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Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute, Frederick Cancer and Research Development Center, Frederick, MD 21702
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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knockout (-/-) mice were greater than
seen in purified cells from normal controls. In contrast, IL-10
production induced by IL-2 and/or IL-12 was not significantly different
in IFN- (-/-) mice and normal controls. These results suggest
IL-13 expression induced by IL-2 + IL-18 may be regulated by IFN- in
vivo, while IL-10 expression may be IFN--independent. Thus,
depending upon the cell type, IL-18 may act as a strong coinducer of
Th1 or Th2 cytokines. Our findings suggest that IL-12 and IL-18 have
different roles in the regulation of gene expression in NK and T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, while Th2 cells were
initially reported to produce IL-4, IL-5, IL-6, IL-10, and IL-13. Th0
cells can produce a combination of the cytokines characteristic of Th1
and Th2 cells, i.e., IL-2, IL-4, IL-13, and IFN-, as well as other
cytokines (1, 2, 3, 4).
IFN- regulates a variety of immunological responses in both innate
and acquired immunity. It is the predominant cytokine during
Th1-dominated immune reactions. IFN- is secreted from T cells and NK
cells stimulated with Ags or mitogens (5, 6). It has been reported that
IL-1, IL-2, IL-12, IL-18, and TNF-
are potent inducers and
coinducers of IFN- in NK and T cells (5, 6, 7, 8, 9, 10, 11, 12, 13). In particular, one of
the key events during innate immune reaction is thought to be IL-12
production by macrophages (7). IL-12 then strongly induces NK and T
cells to express IFN- and GM-CSF mRNA, and is the key cytokine
driving Th1 cell differentiation (7).
IL-18 was originally discovered as an IFN--inducing factor, and the
structural gene for this protein has recently been cloned (10). IL-18
acts as a strong coinducer of IFN- and GM-CSF production in T cells,
NK cells, B cells, and macrophages (9, 10, 11, 12, 13). IL-18 also augments NK
activity and Fas ligand expression in T cells and NK cells (9, 10, 11, 12, 13).
Although IL-18 itself cannot induce strong IFN- expression, IL-18
fully induces IFN- production in synergy with IL-12 (9, 10, 11, 12, 13). IL-18
is thought to reduce Th2 cytokine (IL-10) production via IFN-
induction (14). In contrast to IL-12, IL-18 itself cannot induce Th1
differentiation, but potentiates IL-12-driven Th1 development (11, 12).
Furthermore, recent studies have demonstrated that IL-12 can
up-regulate IL-18 receptor expression in murine Th1 cell clones and
purified T and B cells (15, 16). Thus, it is clear that IL-12 can
potentiate IL-18 functions. Taken together, IL-12 and IL-18 are thought
to be strong inducers or cofactors of Th1 cell development.
IL-13 was initially described as a protein preferentially produced by
activated mouse Th2 cells (4). IL-13 acts on normal and malignant B
cells, monocytes, macrophages, NK cells, polymorphonuclear cells,
osteoblasts, endothelial cells, fibroblasts, and keratinocytes (4).
IL-13 has only a low degree of sequence homology with IL-4, but shares
most, but not all, of its biological functions with IL-4. IL-13 and
IL-4 both induce IgG4 and IgE production by human B cells and
up-regulate CD23, CD71, and MHC class II expression on monocytes and B
cells (17). IL-13 and IL-4 also down-regulate NK and monocyte function,
including cytokine gene expression (18, 19). Recent studies in our
laboratory have demonstrated that IL-13 and IL-4 can induce specific
STAT6 protein DNA complexes after treatment of human NK cells with
these cytokines (19). Moreover, both IL-4 and IL-13 receptor complexes
share common signal transducing components (IL-4R and IL-13R)
(20). In contrast, IL-4R, but not IL-13R, complex uses the IL-2R
chain, and different ligand-binding sites were also observed (4, 20).
In addition to being produced by T cells, EBV-transformed B cells and
mast cells are able to express IL-13 (21). While NK cells are known to
be potent producers of IFN-, GM-CSF, TNF-, IL-5, and IL-10 (5, 6, 22, 23), we have reported recently that human and mouse NK cells can
produce IL-13 in response to IL-2 (24).
In this study, we demonstrate that IL-18 is a potent coinducer of IL-13
production in both NK and T cells. IL-13 mRNA and protein was strongly
induced by IL-2 + IL-18 in murine NK and T cells. In T cells and NK
cells purified from IFN- knockout (-/-) mice, IL-2 + IL-18 induced
more IL-13 mRNA and protein synthesis than observed in cells obtained
from normal controls. In contrast, we found that in IFN- (-/-)
mice, IL-10 production by IL-2, IL-12 and/or IL-18 was not
significantly different from that observed in normal controls. Thus,
the signaling pathways leading to IL-13 and IL-10 gene expression
appear to be distinct. The potential importance of Th1 and Th2 type
cytokine balance in response to cytokine stimulation in vivo is
discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All cell culture was performed utilizing RPMI 1640 medium supplemented with 10% heat-inactivated FBS, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin.
Reagents
Recombinant human (h)4
IL-2 (rhIL-2) was obtained from Hoffmann-La Roche (Nutley, NJ).
Recombinant mouse (m) IL-12 was generously provided by Genetics
Institute (Cambridge, MA), and rmIL-18 was obtained from Pepro Tech
(Rocky Hill, NJ). rhIL-1ß was obtained from Biological Resources
Branch, National Cancer Institute-Frederick Cancer and Research
Development Center (NCI-FCRDC; Frederick, MD). Purified anti-mouse
CD3
(145-2C11) mAb was purchased from PharMingen (San Diego, CA) and
was used for cell culture. PE-conjugated-anti-mouse NK1.1 (PK136),
PE-anti-mouse DX5 (DX5), CyChrome-anti-mouse CD3 (145-2C11),
and FITC-, PE-, or CyChrome-conjugated isotype-matched Ig for FACS
analysis were purchased from PharMingen.
Mice
C57BL/6 (B6), SCID, RAG-2 knockout (-/-) (B6 background) (25),
and B6 IFN- (-/-) mice (26) were used in this study. SCID and
IFN- (-/-) mice were backcrossed more than 10 generations with B6
mice. These mice were maintained under specific pathogen-free
conditions and used for experiments at 8–12 wk of age.
In vivo treatment of mice with IL-2
We used repeated administration of IL-2 to generate large
numbers of murine NK and T cells in the liver and spleen (27). B6,
IFN- (-/-), SCID, and RAG-2 (-/-) mice were injected with 6
x 105 IU rhIL-2 twice a day for 3 days (36 x
105 IU/total/mouse). On day 4, livers and spleens were
harvested.
Spleen cell isolation
Spleens were harvested, and single cell suspensions were made by passing the spleens through a metal mesh screen. RBC were lysed in water, and cells were washed and resuspended in 10% FBS RPMI 1640. The cell suspension was then passed through prewetted nylon wool column to deplete B cells and macrophages. Nylon wool nonadherent cells were collected, washed, and resuspended in 10% FBS RPMI 1640 for additional experiments. For further purification, these cells were sorted by MoFlo (Cytomation, Fort Collins, CO) using CyChrome-conjugated anti-mouse CD3 or PE-anti-DX5 mAb, as previously described (28).
Liver cell isolation
Perfused livers were harvested as previously described (29). Single cell suspensions from the livers were made using a Stomacher 80 (Tekmar, Cincinnati, OH). The cell suspension was passed through sterile gauze with HBSS, and cells were washed and resuspended with HBSS. The cell suspension was passed through a Cell Strainer (Becton Dickinson Labware, Franklin Lakes, NJ) with a 100-µm nylon filter and then washed with HBSS. Using Lympholyte-M (Cedarlane Laboratories, Ontario, Canada), mononuclear cells were isolated by the density gradient centrifugation method. Isolated cells were washed with HBSS two times and resuspended in 10% FBS RPMI 1640 for additional experiments.
mRNA assays
Total RNA was isolated using a single-step phenol/chloroform extraction procedure (Trizol; Life Technologies, Gaithersburg, MD). For the RNase protection assay (RPA), 2.5–5 µg of total cytoplasmic RNA was analyzed using the RiboQuant kit (PharMingen) and [33P]UTP-labeled riboprobes, as described by the manufacturer. For Northern blot analysis, 10 µg of total cellular RNA was analyzed following electrophoresis on a 0.8% formaldehyde agarose gel and hybridized with random-primed 32P-labeled cDNA probes as reported (6). mRNA level was quantitated by a densitometer (Molecular Analyst; Bio-Rad Laboratories, Hercules, CA). Mouse GAPDH or chicken ß action was used as the control for the quantitation.
Cytokine assays
Isolated splenic and liver NK and T cells were treated with
different stimuli (as indicated in Results) for the
specified periods of time, and cell-free supernatants were collected
and assayed for cytokine production by sandwich ELISA. The specific
ELISA kits utilized were: mouse IFN- (R&D Systems, Minneapolis, MN),
IL-4 (R&D Systems), IL-10 (R&D Systems), IL-13 (R&D Systems), and IL-5
(Endogen, Woburn, MA). The sensitivity limits were 2 pg/ml, 2 pg/ml, 4
pg/ml, 1.5 pg/ml, and 5 pg/ml, respectively.
Surface Ag analysis by flow cytometry
Three-color analysis was performed using a FACSort (Becton Dickinson) flow cytometer as previously reported (30). Anti-mouse CD16/CD32 mAb (2.4G2; PharMingen) was used to block the nonspecific binding. FITC-, PE-, or CyChrome-conjugated isotype-matched Ig were used for a control in all FACS analysis. A total of 30,000 cells was analyzed in each experiment.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have recently found that human and murine NK cells could
produce IL-13 in response to IL-2 (24). Utilizing IFN- (-/-) mice,
we have observed that, in the absence of IFN-, IL-13-producing NK
and T cells predominated in vivo (24). It is known that three ILs
(IL-1, IL-12, and IL-18) can be potent producers or coinducers of
IFN- and GM-CSF gene expression in combination with IL-2 in NK
cells, as well as T cells (7, 8, 9, 10, 11, 12, 13). Thus, we investigated whether murine
NK cells and T cells can produce IL-13 in response to IL-1ß, IL-12,
or IL-18. It is known that NK cells in liver and spleen are 
10% and
1–2%, respectively, of the total lymphocytes present in these organs
(27). Therefore, we used the phenomenon of IL-2-induced leukocyte
rebound to generate larger numbers of murine NK cells in the liver and
spleen from in vivo IL-2-treated mice (27). Then, lymphocytes were
isolated from the liver and spleen, as described in Materials
and Methods. Fig. 1
shows the
relative purity of isolated spleen and liver lymphocytes in a
representative experiment. Isolated liver and spleen lymphocytes were
stimulated in vitro with IL-2, IL-1ß, IL-12, IL-18, alone or in
combination for 3 h. Initially, cytokine production was analyzed
with a multiprobe RPA (data not shown). RPA analysis showed that IL-13
mRNA was induced after IL-2 stimulation, but not by IL-1ß, IL-12, nor
IL-18 alone in cells obtained from both IFN- (-/-) and B6 mice.
However, IL-13 mRNA was strongly expressed when cells were treated with
the combination of IL-2 + IL-18, but not when treated with IL-2 +
IL-1ß, IL-2 + IL-12, IL-12 + IL-1ß, IL-1ß + IL-18, or IL-12 +
IL-18 at the 3-h time point. Based on these results, we investigated
IL-13 and IFN- mRNA expression in cells purified from B6 and IFN-
(-/-) mice by Northern blot analysis. Spleen cells were isolated from
IL-2-treated mice, as described in Materials and
Methods, and mRNA was analyzed following treatment with IL-2
(100 U/ml) and/or IL-18 (50 ng/ml) for 3 h (Fig. 2). In both B6 and IFN- (-/-) mice,
IL-13 and IFN- mRNA were not strongly expressed without stimulation.
IFN- mRNA was rapidly and strongly expressed in response to IL-2 +
IL-18 in cells isolated from B6 mice. However, IL-13 mRNA was rapidly
expressed in response to IL-2 + IL-18 in cells obtained from IFN-
(-/-) mice. Although IL-13 mRNA was observed in total RNA extracted
from IL-2 + IL-18-stimulated spleen cells from B6 mice as analyzed by
RPA (data not shown), IL-13 mRNA was barely detectable in the same
total RNA when analyzed by Northern blot. In IFN- (-/-) mice,
IL-13 mRNA levels induced by IL-2 + IL-18 were 3.5- and 2.6-fold higher
than in B6 mice when compared with ß-actin and GAPDH mRNA levels,
respectively. Similar results were obtained with RPA analysis (data not
shown). No significant IL-4 mRNA or protein induction was observed in
these cells following treatment with IL-2 + IL-18 as assayed by
Northern blot, RPA, and ELISA (data not shown). In addition, no
detectable IL-13 mRNA induction by IL-2 + IL-18 was observed in cells
obtained from untreated IFN- (-/-) and B6 mice when assayed by
Northern blot analysis (data not shown).
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(-/-) and
B6 mice also could produce IL-13 protein. Spleen cells were isolated
from IL-2-treated or -untreated B6 or IFN- (-/-) mice, as
described in Materials and Methods. Isolated cells were
incubated (2 x 106/ml) for 18 h in 10% FBS RPMI
1640 with different stimuli, and the culture supernatants were analyzed
by ELISA. Results from one of four independent experiments are shown in
Fig. 3. As expected, IFN- protein was
not detected in the supernatants from spleen cells isolated from
IFN- (-/-) mice. No significant IL-13 production (<10 pg/ml) was
found in the supernatants of spleen cells from untreated B6 and IFN-
(-/-) mice. However, spleen cells from untreated B6 mice
synergistically produced IFN- in response to IL-2 + IL-18, as
previously reported (9, 10). In contrast to untreated mice, IL-13
protein induction was found in spleen cells from both IL-2-treated B6
and IFN- (-/-) mice after anti-CD3, IL-2, or IL-2 + IL-18
stimulation. In IL-2-treated IFN- (-/-) mice, IL-13 protein levels
produced by spleen cells following stimulation with IL-2 or IL-2 +
IL-18 in vitro were higher than the levels detected in spleen cell
culture supernatants from IL-2-treated normal B6 mice. IL-18 alone
induced low levels of IL-13 protein and IL-2 + IL-18 induced much more
IL-13 protein than IL-2 alone when different doses of the cytokines
were tested (Table I). It is clear that
IL-18 has a synergistic activity (i.e., more than additive) to induce
IL-13 production in combination with IL-2.
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(-/-)
mice and control B6 mice when assayed by RPA (data not shown).
Therefore, we investigated cytokine levels in the supernatants of
lymphocytes obtained from livers of IL-2-treated IFN- (-/-) and B6
mice. Results from one of four independent experiments are shown in
Fig. 4. Four different experiments
demonstrated that the levels of IL-13 produced by liver lymphocytes
stimulated by IL-2 or IL-2 + IL-18 were higher than those in spleen
cells purified from IL-2-treated B6 and IFN- (-/-) mice. Moreover,
IL-13 protein levels in the supernatants of liver and spleen
lymphocytes obtained from IFN- (-/-) mice were higher than those
levels detected in cells isolated from B6 mice (Figs. 3
and 4). Thus NK
and T cells migrating to the liver following in vivo IL-2 treatment
appear to have an enhanced ability to express IL-13 when compared with
similar cell populations in the spleen.
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We investigated whether IL-2 and IL-18 stimulation can induce
IL-10 production in lymphocytes obtained from B6 and IFN- (-/-)
mice. No enhanced IL-10 induction by IL-2 + IL-18 was found in liver
and spleen lymphocytes isolated from IL-2-treated IFN- (-/-) mice.
However, IL-18 weakly induced IL-10 production in liver and spleen
cells isolated from IL-2-treated B6 mice in combination with IL-2 (Fig. 4A, and data not shown).
It is known that IL-12 and IL-2 + IL-12 can induce both IL-10 and
IFN- production in T and NK cells (7, 22). In addition, it has been
reported that the combination of IL-12 + IL-18 strongly induces IFN-
production in T cells, NK cells, macrophages, and B cells (9, 10, 11, 12, 13). We
investigated whether IL-12, IL-2 + IL-12, and IL-12 + IL-18 could
induce IL-10 and IL-13 production in NK and T cells obtained from B6
and IFN- (-/-) mice. Although IL-12 did not induce IL-13
production in synergy with IL-2, IL-2 + IL-12 strongly induced IL-10
production in liver and spleen lymphocytes from both B6 and IFN-
(-/-) mice. In contrast, while IL-12 + IL-18 weakly induced IL-10 and
IL-13 production in both B6 or IFN- (-/-) mice, IFN- production
was strongly induced in NK and T cells purified from B6 mice (Fig. 4B, and data not shown).
IL-13 production from NK is higher than from T cells
As described above, the IL-13 production induced by IL-2 + IL-18
from liver lymphocytes was much higher than that in spleen cells in
both IL-2-treated B6 and IFN- (-/-) mice. As shown in Fig. 1, the
CD3- NK1.1+ NK subset was 10–20% and
50–70% of spleen and liver lymphocytes in these mice, respectively,
while the CD3+ NK1.1+ NK-T subset was
15–20% and 15–25%, respectively, as previously reported (24).
Recent studies have suggested that the NK-T (CD3+
NK1.1+) subset can be a potential producer of the Th2
cytokine, IL-4 (31, 32, 33). Therefore, we speculated that both NK and/or
NK-T cells could also produce IL-13 in response to IL-2 + IL-18.
Initially, we used SCID mice (B6 background) that lack T and B cells.
RPA and ELISA analysis revealed that isolated liver and spleen
lymphocytes isolated from IL-2-treated SCID mice expressed IL-13 mRNA
and protein in response to IL-2 + IL-18 (data not shown). However, it
has been reported that old SCID mice have a small number of T cells
(25). Therefore, in this study, we utilized RAG-2 knockout mice that
lack T and B cells to evaluate if NK cells can produce IL-13 in
response to IL-2 + IL-18. CD3- NK1.1+ NK cells
represented 30–40% of spleen and liver lymphocytes in untreated
RAG-2 (-/-) mice. After 3 days of IL-2 treatment in vivo, >90% of
the lymphocytes were CD3- NK1.1+ NK cells in
both the spleen and liver (Fig. 1). There was no significant population
of CD4+, CD8+, TCRß+, and
TCR
+ cells in these RAG-2 (-/-) mice (data
not shown). ELISA and RPA revealed that the liver and spleen NK cells
from IL-2-treated RAG-2 (-/-) mice produced IL-13 protein and mRNA in
response to IL-2 + IL-18 (Fig. 4A, and data not shown).
IL-12, IL-2 + IL-12, and IL-12 + IL-18 induced IL-10 protein and mRNA
in the purified liver and spleen NK cells from IL-2-treated RAG-2
(-/-) mice. However, no enhanced IL-13 production was observed under
these culture conditions (Fig. 4B, and data not shown).
Next, we further purified spleen NK and T cells to verify whether NK
and T cells in IFN- (-/-) mice can produce IL-13 in response to
IL-2 + IL-18. Spleen cells were isolated from IFN- (-/-) and B6
mice and were sorted using anti-CD3 and anti-DX5 mAb to purify
CD3- NK cells and DX5- T cells as described
in Materials and Methods. Highly purified
(>95%) CD3- NK and DX5- T cells were
obtained. A representative result of this study is shown in Fig. 5. In B6 and IFN- (-/-) mice, both
NK and T cells produced IL-13 in response to IL-2 + IL-18. Repeated
experiments revealed that in B6 and IFN- (-/-) mice, greater
amounts (3- to 10-fold) of IL-13 protein were observed in the
supernatants of IL-2 + IL-18-activated spleen NK cells
(CD3-, DX5+) than seen in spleen T cells
(DX5-, CD3+) (Fig. 5, and data not shown). In
addition, greater amounts of IL-13 protein were observed in the
supernatants of IL-2 + IL-18-activated NK and T cells isolated from
IFN- (-/-) mice than seen in equivalent cells isolated from B6
mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(-/-) mice, liver and
spleen NK and T cells produced more IL-13 mRNA and protein in response
to IL-2 + IL-18 than seen in equivalent cells obtained from control B6
mice.
IL-18, originally identified as an IFN--inducing factor, promotes
the production of IFN- and enhances NK activity (10). Although IL-18
alone cannot induce IFN- production by itself, IL-18 synergizes with
IL-12 in inducing IFN- and GM-CSF production (Th1 cytokines) from T
cells and NK cells (9, 10, 11, 12). Despite the fact that IL-18 is not
structurally related to IL-12, IL-18 has functional similarities to
IL-12 (11, 12). Moreover, it has been reported that IL-18 alone does
not drive Th1 development, but strongly potentiates IL-12-driven Th1
development (34). A previous study also showed that IL-18 reduced the
expression of the Th2 cytokine, IL-10 (14). Therefore, IL-18 is thought
to be an important cofactor involved in Th1 cytokine production and Th1
cell development. However, in this study, we demonstrate that IL-18
induces Th2 cytokine IL-13 production in both NK and T cells in synergy
with IL-2 but not with IL-12, although IL-12 + IL-18 or IL-2 + IL-18
synergistically induce IFN- production in NK and T cells. Recent
studies from our laboratory revealed that in the human NK3.3 cell line,
IL-13 production induced by IL-2 was not modulated by IL-12, although
IL-2 and IL-12 synergistically induced IFN- production (24). This
result is consistent with the data presented in this study. Moreover,
in the absence of IFN- (i.e., IFN- (-/-) mice), IL-2 +
IL-18-activated NK and T cells produced more IL-13 mRNA and protein
than normal controls. It has been established that IL-18 alone does not
drive Th1 nor Th2 development, but can be a strong cofactor for Th1
cell development in combination with IL-2 or IL-12 (11, 12, 34).
However, our results suggest that in the absence of IFN- (or when
the levels of IFN- are suppressed), IL-18 may be a cofactor for the
development of humoral immunity in synergy with IL-2. The fact that
significantly more IL-13 was produced in NK and T cells obtained from
IFN- (-/-) mice suggests that IFN- levels may endogenously
regulate IL-13 production by IL-18 and IL-2 in vivo.
It has been reported that IL-12 is an inducer of IL-10, as well
as IFN- gene expression, in combination with IL-2 in both T and NK
cells (7, 22). Our results also show that in IFN- (-/-), RAG-2
(-/-), and control mice, IL-10 was induced by IL-12 in synergy with
IL-2. IL-18 + IL-12 or IL-18 + IL-2 weakly induced IL-10 production in
these mice (Fig. 4). These results suggest that IL-18 is not a strong
inducer of IL-10. Moreover, IL-10 production induced by IL-12 and/or
IL-2 may be IFN--independent, as induction levels were the same in
cells obtained from B6 and IFN- (-/-) mice.
It is unclear whether IFN- directly affects the IL-13-producing
cells identified in this report. There are several possibilities that
could account for the results that we have presented. Previous studies
demonstrated that IFN- inhibited the development of Th2 cell clones
producing IL-4 (35, 36). Therefore, one possibility is that IFN- can
suppress the initial development of these IL-13-producing NK and T
cells from precursors in the bone marrow, and, in the absence of
IFN-, these cells predominate. Alternatively, IFN- may induce
growth factor(s) that directly suppress the development of these
IL-13-producing cells. It is also possible that as the precursors of
IL-13-producing cells mature, these cells might lack IFN- receptors
and become refractory to IFN- effects. In preliminary experiments,
we have observed that in vitro IFN- treatment partially blocked
IL-13 production by IL-2 in cells obtained from IFN- (-/-) mice
(data not shown), thus, suggesting a potential direct effect of IFN-
on IL-13 gene expression. Furthermore, in transient transfection
experiments, we found that IFN- partially inhibits IL-13 promoter
activity (data not shown). Thus, another possibility is that IFN-
directly inhibits IL-13 production in IL-13-producing cells via IFN-
receptor signaling. Recent studies have shown that a strong Th2 cell
response was observed in an infectious disease model using IFN
regulatory factor (IRF)-1 (-/-) mice (37, 38). As IFN- directly
activates IRF, it is possible that IRF-1 could directly or indirectly
alter IL-13 promoter activity. Therefore, it will be of interest to
determine whether IL-2 or IL-2 + IL-18 can induce IL-13 expression in
IRF-1 (-/-) mice.
It has been reported that IL-4/IL-13-producing Th2 cells in vivo can be
a small population of the total conventional T cells (39). Several
reports have shown that the NK-T subset (NK1.1+ T cell) can
produce more IL-4 than conventional T cell subsets (31, 32, 33). However,
it is still unclear which population (conventional T, NK-T, or a NK
subset) is the major population producing IL-13. In this study, we have
demonstrated that, in IFN- (-/-) and B6 mice, liver lymphocytes
can produce more IL-13 mRNA and protein than spleen lymphocytes in
response to IL-2 + IL-18. FACS analysis revealed that in IFN-
(-/-) and B6 mice, a larger number of NK and NK-T cells migrated to
the liver than to the spleen following in vivo treatment with IL-2.
Repeated sorting experiments showed that purified spleen NK cells
produced 3- to 10-fold more IL-13 protein than purified spleen T
cells in response to IL-2 + IL-18. Moreover, RPA and ELISA analyses
revealed that in IL-2-treated and -untreated RAG-2 (-/-) and SCID
mice that lack conventional T, NK-T, and B cells, the levels of IL-13
mRNA and protein production were not significantly different from those
observed in cells obtained from control B6 mice following IL-2 + IL-18
stimulation in vitro (Fig. 4, data not shown). These results
suggest that NK-T and conventional T cell subsets might not be
major producers of IL-13 in response to IL-2 + IL-18. It is also worth
noting that the liver NK cells isolated from SCID and RAG-2 (-/-)
mice produced more IL-13 mRNA and protein than spleen NK cells in
response to IL-2 or IL-2 + IL-18 (data not shown). Thus, the NK cells
that migrated into the liver and spleen in IL-2-treated mice might
represent different NK subpopulations or the expression of the IL-2
receptor or the IL-18 receptor might differ in these populations.
Relatively high doses (50 ng/ml) of IL-18 were needed to induce IL-13
production in both B6 and IFN- (-/-) mice, while low doses of
IL-18 (5 ng/ml) could induce IFN- in combination with IL-2 in B6
mice (Table I). While the basis for this difference is currently
unknown, it may reflect differences in the cell population responding
to IL-18. This hypothesis requires further study.
Our present study has demonstrated that, although purified resting
spleen T and NK cells did not respond to IL-2 + IL-18, in vivo
IL-2-treated spleen cells produce IFN- or IL-13 in response to IL-18
in synergy with IL-2 in vitro. Recent studies have revealed that IL-1
receptor-related protein is an IL-18 receptor (40), and that IL-12 can
up-regulate the IL-18 receptor in mouse Th1 and B cells (15, 16). These
results suggest that resting spleen cells might not express IL-18
receptors, and in vivo IL-2 treatment may up-regulate IL-18 receptor
expression. This issue is currently under investigation.
In conclusion, this study has demonstrated that IL-18 is a potent
coinducer of the Th2 type cytokine, IL-13, in murine NK and T cells. We
have found that in the absence of IFN-, liver and spleen NK and T
cells produced more IL-13 mRNA and protein in response to IL-2 + IL-18
than seen in equivalent cell populations obtained from control B6 mice.
Furthermore, while IL-2 + IL-12 synergized with regard to IL-10 and
IFN- production, no enhanced IL-13 production was observed. Taken
together, our results suggest that when IFN- is suppressed, IL-18
can be a cofactor in the development of the humoral immune response by
inducing IL-13. Thus, IL-12 and IL-18 have different roles in the
regulation of cytokine gene expression that effects the Th1/Th2 balance
in response to Ag challenge.
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Acknowledgments |
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Footnotes |
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2 T.H. is the recipient of a research fellowship from the Uehara Memorial Foundation (Tokyo, Japan) and the 1997 Fukuoka Cancer Society Award (Fukuoka, Japan).
3 Address correspondence and reprint requests to Dr. Howard A. Young, Laboratory of Experimental Immunology, National Cancer Institute, Frederick Cancer and Research Development Center, Building 560, Room 31-93, Frederick, MD 21702. E-mail address:
4 Abbreviations used in this paper: h, human; RPA, RNase protection assay.
Received for publication November 18, 1998. Accepted for publication February 1, 1999.
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in immune cell regulation. J. Leukocyte Biol. 58:373.[Abstract]
production by human large granular lymphocytes. J. Immunol. 139:724.[Abstract]
, interleukin-1ß and interferon--inducing factor on the production of interferon- by natural killer. Eur. J. Immunol. 27:2787.[Medline]
production by T cells. Nature 378:88.[Medline]
production by IL-12 and IL-18. Curr. Opin. Immunol. 10:259.[Medline]
inducing factor. J. Leukocyte Biol. 63:658.[Abstract]
upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J. Exp. Med. 187:2103.-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon- production. Eur. J. Immunol. 26:1647.[Medline]
in response to IL-18. J. Immunol. 160:3759. production. J. Immunol. 161:3400.. J. Immunol. 162:51. genes. Science 259:1739. production and activates IRAK and NF
B. Immunity 7:571.[Medline]
in immune regulation. I. IFN- inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J. Immunol. 140:4245.[Abstract]
in immune regulation. II. IFN- inhibits the proliferation of murine bone marrow cells stimulated with IL-3, IL-4, or granulocyte-macrophage colony-stimulating factor. J. Immunol. 141:2635.[Abstract]
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|
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|
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