assess the capacity of IL-11 to modulate DC IL-12 p75 production, we induced maturation of DCs by incubating them with the murine fibroblasts L-cell line stably transfected with CD40L. For comparison, we evaluated IL-12 production of CD14+ monocytes primed with IFN- and then exposed to LPS for 24 hours (Figure 2). As expected, CD40L proved to
be an optimal inducer of IL-12 secretion by DCs. However, whereas IL-11
inhibited production of IL-12 by activated monocytes
(P < .05), it did not exert any effect on DCs (Figure
2A). Even in the presence of other maturation stimuli, such as LPS,
IL-11 exerted no significant effect on IL-12 production (data not
shown). We then evaluated the capacity of IL-11 to influence production
of TNF-, IL-10, and IL-1 by CD40L-stimulated Mo-DCs. As with
IL-12, secretion of these cytokines was never significantly affected by
IL-11 (Figure 2B). Taken together, these results demonstrate that IL-11
exerts a potent immunomodulatory effect on monocytes, but not
on Mo-DCs.
IL-11 prevents type-1 cytokine response via a direct effect on CD4+CD45RA+ naive T cells We first investigated the expression of IL-11R on a broad spectrum of cell subsets. As shown in Figure 3, CD19+, CD8+, CD4+, and CD4+CD45RA+ cells expressed IL-11R messenger RNA (mRNA). We then investigated the effects of IL-11 on the development of CD4+CD45RA+ naive T cells. Highly purified lymphocytes were stimulated with anti-CD3 and anti-CD28 MoAbs in the presence of IL-11 or IL-4, expanded with IL-2, and then reactivated with PMA plus ionomycin prior to the final assessment of their intracellular cytokine content. T cells that were not restimulated at day 6 with IL-2 did not show production of any of the cytokines assessed (data not shown).
As reported in the representative example in Figure
4, IL-11 was able to prevent Th1
polarization by increasing the percentage of IL-4+ cells
(from 2% ± 2% to 12% ± 4%; n = 3; P < .05)
and by reducing the percentage of IFN-
The same pattern of type-2 cytokine production and secretion was found
when CD4+CD45RA+ cells were stimulated with
TNF- Taken together, these results demonstrate that IL-11 directly affects T cells by driving the polarization of naive CD4+ lymphocytes to Th2 cells, and that this effect is similar to that exerted by IL-4. Moreover, IL-11 maintained the Th2-polarizing effect even when T cells were incubated with DCs, which provide a highly potent stimulus to Th1 cell differentiation.
In T-cell polarization, naive CD4+ cells differentiate
into either Th1 or Th2 effector cells. Th1 cells mainly produce IL-2 and IFN- Interleukin 11 is an IL-6-like cytokine.1 IL-11 and IL-6
both share the gp 130 molecule in their receptor complexes. IL-11 has
demonstrated an anti-inflammatory activity by inhibiting
proinflammatory cytokine gene expression in
macrophages.4-6 In mice, administration of IL-11 during
allogeneic bone marrow transplantation results in polarization of the
T-cell response to Th2-type cells production, with correspondingly
reduced IFN- No data are currently available on the possible effects of IL-11 on
human DCs, which are the most potent IL-12-mediated inducers of Th1
immune responses. Moreover, the hypothesis that IL-11R is expressed on
T cells and that IL-11 can therefore exert a direct effect on T cells
and NK cells, the main producers of IFN- Earlier studies have shown that IL-11 inhibits IL-12 production by activated human macrophages.6 Although confirming this finding, the results of the present study indicate that unlike IL-6, which inhibits DCs differentiation from CD34+ cells,21 IL-11 plays no part in the generation or functioning of DCs. We came to this conclusion after studying the development of Mo-DCs from CD14+ monocytes in the presence and absence of IL-11, as well as DC terminal maturation and cytokine production. It should be pointed out that Mo-DCs were cultured in the presence of FCS, the addition of which might have already matured the Mo-DCs before the addition of IL-11, rendering them less sensitive to its effect. However, the phenotypic profile of the Mo-DCs prior to the addition of IL-11 and maturation stimuli (Figure 1A) was typical of immature DCs, with high CD1a and low or absent CD83 expression. On the other hand, our study also provides the first demonstration that
IL-11 does indeed induce T-cell polarization by exerting a direct
effect on CD4+ naive T lymphocytes that bear IL-11R. We
found that IL-11 inhibited IFN- The finding that IL-11 is a potent anti-inflammatory and Th2-polarizing cytokine underscores the clinical potential of IL-11 in Th1-predominant inflammatory diseases such as autoimmune disorders and GVHD.10-12 Administration of IL-11 might also help to avoid rejection of solid organ transplants. The notion that IL-11 exerts its modulatory effects on naive T cells suggests that its administration may minimize impairment of amnestic immune responses.
We are grateful to Robin M. T. Cooke for editing.
Submitted July 24, 2000; accepted December 28, 2000.
Supported by Italian Association for the Research against Cancer (AIRC), Milan, Italy, and the Istituto Superiore di Sanità (AIDS project) CNR (N. 00.00118-ST97), and MURST EX-40%.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Roberto M. Lemoli, Institute of Hematology and Medical Oncology "Seràgnoli" Via Massarenti, 9 Bologna, Italy; e-mail: rmlemoli{at}med.unibo.it.
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© 2001 by The American Society of Hematology.
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  D. de Totero, R. Meazza, M. Capaia, M. Fabbi, B. Azzarone, E. Balleari, M. Gobbi, G. Cutrona, M. Ferrarini, and S. Ferrini The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways Blood, January 15, 2008; 111(2): 517 - 524. [Abstract] [Full Text] [PDF]
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A. Curti, S. Pandolfi, B. Valzasina, M. Aluigi, A. Isidori, E. Ferri, V. Salvestrini, G. Bonanno, S. Rutella, I. Durelli, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells Blood, April 1, 2007; 109(7): 2871 - 2877. [Abstract] [Full Text] [PDF]
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D. de Totero, R. Meazza, S. Zupo, G. Cutrona, S. Matis, M. Colombo, E. Balleari, I. Pierri, M. Fabbi, M. Capaia, et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells Blood, May 1, 2006; 107(9): 3708 - 3715. [Abstract] [Full Text] [PDF]
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 H. Cakmak, F. Schatz, S.-T. J. Huang, L. Buchwalder, M. Rahman, A. Arici, and C. J. Lockwood Progestin Suppresses Thrombin- and Interleukin-1{beta}-Induced Interleukin-11 Production in Term Decidual Cells: Implications for Preterm Delivery J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5279 - 5286. [Abstract] [Full Text] [PDF]
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 S. Bamba, A. Andoh, H. Yasui, J. Makino, S. Kim, and Y. Fujiyama Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways Am J Physiol Gastrointest Liver Physiol, August 8, 2003; 285(3): G529 - G538. [Abstract] [Full Text] [PDF]
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
) or absence (
) of IL-11. Supernatants were
collected after 40 hours of coculture and assayed for IL-12 (p75) (A),
IL10, TNF-
