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Department of Microbiology and Infectious Diseases and Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Center, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a
characteristic Th1 cytokine, and IL-4, a characteristic Th2 cytokine,
in islet infiltrates of female and male NOD mice at various ages. We
found that the most significant difference in cytokine production
between sexes was during the early stages of insulitis at 4 wk of age.
IFN- was significantly higher in young females, whereas IL-4 was
higher in young males. CD4+ T cells isolated from lymph
nodes of female mice and activated with anti-CD3 and anti-CD28
Abs produced more IFN-, but less IL-4, as compared with males.
Treatment of CD4+ T cells with estrogen significantly
increased, whereas testosterone treatment decreased the IL-12-induced
production of IFN-. We then examined whether the change in
IL-12-induced IFN- production by treatment with sex hormones was due
to the regulation of STAT4 activation. We found that estrogen treatment
increased the phosphorylation of STAT4 in IL-12-stimulated T cells. We
conclude that the increased susceptibility of female NOD mice to the
development of autoimmune diabetes could be due to the enhancement of
the Th1 immune response through the increase of IL-12-induced STAT4
activation by estrogen. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cells by
cell-specific, cell-mediated autoimmune responses (1, 2, 3).
Nonobese diabetic
(NOD)4 mice
spontaneously develop autoimmune type 1 diabetes and are considered to
be one of the best animal models for human insulin-dependent diabetes
mellitus (4). The destruction of pancreatic cells in
NOD mice is preceded by infiltration of dendritic cells/macrophages and
then T and B cells into the pancreatic islets (5, 6, 7, 8, 9, 10).
Infiltration of immunocytes into the periislet region of the pancreas
(periinsulitis) begins at 3–4 wk of age, followed by the slow,
progressive, and selective destruction of insulin-producing cells
at 4–6 mo of age (11). Both female and male NOD mice show
insulitis; however, females exhibit more invasive and destructive
insulitis, leading to an earlier onset (12 wk of age) and higher
incidence (80–90%) of diabetes as compared with males (20 wk of age,
10–30%). It has been suggested that sex hormones are associated with the sexual dimorphism in the onset of autoimmune diabetes in NOD mice. The incidence of diabetes was significantly increased in male NOD mice, but decreased in females, by castration at the time of weaning (12). The basal circulating levels of estrogen were found to be about twice as high in female NOD mice as in other strains of mice (13). In addition, the long-term administration of androgen or its derivatives to young female NOD mice resulted in a decrease in the incidence of diabetes (14, 15, 16). However, it is poorly understood how sex hormones modulate the incidence of diabetes in NOD mice. This investigation was initiated to find mechanisms by which sex hormones affect the development of autoimmune diabetes in NOD mice. We found that estrogen increased the IL-12-induced activation of STAT4, which enhanced the Th1 immune response, whereas testosterone (TS) did not significantly change the activation of STAT4. Thus, sex hormones may modulate the Th1/Th2 immune balance through the regulation of IL-12-induced STAT4 activation in the early stages of the T cell-mediated autoimmune process and affect the development of diabetes in NOD mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice used in this study were purchased from Taconic Farms (Germantown, NY) and maintained in the pathogen-free facility in the Health Science Center of the University of Calgary (Calgary, Alberta, Canada). The use and care of the animals in this study were approved by the Animal Care Committee, Faculty of Medicine, University of Calgary.
Isolation of islets
Islets were isolated from female and male NOD mice at 4, 8, 16, and 20 wk of age and from C57BL/6 mice at 20 wk of age by collagenase digestion and Ficoll gradient centrifugation (Sigma-Aldrich, St. Louis, MO), as described elsewhere (17), and pooled for RNA extraction. Each group contains pooled islet RNA from four to six mice.
Isolation of CD4+ T cells
Lymphocytes were prepared from the lymph nodes of female and male NOD mice at 4 and 10 wk of age, and CD4+ T cells were purified using the MACS system anti-CD4 beads (Miltenyi Biotec, München, Germany).The purity was >90% when determined by flow cytometric analysis.
RT-PCR analysis of gene expression
Total RNA was extracted from islets or cultured lymphocytes
using TRIzol reagent (Life Technologies, Burlington, Ontario, Canada),
according to the manufacturer’s protocol. A total of 3 µg RNA was
subjected to the first-strand cDNA synthesis in 20 µl reaction
mixture containing 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM
MgCl2, 10 µg/ml oligo(dT), 10 mM DTT, 0.5 mM of
each nucleotide, 2 U/ml RNase inhibitor, and 2.5 U Superscript II
reverse transcriptase (Life Technologies) at 37°C for 60 min. The
samples were then heated at 95°C for 5 min to inactivate the enzymes
and diluted to 100 µl with distilled water. Five microliters of
serially diluted cDNA samples were added to 15 µl reaction mixture
containing 0.2 U Taq DNA polymerase (Sigma-Aldrich) for PCR.
The reaction conditions were optimized for each pair of primers.
Primers were as follows: -actin sense (5'-GTTACCAACTGGGACGACA-3')
and antisense (5'-TGGCCATCTCCTGCTCGAA-3'); IFN- sense
(5'-AGCTCTGAGACAATGAACGC-3') and antisense
(5'-GGACAATCTCTTCCCCACCC-3'); IL-4 sense
(5'-TCTTTCTCGAATGTACCAGG-3') and antisense
(5'-CATGGTGGCTCAGTACTACG-3'); estrogen receptor (ER)-
sense
(5'-GAGACTGTCCAGCAGTAACGAGAA-3') and antisense
(5'-GGACAAGGCAGGGCTATTC-3'); and TS receptor (TSR) sense
(5'-TCTCAAGAGTTTGAATGGCTCC-3') and antisense
(5'-GAGATGATCTCTGCCATCATTTC-3'). The PCR products were visualized
on a 1.5% agarose gel by ethidium bromide staining, and the
densitometric analysis of the PCR products was performed by Adobe
Photoshop 4.1 software (Adobe Systems, Mountain View, CA).
T cell proliferation assay
The isolated CD4+ T cells from lymph nodes were washed and resuspended in serum-free RPMI 1640 medium. The cells (5 x 105 cells/well) were seeded into 96-well round-bottom culture plates coated with 0, 1.25, 2.5, or 5 µg/ml anti-CD3 Ab (145.2C11; BD PharMingen, San Diego, CA) and incubated for 72 h in the presence of 2 µg/ml anti-CD28 Ab (BD PharMingen). [3H]Thymidine (1 µCi) was added to each well, and the cells were cultured for an additional 16 h. The cells were harvested to determine the incorporation of [3H]thymidine.
ELISA for cytokine production
CD4+ T cells were activated with
anti-CD3 and anti-CD28 Ab for 72 h, as described above.
The culture supernatant was collected, and the production of IFN-
and IL-4 was determined by ELISA using Duoset ELISA development system
(R&D Systems, Minneapolis, MN), according to the manufacturer’s
protocol.
IL-4- and IL-12-induced activation of CD4+ T cells
CD4+ T cells (2.5 x
106/ml) isolated from lymph nodes of 4- and
10-wk-old female or male NOD mice were activated with Con A (2.5
µg/ml; Sigma-Aldrich) and IL-2 (20 U/ml; Takeda Chemical Industries,
Osaka, Japan) for 3 days. The cells were then washed and reincubated in
serum-free RPMI medium in the presence of IL-2 for another 4 days. The
cells were washed again and incubated in serum-free culture medium with
or without 17-estradiol (E2, 25 ng/ml; Sigma-Aldrich) or TS (25
ng/ml) for 20 h. IL-12 (20 ng/ml; PeproTech, Rocky Hill, NJ) was
added to the culture medium, and the cells were incubated for an
additional 48 h. The supernatant was collected for cytokine ELISA,
and cells were harvested for RNA extraction to perform RT-PCR analysis.
For immunoprecipitation and immunoblot analysis of STAT4 activation,
the cells (5 x 106/ml) were incubated for
20 min, instead of 48 h, in the presence of IL-12 (20 ng/ml). For
analysis of STAT6 activation, cells were incubated with IL-4 (40
ng/ml), instead of IL-12, for 40 min after sex hormone treatment.
Flow cytometric analysis of IL-12R expression in CD4+ T cells
CD4+ T cells were activated with Con A,
rested, and treated with E2 or TS, as described above. The cells were
harvested and incubated with purified anti-mouse IL-12R 1 Ab (BD
PharMingen). The cells were washed and incubated with biotinylated
anti-mouse IgG, followed by incubation with streptavidin-PerCP. The
expression of IL-12R was measured by flow cytometry.
Immunoprecipitation and immunoblotting
The cells were washed and lysed in ice-cold lysis buffer containing 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, 10 mg/ml PMSF, 30 mM aprotinin, and 100 mM sodium orthovanadate. The lysates were left on ice for 20 min and centrifuged at 12,000 x g for 20 min at 4°C. The cleared lysates were then immunoprecipitated with anti-STAT4 or anti-STAT6 Ab (Upstate Biotechnology, Lake Placid, NY). The precipitated protein was resolved on 10% SDS-PAGE and transferred to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA). The membranes were first probed with anti-phosphotyrosine Ab (4G10; Upstate Biotechnology) and visualized by the ECL system (Amersham Life Science, Arlington Heights, IL). The membranes were subsequently stripped using a solution containing 100 mM 2-ME, 2% SDS, and 62.5 mM Tris-HCl (pH 8), and reprobed with anti-STAT4 or anti-STAT6 Ab (Upstate Biotechnology).
Statistical analysis
Student’s t test was used to calculate statistical significance in all experiments. A value of p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether there is a difference in the level of
expression of Th1 (IFN-) and Th2 (IL-4) cytokines in
islet-infiltrating lymphocytes between female and male NOD mice, we
isolated islets from female or male NOD mice at 4, 8, 16, and 20 wk of
age and examined the expression of IFN- and IL-4 by RT-PCR analysis.
The expression of IFN- and IL-4 was readily detected in the islets
from all ages tested of NOD mice, whereas the expression of these
cytokines was not detected in the islets from C57BL/6 mice (Fig. 1
A). The expression of IFN-
increased with increasing age in both female and male NOD mice up to 16
wk of age, with females showing significantly higher expression of
IFN- than males at 4 wk of age (Fig. 1, A and
B). The expression of IL-4 increased between 4 and 8 wk of
age and plateaued thereafter in both males and females. At all ages
tested, the expression of IL-4 was significantly higher in males than
in females (Fig. 1, A and C). When we examined
the ratio of IFN- and IL-4 gene expression, it was found to be
significantly higher in females than in males at 4 and 8 wk of age
(Fig. 1D).
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To determine whether there is a difference in Th1/Th2 cytokine
production in T cells of female and male NOD mice, we isolated
CD4+ T cells from lymph nodes of young (4-wk-old)
and adult (10-wk-old) NOD mice of both sexes and activated them with
anti-CD3 and anti-CD28 Abs in serum-free medium, to avoid any
contamination by sex hormones. We then examined the proliferative
response of the cells and the production of IFN- and IL-4. We found
that CD4+ T cells from both female and male mice
at both ages proliferated equally well at all concentrations of
anti-CD3 Ab (Fig. 2, A and
B), but T cells from both female and male NOD mice produced
more IFN- and IL-4 at 10 wk of age compared with 4 wk of age (Fig. 2, C–F). There were considerable differences in the
production of IFN- and IL-4 between T cells from female and male NOD
mice. At 4 wk of age, CD4+ T cells from female
NOD mice produced significantly higher amounts of IFN- (Fig. 2C), but lower amounts of IL-4 (Fig. 2E),
compared with CD4+ T cells from males. This
difference was more pronounced when CD4+ T cells
were activated with higher concentrations of anti-CD3 Ab. At 10 wk
of age, the amount of IFN- produced by CD4+ T
cells from female NOD mice was still higher than that from males (Fig. 2D), but the production of IL-4 was almost equal between
females and males (Fig. 2F). When we calculated these
results as a ratio of IFN-:IL-4, we found that this ratio was
significantly higher in female mice than in male mice at 4 wk of age
(Fig. 2G), whereas it was not different between females and
males at 10 wk of age (Fig. 2H). These results suggest that
the gender-associated activation of the Th1 response, as indicated by
the up-regulation of IFN-, occurs predominantly in the T cells of
young mice as compared with adult mice.
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and IL-4 in CD4+ T
cells was also examined at the mRNA level by semiquantitative RT-PCR.
The expression of IFN- was higher in females than in males at both 4
and 10 wk of age. However, the expression of IL-4 was higher in males
than in females at 4 wk of age (Fig. 3, A and C). The ratio of IFN-:IL-4 mRNA was
significantly higher in females than in males at 4 wk of age (Fig. 3B), but was not different at 10 wk of age (Fig. 3D), consistent with the production of these cytokines at
the protein level. This result indicates that gender factors influence
the expression of IFN- and IL-4 at the transcriptional level. To
determine whether this differential expression in T cells between
female and male mice is due to different levels of expression of sex
hormone receptors, we examined the expression of ER and TSR in
CD4+ T cells from 4- and 10-wk-old NOD mice. We
found no difference in the expression level of sex hormone receptors in
the T cells between males and females at any age (Fig. 4).
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in T cells by
estrogen treatment and decrease by TS treatment
As we found that there was a gender difference in the production
of IFN- at 4 wk of age, but not at 10 wk of age, we asked whether
exposure to TS or E2 in vitro might reveal a gender difference in
cytokine production by CD4+ T cells from
10-wk-old NOD mice. Purified CD4+ T cells from
lymph nodes from 10-wk-old female or male NOD mice were activated with
Con A or anti-CD3 Ab in the presence of E2 or TS. However, we found
no difference in the production of IFN- and IL-4 between T cells
from female or male mice treated with or without E2 or TS (data not
shown). We then asked whether prolonged cell proliferation and rest in
the absence of sex steroids would result in a response to subsequent
sex steroid treatment of CD4+ T cells from
10-wk-old mice. In this experiment, CD4+ T cells
from 10-wk-old female NOD mice were first activated with Con A for 3
days, rested in IL-2-containing serum-free medium for another 4 days,
and exposed to E2 or TS for 20 h before being stimulated with
IL-12, a potent inducer of Th1 cytokines. We found that steroid
treatment did not affect the proliferative response of the T cells to
Con A and IL-12 in male or female NOD mice (data not shown). However,
we found that E2-treated T cells from both males and females clearly
showed an increased production of IFN-, whereas TS-treated T cells
from females, but not males, showed a decreased production of IFN-
compared with untreated IL-12-stimulated T cells (Fig. 5A). IFN- mRNA expression
was also increased by estrogen treatment and decreased by TS treatment
in female NOD mice (Fig. 5, B and C). Similar
results were obtained for CD4+ T cells from both
female and male NOD mice; therefore, only the data from female mice are
shown in Fig. 5, B and C. These results indicate
that sex hormones directly regulate IL-12-induced cytokine production
of T cells.
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production in
E2- or TS-treated T cells was due to a change in IL-12R expression,
which is up-regulated in Th1 cells, we examined the gene expression of
IL-12R 1 in T cells activated by Con A and IL-2 and treated with E2
or TS by flow cytometric analysis. We found that treatment with E2 or
TS did not significantly change the expression of the IL-12R (Fig. 6A). In addition, we examined
the expression of sex hormone receptors by RT-PCR and found that
treatment with sex hormones did not affect the expression of E2 or TS
receptors in these cells (Fig. 6B).
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To determine whether the differential expression of IFN- in
IL-12-stimulated T cells results from the modulation of the activation
of STAT4, which is known to play a key role in IL-12-induced IFN-
expression (18, 19), CD4+ T cells
were activated with Con A, rested, and then incubated with E2 or TS for
20 h. After incubation of these cells with IL-12 for 20 min, we
examined the level of phosphorylated STAT4 by Western blot. We found
that T cells treated with E2 had increased phosphorylation of STAT4,
whereas this was not significantly different in T cells treated with TS
as compared with untreated T cells (Fig. 7, A and B). When
we examined the effect of sex hormones on IL-4-induced activation of
STAT6, which play a pivotal role in Th2 differentiation (20, 21), we found no change in the phosphorylation of STAT6 in
IL-4-stimulated T cells in the presence of estrogen or TS (Fig. 7, C and D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The immune systems of females and males have different characteristics.
For example, higher Ab production after immunization was observed in
female mice, women have higher absolute numbers of
CD4+ T lymphocytes (23), and higher
Th1 cytokine production was observed in female mice (24).
In addition, sex hormones were shown to modulate the cytokine profiles
in immunocytes (25) and T cell lines and clones (26, 27) in vitro. As well, the expression of cytokine genes was
found to be influenced by sex hormones in an animal model of
experimental autoimmune encephalitis. The production of Th1 cytokines
such as IL-12 and IFN- was significantly less in lymph node cells
from male as compared with female mice after Ag-specific stimulation
(28). Therefore, it is conceivable that sex hormones may
contribute to the gender difference in the development of diabetes in
NOD mice by influencing the balance of Th1/Th2 cytokine production, as
it is known that the Th1 response plays a pathogenic role and the Th2
response plays a preventive role in the development of autoimmune
diabetes in NOD mice (29, 30, 31, 32, 33).
We first examined the expression of IFN-, as a characteristic Th1
cytokine, and IL-4, as a characteristic Th2 cytokine, in the islet
infiltrates in female and male NOD mice at various ages. We found that
the most significant difference between sexes was during the early
stages of insulitis at 4 wk of age; the expression of IFN- was high
in females, whereas the expression of IL-4 was high in males. A similar
result was also reported in a previous study (34). Mice
approach sexual maturation at 4 wk of age, and the levels of sex
hormones increase in the circulation at this time. The increased levels
of sex hormones at this age probably influence cytokine gene
expression.
Second, we examined the production of Th1/Th2 cytokines in
CD4+ T cells activated with anti-CD3 Ab in
female and male NOD mice. We found that T cells from 10-wk-old mice
produced more IFN- and IL-4 than T cells from 4-wk-old mice. This
might be due to the relatively poor activation of T cells from young
NOD mice as compared with adults (32, 35). However, female
mice produced significantly higher amounts of IFN-, but lesser
amounts of IL-4 at 4 wk of age, whereas only a slight difference
between females and males was observed at 10 wk of age. Therefore, the
major impact of gender factors on the pathogenesis of autoimmune
diabetes in NOD mice may be at an early, rather than later, age.
Consistent with this notion, castration at weaning drastically changed
the course of the development of autoimmune diabetes in both female and
male NOD mice (12). One possible explanation for this
difference in cytokine production between T cells from 4- and 10-wk-old
NOD mice is that the T cells might express different levels of sex
hormone receptors and respond to sex hormones according to the numbers
of receptors in the cells. Thus, we examined the expression of ER and
TSR on CD4+ T cells of young (4-wk-old) and adult
(10-wk-old) mice. We found no difference in the level of expression of
these receptors at any age, indicating that sex hormone receptors on
the CD4+ T cells are not involved in the effect
of age on the production of cytokines from these cells.
Third, we examined whether treatment with estrogen or TS would alter
the Th1/Th2 (IFN-/IL-4) cytokine profile of activated
CD4+ T cells from female and male NOD mice. We
could not find any difference in the production of these cytokines when
we activated T cells with Con A or anti-CD3 Ab in the presence of
estrogen or TS. Therefore, we activated T cells with Con A, rested them
in IL-2 for 4 days in the absence of sex hormones, exposed them to
estrogen or TS, and then activated them with IL-12. We found that
estrogen treatment clearly increased, whereas TS treatment decreased
IFN- mRNA expression and IFN- production. These results suggest
that transcriptional regulation of cytokine gene expression is
programmed by an initial exposure to sex hormones, and reprogram of the
gene expression by a different sex hormone requires a long time. An
earlier study found that female recipient mice implanted with
dihydrotestosterone pellets for 10–14 days before the transfer of
encephalitogenic T cells showed a significantly less severe course of
encephalitis as compared with control placebo pellet-implanted female
mice (36). This may have been due to the enhancement of
the Th2 shift by the TS treatment. In addition, Ag-specific T cells
from male donors induced experimental autoimmune encephalomyelitis in
female recipients with a lower severity than that induced by T cells
from female donors (37), as female hormones in the
recipients could not change the cytokine gene expression of T cells
from male donors (Th2 biased) during the disease induction period,
10 days.
Fourth, we determined whether the change in IL-12-induced IFN-
production by treatment with sex hormones may result from a modulation
of IL-12R 1 expression on the T cells. The high affinity IL-12R
complex requires both 1 and 2 subunits, and these two subunits
are up-regulated by T cell activation (38, 39, 40, 41). We found
that there was no change in the expression of IL-12R 1 by treatment
with sex hormones.
Fifth, we then examined whether the change in IL-12-induced IFN-
production by treatment with sex hormones is due to the regulation of
STAT4 activation. We found that estrogen treatment increased the
phosphorylation of STAT4 in IL-12-stimulated T cells. It was reported
that the sequences similar to the estrogen-responsive element were
identified in the IFN- gene promoter region (42).
However, there is no evidence showing that estrogen/ER complex directly
binds to the IFN- gene promoter. STAT4 is a key transcription factor
for IL-12-induced IFN- gene expression (18, 19).
Therefore, it is conceivable that sex hormones may modulate IFN-
gene expression possibly by regulating the activation of STAT4,
although the mechanisms remain to be elucidated.
In conclusion, we have shown that there are gender differences in
Th1/Th2 cytokine expression in T cells of NOD mice. The expression of
IFN- was significantly higher in T cells from young female mice,
whereas the expression of IL-4 was significantly higher in T cells from
young male mice. This differential expression was found to be due to
the up-regulation of IL-12-induced STAT4 activation by estrogen.
Therefore, sex hormones may affect the development of autoimmune
diabetes by modulating Th1/Th2 cytokine production via the regulation
of IL-12-induced STAT4 activation.
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Acknowledgments |
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Footnotes |
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2 M.B. and Y.Y. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ji-Won Yoon, Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Center, Faculty of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1. E-mail address: yoon{at}ucalgary.ca
4 Abbreviations used in this paper: NOD, nonobese diabetic; E2, 17-estradiol; ER, estrogen receptor; TS, testosterone; TSR, TS receptor.
Received for publication January 15, 2002. Accepted for publication March 15, 2002.
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as an amplifying factor in IL-12 induction of the functional IL-18 receptor complex. J. Immunol. 167:1306. synergize for IL-12R expression at low antigen dose. Int. Immunol. 13:1433. promoter. J. Immunol. 146:4362.[Abstract]This article has been cited by other articles:
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