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*
Diabetes Research Institute, Heinrich-Heine University, Düsseldorf, Germany;
Institute of Diabetes Research, Munich, Germany;
Department of Endocrinology, Katholieke University, Leuven, Belgium;
Hyogo College of Medicine, Fujisaka, Japan; and
¶
Fujisaki Institute, Fujisaki, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10 mRNA
levels in tissue. The deficient progression was probably due to lesser
mRNA expression of the Th1 driving cytokines IL-12 and IL-18 by the
innate immune system (p < 0.05). Furthermore, the
mRNA expression of inducible NO synthase, a marker of destructive
insulitis, was also not up-regulated in the IL-18-treated group. IL-18
did not exert its effect at the levels of islet cells. Cultivation of
islets with IL-18 affected NO production or mitochondrial activity and
did not protect from the toxicity mediated by IL-1
, TNF-
, and
IFN-. In conclusion, we show for the first time that administration
of IL-18, a mediator of the innate immune system, suppresses autoimmune
diabetes in nonobese diabetic mice by targeting the Th1/Th2 balance of
inflammatory immune reactivity in the pancreas. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-18 is a single chain cytokine that is produced by cells of the innate immune system and induces Th1 cell proliferation in vitro (13, 14). Protein structure similarities to IL-1 are observed (15), and the latter is known to have direct effects on pancreatic islet cells, such as inducing cell death via the induction of NO (16). In the animal model of the cyclophosphamide accelerated and synchronized diabetes development of the NOD mouse, IL-18 gene expression is up-regulated early on in the pancreas as well as in the periphery and is thought to drive the shift from Th2-dependent to Th1-dependent insulitis (17, 18). Interestingly, the gene is located on chromosome 9 in or near Idd2 and is therefore discussed as being a candidate gene for this diabetes-associated gene locus (17). In our present study, we analyzed further the possible role of the innate immune system in autoimmune diabetes of NOD mice by administrating IL-18 to the prediabetic NOD mice. To our knowledge, this is the first attempt to interfere in autoimmune disease by this innate cytokine.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female NOD mice, which were originally obtained from Prof. C. Y. Wu in 1990 (University of Beijing, Beijing, China), were bred in the animal house at Katholieke University and maintained under conventional conditions (19). The diabetes incidence of female mice was 75%. The colony was screened regularly for viral or bacterial infections. Mice were fed a standard diet (Hope Farms, Woerden, The Netherlands) and tap water ad libitum. One group of animals (n = 44) was treated daily with 0.3 µg of IL-18 (Fujisaki Institute, Fujisaka, Japan) plus 2 mg of OVA as a carrier protein (OVA, grade VI, Sigma, Deisenhofen, Germany) per animal daily starting at 10 wk of age. The control group (n = 45) was treated daily with 2 mg of OVA only. BALB/c mice were purchased from Charles River (Wiga, Sulzfeld, Germany) and treated daily with 0.3 µg of IL-18 plus 2 mg of OVA. Urinary glucose analysis was done daily starting at 8 days posttreatment in both animal groups; hyperglycemia was confirmed by blood glucose determination (Glucocard, Menarini, Florence, Italy). Animals were regarded as diabetic when blood glucose levels were found to be >16.7 mmol/l (300 mg/dl). Groups of six normoglycemic animals were killed before and 14 and 21 days after starting the injection of IL-18. Mice were sacrificed under anesthesia, and the pancreas was excised and cut in half longitudinally for histological examination and mRNA analysis. The principles of laboratory animal care were followed (National Institutes of Health publication no. 85-23, revised 1985).
mRNA analysis
Total RNA was isolated from fresh pancreatic tissue by
guanidinium thiocyanate-phenol-chloroform extraction (17).
Isolated RNA quality was verified by running a 1.2% agarose gel with
4% formaldehyde. All isolated pancreas RNA samples showed intact 18S
and 28S rRNA bands without visible degradation of the mRNA, similar to
the total RNA of spleens, which was always isolated in parallel.
Determination and quantification of specific mRNA was performed by
RT-PCR as described elsewhere (17, 18). Specific primers
for -actin, IFN-, and IL-10 were purchased from Clontech (Palo
Alto, CA). The specific primers for inducible NO synthase (iNOS),
IL-12p40, IL-12p35, and IL-18 were used as described previously
(5, 17, 20). PCR products were subjected to
electrophoresis on a 2% agarose gel followed by hybridization with
specific 32P-labeled probes binding at the sites
between the primer sequences. Signals were quantified by measuring the
32P-stimulated luminescence (PSL) with a phosphor imager
(Fuji, BAF1000, Raytest, Staubenhardt, Germany). The relative PSLs of
PCR products were calculated by normalization of the measured PSL to
the strength of the -actin signal (5, 17). RT-PCR
analysis of mRNAs was repeated by varying the cycle number for specific
mRNA amplification (n = 29, 32, 35) and for -actin
mRNA amplification (n = 20, 23, 26, 29, 32). The
relative PSL values generated in these experiments did not differ by
>25%.
Isolation and exposure of pancreatic islets
Pancreatic islets were prepared from C57BL/6J mice from our own breeding colony at the Diabetes Research Institute as described previously (21). Briefly, islets were isolated from the pancreas by injection of a collagenase solution into the duct (Serva, Heidelberg, Germany; 0.48 U/mg in HBSS). After incubation for 25 min (37°C), the islets were enriched on a Ficoll density gradient (Ficoll 400, Pharmacia, Freiburg, Germany) followed by hand picking.
For cytokine exposure, 20 freshly isolated islets were seeded per well
of a half area 96-well microtiter plate in 150 µl of RPMI 1640 medium
supplemented with 1 mmol/l pyruvate, 2 mmol/l L-glutamine,
10 ml/l nonessential amino acids (100x, Life Technologies Europe,
Heidelberg, Germany), 2 g/l NaHCO3, 2.38 g/l
HEPES (Serva), 25 mg/l ampicillin, 120 mg/l penicillin, 270 mg/l
streptomycin (Serva), and 10% FCS (Sigma). After 1 day of
precultivation (37°C, 5% CO2) the recombinant
mouse cytokines IL-1 (Endogen, Woburn, MA, 50 U/ml), TNF-
(Genzyme, Cambridge, MA, 500 U/ml), and IFN- (Genzyme, 100 U/ml)
were added; the incubation was continued for 72 h (37°C, 5%
CO2). Mouse rIL-18 (1000/ml) was added at the
beginning of or at 4 h before exposure to
IL-1/TNF-/IFN-.
Nitrite determination
The release of NO from islets was assessed by determining the concentration of accumulated NO2- in the culture supernatant using the Griess reaction (22). At the end of the experiment, 50 µl of the islet culture supernatants was removed and added to 50 µl of a 1:1 mixture of a sulfanilamide solution (Sigma, 0.03 g in 10 ml 2.5% H3PO4) and a napthylethylenediamine solution (Sigma, 0.03 g in 10 ml 2.5% H3PO4) in the wells of a 96-well, flat-bottom microtiter plate. The OD of the resulting solution was determined photometrically at 550 nm, and the NO2- concentrations were quantified from a standard curve obtained with NaNO2-.
MTT assay
The mitochondrial activity of the islets was assessed by a colorimetric test that detects the conversion of the tetrazolium salt MTT (Sigma) into its formazan product (23) by enzymes of the respiratory chain. After the end of the cytokine exposure period, the islet culture supernatant was replaced by an MTT solution (1 mg/ml in RPMI 1640 medium with supplements). After 4 h of incubation (5% CO2, 37°C), the formazan crystals were dissolved in 50 µl of isopropanol and the OD of the resulting blue solution was determined photometrically (540 nm, reference wavelength of 650 nm). The residual mitochondrial activity of the islets was calculated as a percentage of the untreated sample.
Histology
Pancreatic tissue was snap frozen in liquid nitrogen, and
cryostat sections were stained with hematoxylin-eosin for evaluation of
infiltrating immune cells by light microscopy. Analysis was done from
all islets in different sections at intervals of 200 µm, yielding a
total of 
20 islets per animal. Grade 0 was defined as no
infiltration, grade 1 as two to five mononuclear cells around the
islet, grade 2 as more than five mononuclear cells surrounding the
islet without intraislet infiltration, grade 3 as <20% of the
intraislet area infiltrated, and grade 4 as >20% of the intraislet
area infiltrated. Slides were coded, and insulitis grades were rated
independently by two observers. The histology score gives the mean
infiltration grade of the islets analyzed.
Statistical analysis
The mean radioactive signals of the RT-PCR products, the results
of the NO2- accumulation, and the mitochondrial
activity were compared by the Wilcoxon U test, Student’s
t test, or the rank correlation assay of Spearman.
Statistical analysis for incidence of diabetes was performed by
Kaplan-Meier survival analysis; the degree of insulitis was performed
by the 
2 test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In the sham-treated group, the first
animals became diabetic at day 70 of age, whereas in the IL-18-treated
group, the first animal developed diabetes significantly later, at day
96 (p < 0.005). Treating non-diabetes-prone
BALB/c mice did not induce diabetes development (0 of 30 mice).
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), with a mean insulitis score of 2.4
(Fig. 2). A substantial progression of insulitis was seen at 14 and 21
days after starting treatment in control-treated, normoglycemic NOD
mice. Nearly all islets exhibited an advanced insulitis grade with
intraislet infiltration (78% and 68%, Fig. 2). Interestingly, in
normoglycemic, IL-18-treated NOD mice, there was no progression of
islet infiltration over time. The percentage of islets with intraislet
infiltration did not increase (31%; 32%; Fig. 2) but was
significantly decreased compared with 70-day-old NOD mice
(p < 0.05). The insulitis score of the
IL-18-treated animals was significantly less after 14 days
(p < 0.005) and 21 days
(p < 0.05) of treatment in contrast to the
sham-treated animals (Fig. 2).
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at 21 days
after the start of the experiment (p < 0.05,
Fig. 3A). There was also a
significant increase in IFN- mRNA expression in normoglycemic,
IL-18-treated NOD mice (p < 0.01); however,
there was no difference between the IL-18-treated group and the control
group (Fig. 3A). The gene expression of the Th2-type
cytokine IL-10 was not changed in IL-18-treated NOD and control-treated
NOD mice within 14 and 21 days after starting treatment of the animals
(Fig. 3B). A significant impact of the treatment with IL-18
became evident when calculating the ratio of mRNA levels of IFN- vs
IL-10 in individual animals. Control-treated NOD mice showed an
increased IFN-/IL-10 ratio, indicating a shift toward Th1-type
reactivity in the pancreas at 14 and 21 days after the start of
treatment, whereas IL-18 treatment prohibited such shift toward
Th1-type reactivity (Fig. 3C; 14 days, p <
0.05; 21 days, p < 0.01; 21 days, p <
0.05 when excluding the highest values). The expression of the Th2
cytokine IL-4 was higher in IL-18-treated mice than in sham-treated
mice at 21 days after treatment of the animals
(p < 0.05, Fig. 3C). As a
consequence, treatment with IL-18 also prevented progression toward
Th1-biased insulitis when considering the ratio of IFN- vs IL-4 mRNA
levels in the pancreas (Fig. 3E, 21day, p <
0.002).
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. At 14
and 21 days after starting with animal treatment, the ratio of IL-12p40
vs IL-12p35 mRNA levels of individual animals was calculated. The group
treated with IL-18 did not show an up-regulation of mRNA expression of
IL-12 (Fig. 4B) and IL-18 (Fig. 4A). The
control-treated NOD mice showed a significant up-regulation for these
two cytokines at 21 days after the start of treatment, in contrast to
IL-18-treated NOD mice (p < 0.05; Fig. 4, A and B), and expression of these cytokines
significantly correlated in individual animals at 21 days after the
start of treatment (IL-12p40/p35, p < 0.01).
Furthermore, there was a significant correlation of intrainsulitis and
IL-18 (p < 0.01) or IL-12 mRNA expression
(p < 0.05) at 21 days after the start of
treatment.
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cell destruction (5). iNOS mRNA
expression increased by 14 days posttreatment in the control NOD group,
whereas iNOS expression in the IL-18-treated NOD group was
significantly reduced at 14 days (p < 0.005)
and 21 days (p < 0.05) after the start of
treatment in comparison with the control groups after 14 days and 21
days (Fig. 5A). Furthermore, a
high expression of iNOS in the pancreas correlated with high
intrainsulitis at 21 days after the start of treatment
(p < 0.01). In addition, animals with a high
ratio of Th1- vs Th2-associated cytokines also showed high iNOS
expression (Fig. 5B). The correlation between iNOS mRNA
levels and the ratio of IFN-/IL-10 mRNA was calculated as
r = 0.83, p < 0.05 for all animals; when
the highest values were excluded, the correlation was calculated as
r = 0.77, p < 0.05. The
correlation between iNOS mRNA levels and the ratio of IFN-/IL-4 was
calculated as r = 0.94, p < 0.01 (Fig. 5C).
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alone or in combination with TNF- and IFN-. After 72 h of
exposure, IL-18 alone at a dose of 1000 U/ml showed neither an effect
on the NO release nor an effect on the residual mitochondrial
activity of the islets (Fig. 6,
A and B). Islets exposed to 50 U/ml IL-1
released a significantly increased amount of NO (3.3 ± 0.6 nmol/l
NO2-, p < 0.001 compared with the
untreated control), which induced stimulation of the respiratory
activity (152.1 ± 16.6%, p < 0.001 compared
with the untreated control). As expected, exposure to a combination of
the inflammatory mediators IL-1, TNF-, and IFN- resulted in a
further, significantly increased release of high amounts of NO
(Fig. 6A, 6.0 ± 1.8 nmol/l NO2-,
p < 0.01 compared with the NO2-
concentration detected after IL-1 exposure) that strongly depressed
the mitochondrial activity of the islets (Fig. 6B, 36.8
± 10.6%, p < 0.001 compared with the untreated
control). However, no effect was seen when IL-18 was added to the
islets at the beginning or at 4 h before the exposure to the
inflammatory cytokines. IL-18 was unable to modulate the
cytokine-induced alterations of NO release and the metabolic
activity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is probable that this effect is due to the counterregulation of the
immune system. Instead of inducing a Th1 response, there is still a Th2
response in IL-18-treated NOD mice, which will not lead to destructive
insulitis (24). Similar effects have been observed for
systemically administered IL-12 and TNF- (12, 25, 26, 27).
Especially in the case of IL-12 treatment, it is known that low doses
of IL-12 suppress diabetes development, whereas high doses accelerate
diabetes development (12, 25). During preparation of this
manuscript, parallel work by Tokui et al. (28) was
published in an abstract form; this work also describes an inhibitory
effect of IL-18 administration on the cyclophosphamide-accelerated
disease process in NOD mice. The latter finding suggests that the
effect of exogenous IL-18 on disease progression is quite robust and is
not dependent upon a selective treatment protocol or on the NOD mouse
colony.
Previous studies linked a shift toward Th1-dominated insulitis
progression from benign toward destructive insulitis and subsequent
diabetes onset. Therefore, we analyzed mice before and at 14 and 21
days after treatment with IL-18 for progression toward Th1 insulitis.
In the case of diabetes acceleration by systemically administered
IL-12, NOD mice developed diabetes within this time course
(12). Cytokine mRNA expression was analyzed in the total
pancreas, because islet isolation in our hands introduces a bias due to
poor islet yield in animals with advanced stages of insulitis and due
to the preferential loss of periductular and periinsular over
intrainsular leukocytes during the isolation procedure. Previous
studies have shown a close correlation between cytokine mRNA levels in
the total pancreas and the mean insulitis score in individual animals
(29). Furthermore, we were also able to demonstrate a
close correlation between total pancreas mRNA levels and
immunohistochemical staining of cytokines in islets of the same
pancreas (5). Analysis of pancreatic RNA at 70, 84, and 91
days revealed a progression of inflammation toward the Th1 type, as
evidenced by an increase of IFN- over IL-10 and IL-4 mRNA levels.
However, animals treated with IL-18 did not show such progression.
Therefore, we conclude that exogenous IL-18 interfered with inhibition
of the natural Th1 shift in NOD mice, leading to a dampening of
Th1-dependent destructive insulitis. This conclusion concurs with the
results of semiquantitative graded insulitis, which showed a
significantly lesser intraislet infiltration in mice receiving
IL-18.
The reduced aggressiveness of the insulitis process in mice treated
with IL-18 is also recognizable from a significantly decreased
expression of iNOS mRNA. iNOS mRNA is induced in macrophages,
endothelial cells, and cells by inflammatory cytokines such as
IFN-, IL-1, and TNF-, whereas Th2 cytokines are inhibitory
(29, 30, 31, 32). A close correlation between pancreatic iNOS mRNA
levels and destructive intraislet infiltration has been reported by our
group (5, 33). Furthermore, iNOS expression is a marker of
macrophage activation. The decreased expression of iNOS mRNA in the
pancreata of NOD mice receiving IL-18 indicates a dampening of the
diabetogenic inflammatory process.
Interestingly, the systemic administration of IL-18 down-regulated the proinflammatory activities of the innate immune system, as demonstrated by a lesser gene expression of IL-12 and of IL-18 itself. This may be due to the stimulation of Th2-type cytokines by IL-18 in cells of the innate immune system, as described recently (34).
The suppression of the Th1-driving activities of the innate immune
system by exogenous IL-18 provides a possible mechanism for the lack of
progression toward destructive intrainsulitis. Another possible mode of
action is that IL-18 acts directly on pancreatic islets and modulates
their functional activity under inflammatory cytokines. IL-1,
TNF-, and IFN- induced the release of NO, which was identified as
a major cell toxic mediator in experimental systems of the
pathogenesis of type 1 diabetes (35). As expected, low
concentrations of IL-1 induced the release of moderate amounts of NO
and exerted a stimulatory effect on islet metabolism (36, 37). Exposure to a combination of the cytokines IL-1,
TNF-, and IFN- resulted in the formation of high amounts of NO,
which led to a strong reduction of the islet respiratory activity
indicative of the islet cell toxic effect of high NO concentrations
(38, 39). However, the addition of IL-18 had no effect on
the stimulatory or inhibitory effects on NO release and on
mitochondrial activity induced by the inflammatory cytokines. These
results imply that IL-18 has no direct effect on islet cells, because
the cytokine can neither induce the protection of islets nor induce
sensitization to increase their susceptibility toward the damaging
effects of inflammatory mediators.
In conclusion, we have shown that exogenously administered IL-18
interferes with diabetes development and limits Th1 reactivity.
Furthermore, the decreased expression of iNOS in the pancreata of
IL-18-treated mice indicated a lower activation of inflammatory cells,
which promote cell survival, whereas IL-18 itself did not show any
effect on insulin-producing cells. These findings demonstrate for
the first time a modulatory function of IL-18 in autoimmune disease and
underscore the potent instructive role of the innate immune system on
adaptive T cell-dependent immune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Helga Rothe, Institute of Diabetes Research, Koelner Platz 1, D-80804 München, Germany. E-mail address:
3 Abbreviations used in this paper: NOD, nonobese diabetic; PSL, 32P-stimulated luminescence; iNOS, inducible NO synthase.
Received for publication February 2, 1999. Accepted for publication May 18, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and with enhanced expression of inducible NO-synthase in pancreatic lesions. Diabetologia 37:1154.[Medline]
production by T cells. Nature 78:88.
-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]
against pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology 129:103.
inducing factor (IGIF) is involved in the development of Th1 insulitis in NOD mice. J. Autoimmun. 10:251.[Medline]
and TNF- in the NOD mouse. J Autoimmun. 4:249.[Medline]
and tumour necrosis factor- via an L-arginine-dependent nitric oxide-generating mechanism. FEBS Lett. 276:42.[Medline]
-mediated induction regulated by tumor necrosis factor- and IFN-. J. Immunol. 15:3283.
and IFN- potentiate the deleterious effects of IL-1 on mouse pancreatic islets mainly via generation of nitric oxide. Cytokine 6:399.[Medline]
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),
the IL-18-treated NOD group (•), and the IL-18-treated BALB/c group
(
) are shown.
)
and intrainsulitis (
).
