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Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA. These data
suggest that Th2 IL-4 production may contribute to the down-regulation
of immune responses by directly enhancing Th2 IL-10 production. In
addition, the data clearly demonstrate that exogenous cytokines can
significantly influence effector cytokine production by effector T
cells without the requirement for TCR signals. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production during and after Th1 differentiation
(reviewed in 1 .
The effector functions of IL-4 are important in the immune response to
a variety of infections and are also clearly implicated in the
pathogenesis of atopic disease (1). In these conditions, IL-4 functions
in part by its ability to induce IgE class switching in B cells. IL-4
also plays a role in down-regulating immune responses leading to
reduced allograft rejection (2, 3) and prevention or amelioration of
experimental autoimmune disease (4, 5, 6, 7, 8, 9). In these cases, IL-4 is assumed
to act as regulatory cytokine by several mechanisms: IL-4 drives T cell
differentiation toward the Th2 phenotype and counteracts Th1
differentiation (1); and IL-4 modulates macrophages activity by
suppressing TNF-
, macrophage CSF receptor, IL-1, IL-6, and
PGE2 (10, 11, 12) and induces the anti-inflammatory,
soluble IL-1R antagonist (13). In addition, IL-4 is assumed to
play an important role in the induction or maintenance of immunological
tolerance (reviewed in 14 , but the mechanisms are not clear.
T cell unresponsiveness can be induced by IL-10 in vitro. IL-10 suppresses the proliferation and cytokine expression of Th1 and Th2 cells (15, 16); this may be due to an indirect effect of down-regulating MHC II and costimulatory molecules on the APCs (reviewed in 17 . Besides these effects on the APCs, IL-10 supports differentiation of T cells to a nonproliferating, IL-10-producing phenotype, named the T repressor cell (18). Taken together, these in vitro data indicate that IL-10 is a down-regulator of T cell responsiveness.
There are several types of evidence suggesting that IL-10 is involved in the down-regulation of immune responses and/or tolerance induction in vivo. For example, IL-10-deficient mice succumb to inflammatory bowel disease (19). EBV uses an IL-10 homologue to escape recognition by the immune system, presumably by inducing a tolerogenic environment (17, 20). High IL-10 secretion is a characteristic of T cells, which ameliorate autoimmune disease in mice (18, 21). Furthermore, allograft survival is significantly increased in animals treated with adenovirus-encoded IL-10 (22).
Because both IL-4 and IL-10 are implicated in down-regulation of immune responses and tolerance, we have investigated potential links between the immunoregulatory effects of both these cytokines. The studies described here examine the influence of IL-4 on T cell IL-10 production. The findings support a new role for IL-4 in enhancing IL-10 production in the absence of Ag stimulation. Thus, Th2-derived IL-4 may contribute to the down-regulation of immune responses by autocrine and paracrine induction of IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Transgenic mice expressing the DO.11.10 TCR (DO.11) specific for chicken OVA peptide 323–339 in the context of the MHC class II molecule I-Ad (23) were bred in our pathogen-free animal facility. All animals were maintained in accordance with the guidelines of the committee on animals of the Harvard Medical School and those prepared by the committee on care and use of laboratory animals of the Institute of Laboratory Resources, National Research Council (Department of Health, Education, and Welfare Publication (National Institutes of Health) FS-23). Transgenic TCR expression was assessed by staining blood mononuclear cells with the DO.11 anti-clonotypic Ab KJ126 followed by flow cytometric analysis.
Ags, cytokines, Abs, and kinase inhibitors
The Ag used in all studies was the chicken OVA peptide 323–339
obtained from the peptide synthesis facility of the Center for
Neurologic Diseases, Brigham and Women’s Hospital (Boston, MA).
Supernatant containing recombinant murine IL-4 was generated from the
I3L6 cell line transfected with a constitutively expressed murine IL-4
cDNA (a gift from Dr. Robert Tepper, Massachusetts General Hospital,
Boston, MA). The effects of the I3L6 supernatant described in this
paper could be inhibited by anti-IL-4 mAb 11B11 (see below) and
reproduced with purified rIL-4 obtained from the National Biological
Standards Board (Hertfordshire, U.K.). IL-2-containing supernatants
were obtained from the X63-IL2 cell line, which expresses a stably
transfected murine IL-2 gene (24) (obtained from Dr. Fritz Melchers,
Basel Institute of Immunology, Basel, Switzerland). Recombinant murine
IL-6 and IFN- were purchased from Endogen and Genzyme, respectively
(both Cambridge, MA). Recombinant murine IL-12 was a gift from Dr. Stan
Wolf, Genetics Institute (Cambridge, MA). Anti-IL-4 and anti-CD3
mAbs were generated from the 11B11 (25) and the 145-2C11 (26) B cell
hybridomas, respectively, and purified on a protein A column
(Pharmacia, Piscataway, NJ).
Inhibitors were used at a 1- to 10-µM concentration, as indicated in the figure legends, and were preincubated with the cells for 5 min at room temperature. Cyclosporin A (CsA)4 and ionomycin were purchased from Sigma (St. Louis, MO), rottlerin and GO 6976 were obtained from Alexis Corp. (San Diego, CA), and tyrophostin B42 (also called AG490) was purchased from Calbiochem (La Jolla, CA).
Cell preparation and culture
All cultures were conducted in RPMI 1640 supplemented with 1 mM L-glutamine, sodium pyruvate, nonessential amino acids, 5 x 10-5 2-ME, and 10% heat-inactivated FCS (all from Life Technologies, Grand Island, NY). Th1 and Th2 cells were generated as previously described (27). Briefly, CD4+ T cells were purified from peripheral and mesenteric lymph nodes and spleen cells of 6- to 8-wk-old DO.11 mice using CD4- Dynal magnetic beads and Detach-a-Bead (both from Dynal, Lake Success, NY). The efficiency of purification was initially tested by flow cytometry and was >95% CD3+ CD4+. APCs were spleen cells purified from BALB/c mice and treated with 50 µg/ml mitomycin C (Sigma) at 37°C for 30 min as previously described (27). T cell differentiation was induced by culturing 2 x 105 purified CD4+ TCR transgenic T cells with 2 x 106 APCs, 1 µM OVA peptide 323–339, and either IL-12 (10 ng/ml) plus anti-IL-4 (1/1000 dilution of ascites) for Th1 differentiation or IL-4 (1000 U/ml) for Th2 differentiation, in 1 ml of medium. The cultures were fed with fresh medium containing 10 U/ml IL-2 after 4 days and harvested for restimulation after 6 days.
The D10.G4.1 T cell clone was obtained from the American Type Culture Collection (Manassas, VA) and maintained as previously described (28). Briefly, cells were grown in RPMI medium supplemented with 1 mM L-glutamine, sodium pyruvate, nonessential amino acids, 5 x 10-5 2-ME 10% heat-inactivated FCS (all from Life Technologies), 50 U of IL-4 (I3L6 supernatant), and 10 U of IL-2 (X63 supernatant). D10.G4.1 cells were restimulated every 7–14 days with conalbumin (Sigma) and mitomycin C-treated spleen cells from AKR/J mice. One day before the experiment, cells were rested in medium lacking IL-4.
RNase protection assay
For RNA collection, Th1 or Th2 cells were cultured at 4 x
106 cells/ml in 2-ml wells and restimulated with
exogenously added cytokines or plate-bound anti-CD3 (27) as
indicated in the figures. After 6 h, the cells were lysed with
guanidinium thiocyanate solution. RNA was precipitated with
isopropanol, washed with 70% ethanol, and subjected to RNase
protection assay. Cytokine mRNA levels were analyzed by RNase
protection assay using the Riboquant multiprobe set (PharMingen, San
Diego, CA) following the instructions of the supplier. In brief, all
RNA obtained from 4 x 106 cells (
4–6 µg RNA)
were hybridized overnight to the 32P-labeled RNA probe,
which had been previously synthesized from the supplied template set
(mck-1 from PharMingen). Single-stranded RNA and free probe were
digested by RNase A and T1. Subsequently, protected RNA was phenolized,
precipitated, and analyzed on a 6% denaturing polyacrylamide gel. The
quantity of protected RNAs was determined using a PhosphorImager and
ImageQuant software (both from Molecular Dynamics, Sunnyvale, CA). The
cytokine transcripts were identified by the length of the respective
fragments. For quantitation, cytokine values were expressed as a
percentage of the mean values of the housekeeping genes L32 and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for each condition/gel
lane.
ELISA determination of IL-10
Cell culture supernatants were analyzed by ELISA as previously described (29). The anti-IL-10 mAb 16E3 (Endogen) was used as capture Ab, and the biotinylated anti IL-10 mAb 2A5 (Endogen) was used for detection of plate-bound IL-10.
Electrophoretic mobility shift assays (EMSAs)
EMSAs were performed as previously described (28). Briefly, nuclear extracts of Th2 cells were prepared as follows. Cells were lysed in hypo-osmotic buffer containing 10 mM KCl, 1 mM DTT, 0.5 mM EDTA, 10 mM HEPES (pH 7.9; all from Sigma), and protease inhibitors (Complete, Boehringer Mannheim, Indianapolis, IN) followed by addition of Nonidet P-40 (Sigma) to a 1% final concentration. Nuclei were pelleted by microcentrifugation for 1 min and washed once with the buffer described above. Nuclei were lysed in 50 µl of a high salt buffer containing 400 mM NaCl, 50 mM DTT, 20 mM HEPES, 0.5 mM EDTA, and protease inhibitors. The nuclear debris was removed by centrifugation at 4°C, and the supernatant was stored in a fresh tube at -70°C. Nuclear extracts were normalized for equal protein content using a colorometric assay as described by the manufacturer (Bio-Rad, Hercules, CA).
For binding reactions, nuclear extracts were incubated with an
oligonucleotide (18 mer) that corresponds to a consensus STAT6
DNA-binding element of the murine IL-4 promoter (TGATTTCACAGGAAAATT) as
previously described (28). The two strands of the oligonucleotides were
labeled with [-32P]ATP using T4 kinase (Life
Technologies). Subsequently, the oligonucleotides were separated from
free [-32P]ATP by running the labeling mix over a
Chromaspin-10 column (Clontech, Palo Alto, CA). Single-stranded
oligonucleotides were eliminated by gel purification of the column
eluate on a 28% polyacrylamide gel. The eluted probe was precipitated,
and 5,000–10,000 cpm of the diluted probe were incubated for 15 min
with nuclear lysate in a reaction buffer containing 50 mM Tris base,
25% glycerol, 0.1 mg/ml poly(dI-dC), 5 mM DTT, and 1 mg/ml BSA. The
mixture was incubated for 10 min at room temperature and loaded on a
5% nondenaturing polyacrylamide gel. Following electrophoresis,
the gel was dried and subjected to autoradiography and
phosphorimaging.
Statistics
The nonparametric Mann-Whitney U test was applied to analyze differences for all parameters examined. Differences were considered statistically significant at p < 0.01.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Th1 or Th2 populations that had been differentiated from purified
DO.11 CD4+ T cells were stimulated for 6 h with
medium, IL-4, or plate-bound anti-CD3 as a positive control. To all
cultures lacking exogenously added IL-4, anti-IL-4 Abs were added
to neutralize any endogenously produced IL-4. Without stimulation, Th1
cells expressed only traces of IL-10, IL-13, and IL-2 and low levels of
IFN- mRNA (Fig. 1
A,lane 2). In contrast, Th2 cells expressed a detectable, but low,
amount of IL-10 mRNA, and only trace or undetectable amounts of message
for other cytokines (Fig. 1A, lane 6). To confirm
the success of the subset differentiation, T cells were restimulated
with plate-bound anti-CD3 Abs. As expected, anti-CD3-stimulated
Th2 cells showed marked induction of mRNAs encoding IL-4, IL-13, IL-10,
and, to a lesser extent, IL-5. In contrast, IL-2 and IFN- mRNAs were
expressed in only very limited amounts (Fig. 1A, lane
8). Anti-CD3-stimulated Th1 cells expressed marked levels of
IFN- message and very little IL-4, IL-5, IL-10, or IL-13 mRNAs. When
Th2 cells were incubated with IL-4 in the absence of anti-CD3,
there was a significant and consistent enhancement of IL-10 mRNA (Fig. 1, A and B). In 13 independent experiments, IL-4
increased the expression of IL-10 mRNA 7-fold
(p < 0.01). In addition, IL-4 caused a 4-fold
enhancement of IL-13 mRNA. IL-13 mRNA levels were about one-half as
high as IL-10 mRNA levels if compared with the level of housekeeping
gene expression. In contrast, IL-4 did not enhance expression of IL-2,
IL-5, IL-6, IL-9, or IFN-. Similar observations were made using a
well-established Th2 cell clone, D10.G4.1 (data not shown). Although
the experiments in the present study were performed at saturating
levels of IL-4 (1000 U), titration experiments demonstrated increased
IL-10 mRNA levels in DO.11 Th2 cells stimulated with as little as 50 U
of IL-4 (data not shown). When Th1 cells were incubated with IL-4, no
IL-10 induction could be observed. Interestingly, an approximately
6-fold increase in the level of IFN- was observed (Fig. 1A); however, this level was small in relation to levels of
housekeeping gene expression.
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Additional cultures were set up to determine whether other
cytokines besides IL-4 could up-regulate T cell IL-10 production in the
absence of TCR engagement. In Th1 cells, no substantial effect of
IFN-, IL-12, IL-2, or IL-6 on IL-10 mRNA expression could be
detected. IL-2, however, enhanced IFN- production 7-fold, whereas
IL-4 or IL-12 enhanced IFN- expression only 1.7- or 1.6-fold,
respectively (Fig. 2, lane 3).
IFN- or IL-6 had no effect on IFN- expression. None of the added
cytokines enhanced Th1 expression of IL-4, IL-5, IL-10, IL-13, IL-15,
IL-9, IL-2, or IL-6 mRNA.
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, lanes 9 and 12). IFN-, IL-12, or
IL-6 had no effect on IL-10 mRNA expression. Other Th2 cytokines were
not significantly induced with IL-4, IFN-, IL-12, IL-2, or IL-6. IL-4 and IL-2 enhance IL-10 protein expression in Th2 cultures in the absence of TCR engagement
To determine whether the effects of IL-4 on IL-10 mRNA levels
correlated with enhanced IL-10 protein expression, cytokine ELISAs were
performed on supernatants taken 24 h following addition of the
cytokines. Protein levels were too low to be measured at earlier time
points. The IL-10 production of Th2 cells in the absence of any
stimulation was either under the detection limit of the ELISA (10
pg/ml) or slightly above it. The addition of IL-4 increased the level
of IL-10 to 80 pg/ml after 24 h (Fig. 3). Incubation with IL-2 increased the
IL-10 level to 40 pg/ml. These results correlate very well with the
mRNA levels reported above.
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One way in which IL-10 could act to increase steady state IL-10
mRNA levels is to enhance mRNA stability. To address this possibility,
IL-10 mRNA levels were examined in IL-4-activated Th2 cells after the
addition of actinomycin D, which blocks de novo transcription. Fig. 4 shows that IL-10 message decayed at the
same rate with or without IL-4 present. Interestingly, the level of
IL-10 mRNA dropped dramatically within 30 min (>50% of the amount at
0 min; Fig. 4, A and B), whereas housekeeping
genes remained unaffected for up to 5 h. The rapid loss of IL-10
message was also observed in D10.G4.1 cells. When D10.G4.1 cells were
stimulated with anti-CD3 instead of IL-4, IL-10 mRNA disappeared
faster than the other Th2 cell cytokines, IL-4, IL-5, and IL-13 (data
not shown).
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The effects of specific inhibitors of protein kinases and
phosphatases on IL-4 induction of IL-10 mRNA were examined to determine
which signaling pathways may be involved in the effect (Fig. 5). The effect of the drugs were tested
after a 6-h incubation period. The cell viability in all conditions
shown in Fig. 5 was >95% as assessed by trypan blue dye exclusion.
CsA was used to block potential residual NF-AT-dependent TCR signaling
in the differentiated cells. Interestingly, while CsA effectively
blocked anti-CD3-induced IL-10 mRNA expression in Th2 cells (data
not shown) as well as ionomycin-induced IL-4 expression (Fig. 5A, lane 6), this drug did not block
IL-4-mediated enhancement of IL-10 mRNA expression (Fig. 5A, lane 9). Furthermore, IL-13 enhancement by
IL-4 was also resistant to CsA, while IL-13 enhancement by ionomycin
was not. We also found that the JAK kinase inhibitor tyrophostin B42
(30, 31) could block STAT6 activation in DO.11 cells in a
dose-dependent manner (Fig. 5C), but this drug had no effect
on IL-4 enhancement of IL-10 mRNA expression (Fig. 5B). Only
protein kinase C (PKC) inhibitors, in particular rottlerin, which
preferentially blocks the PKC
isoform, interfered with IL-4
enhancement of IL-10 expression (Fig. 5A, lanes 4
and 5). Maximal inhibition was achieved all across a
titrated rottlerin concentration range from 0.5–300 µM. At
concentrations >200 µM, 40% trypan blue-positive cells were
observed. IL-10 mRNA could never be 100% inhibited, suggesting that a
basic level is constitutively expressed in Th2 cells and therefore
regulated by transcriptional elements independent of PKC activation.
IL-4 enhancement of IL-13 was also sensitive to PKC inhibitors. In
contrast to IL-10, IL-13 induction was most sensitive to GO 6976, a
selective blocker of PKC, -ß, and - isoforms (Fig. 5A, lane 3).
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D demonstrates that, in fact, PMA, a
potent inducer of PKC activation, was sufficient to induce IL-10 and
IL-13 mRNA expression and, to a lesser degree also IL-5. In contrast,
PMA did not induce IL-4 mRNA expression. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The data indicate that IL-4 does not enhance IL-10 in Th1 cells despite
the capability of these T cells to respond to IL-4 (27, 32, 33). This
is in agreement with previous studies showing that IL-10 is an
exclusive Th2 cytokine in the mouse; in contrast, human Th1 cells are
reported to produce IL-10 (15, 34). The finding that IL-4 also enhanced
IFN- gene expression to some degree was unexpected; however, the
induced levels were low compared with those of housekeeping genes.
Although the biological significance of this finding is not clear, it
should be noted that IFN- expression is impaired in IL-4 knockout
mice (35).
In addition to the IL-4 effects, the data reported here indicate that
IL-2 enhances T cell cytokine gene expression in the absence of TCR
signals. For example, IL-2 increases IL-10 mRNA and protein expression
in Th2 cells. Similarly, IL-2 enhances TCR-induced IL-10 production in
human T cells (36). IL-2 induction of IL-10 by human Th1 cells
apparently leads to down-regulation of Ag-presenting functions of
macrophages and therefore reduced IL-2 production and proliferation of
Th1 cells. This has been invoked as a mechanism of negative feedback
regulation of Th1 responses (15, 16, 36). An IL-10-mediated negative
feedback regulation has also recently been reported in an in vivo model
of allergic encephalomyelitis (37). In the experiments reported here,
IL-2 also increased IFN- expression 7-fold in Th1 cells. These
results confirm previous data showing that IL-2 can induce IFN-
expression in murine T cell lines (38). It is perhaps useful to compare
the effects of IL-2 on Th1 and Th2 cells. In the former case, IL-2
synergizes with IL-12 to induce IFN-, and this would favor
macrophage activation. In the latter case, IL-2 appears to work with
IL-4 to induce IL-10, favoring down-regulation of macrophage function.
The data reported in this paper also show that IL-4 significantly enhances IL-13 mRNA production by Th2 cells, albeit to lower levels than that induced by IL-10. This finding contradicts a report that IL-4 does not influence IL-13 mRNA expression (39). This discrepancy may reflect the sensitivity of the methods used; the quantitative RNase protection assays employed here are probably more sensitive than semiquantitative RT-PCR, which does not allow reliable detection of less than 5-fold differences.
The present study shows that IL-4 enhanced IL-10 mRNA expression is presumably a result of transcriptional activation of the IL-10 gene and not a result of mRNA stabilization, as it has been reported for several cytokines (reviewed in 40 . Interestingly, the IL-10 mRNA rapidly drops after inhibition of RNA de novo synthesis by actinomycin D. We also have preliminary evidence that TCR induced IL-10 mRNA drops much faster than other Th2 cytokines, such as IL-4, IL-5, and IL-13. The short half-life of IL-10 mRNA might be important to limit the duration of IL-10-mediated down-regulation of bystander T cells and macrophages.
The fact that one T cell cytokine enhances expression other T cell
cytokines in the absence of TCR engagement raises interesting questions
about the signal requirements for activation of different T cell
cytokine genes. Cytokine induction in the absence of the TCR receptor
engagement has been reported previously for a mouse Th2 cell clone
(D10.G4.1). These cells express IL-5, IL-6, and IL-10 following
stimulation in vitro with IL-1 (41). Some T cell cytokines, such as
granulocyte-macrophage CSF and IL-2, are characterized by a strict
requirement of activation of both the PKC- and calcium-dependent
pathways. IFN-, IL-3, and IL-4 are all partially induced by calcium
ionophore alone, and IL-5, IL-6, and IL-10 are partially induced by
either PMA or calcium ionophore alone (41, 42). The data presented
here indicate that IL-10 can be induced by PMA alone or ionomycin
alone, and it is of interest to know whether the IL-4 pathway of IL-10
enhancement involves either PKC activation or calcium/NF-AT signals.
IL-4-enhanced IL-10 expression was not blocked by PKA or
mitogen-activated protein kinase inhibitors (data not shown) or by CsA
(Fig. 5). In contrast, CsA did prevent calcium ionophore-induced IL-10
expression. These results indicate that IL-10 gene expression can be
enhanced by at least two independent signaling pathways. Surprisingly,
the JAK kinase inhibitor (tyrophostin B42) did not show any effect on
IL-4-induced IL-10 expression. However, the PKC inhibitor rottlerin did
inhibit the IL-4-induced IL-10 expression. These results suggest that
IL-4 engages a signaling pathway that is distinct from the JAK/STAT
pathway and involves PKC. However, pharmacological inhibitors are never
completely substrate specific, and therefore further biochemical
analysis of this putative pathway will be required. Nonetheless, the
association of IL-4R signaling and PKC activation has been demonstrated
in macrophages (43). Preliminary results from our laboratory indicate
that IL-7 also induces IL-10 mRNA in DO.11 and D10.G4.1 T cells. We
speculate that the common -chain that is shared by the
receptors for IL-2, IL-4, and IL-7 is involved in a PKC-dependent,
STAT6-independent signaling pathway that induces IL-10 expression.
In conclusion, IL-4 markedly enhances IL-10 gene expression in primary Th2 cells but not in Th1 cells. This subset-specific effect of IL-4 is independent of TCR signaling and may have important consequences on the paracrine regulation of the immune responses. In addition, IL-4 enhancement of IL-10 may be involved in T cell differentiation toward the recently described T repressor phenotype (18). We hypothesize that IL-4-enhanced IL-10 expression represents a negative feedback regulation of immune responses.
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Footnotes |
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2 Current address: Swiss Institute of Allergy and Asthma Research, Obere Strasse 22, CM-7270 Ilavos, Switzerland.
3 Address correspondence and reprint requests to Dr. Andrew H. Lichtman, Department of Pathology, Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115-5814. E-mail address:
4 Abbreviations used in this paper: CsA, cyclosporin A; EMSA, electrophoretic mobility shift assay; PKC, protein kinase C.
Received for publication June 3, 1998. Accepted for publication September 22, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production. J. Immunol. 159:3247.[Abstract]
or IL-2 determines their function. Int. Immunol. 7:1287. mRNA synthesis. J. Immunol. 137:3836.[Abstract]
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