(Circulation. 1999;100:1102-1108.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Treatment of Experimental Viral Myocarditis With Interleukin-10
From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, and the Department of Internal Medicine, Utano National Hospital (H.I.), Kyoto, Japan.
Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Background—The T helper cell type 2–associated cytokine interleukin (IL)-10 has a variety of immunomodulatory properties. However, the effects of the cytokine on viral myocarditis remain unclear.
Methods and Results—We studied the effects of recombinant human
IL-10 (rhIL-10) fully active on mouse cells in a murine experimental
model of acute viral myocarditis caused by the encephalomyocarditis
virus (EMCV). Four-week-old DBA/2 mice were inoculated with EMCV (day
0). rhIL-10 (10 µg/mouse) was administered once daily, starting on
day 0, and control mice received vehicle only. Survival rates were
determined on day 14. Myocardial histopathology, cytokine
levels in the heart by ELISA assay, and myocardial virus concentration
were examined on day 6, and the expression levels of myocardial
inducible nitric oxide synthase (iNOS) mRNA were measured by
competitive polymerase chain reaction. The 14-day survival in mice
treated with rhIL-10 was significantly higher (80%) than in the
control group (30%, n=10 in each, P<0.05). rhIL-10
treatment significantly attenuated myocardial lesions and suppressed
tumor necrosis factor-
and IL-2 in the heart. rhIL-10 treatment had
little effect on myocardial virus concentration. The expression levels
of myocardial iNOS mRNA were significantly decreased in the group
treated with rhIL-10 (8.6±4.7 amol/mg total RNA in treated versus
26.5±7.1 amol/mg total RNA in control mice,
P<0.05).
Conclusions—These findings provide new insights into the in vivo effects of IL-10 on viral infection and suggest a therapeutic effect of IL-10 on viral myocarditis.
Key Words: interleukins • myocarditis • tumor necrosis factor • nitric oxide synthase
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Current concepts of the immune responses focus on the cross-regulation between the 2 types of helper T cell.1 T helper type 1 (Th1) cells produce proinflammatory cytokines and contribute to cell-mediated immunity. The Th2-associated cytokines augment humoral immunity. The cytokines produced by one type of helper T cell regulate the others.
The Th2-associated cytokine interleukin-10 (IL-10) has a
variety of immunomodulatory properties involving the inhibition of Th1
cells, macrophage function, and the production of
proinflammatory cytokines.2 3 IL-10 inhibits the
inflammatory response by inhibiting the activation of nuclear
factor-
B through preservation of IB-.4 Recent
reports have suggested that the profound immunosuppressive effects
associated with IL-10 may be effective against transplanted organ
rejection, immune complex diseases, and sepsis,5 and
clinical trials of IL-10 have been carried out in patients with these
disorders. However, its use in infectious diseases has produced mixed
results, impairing immune activities and promoting infection while
suppressing inflammation without reducing the host
defense.6
Viral myocarditis is one of the clinically important causes of congestive heart failure and may lead to dilated cardiomyopathy.7 Recent reports have emphasized the important role of cytokines in the pathophysiology of viral myocarditis.8 We and others have reported the expression and the role of cytokines in a murine model of viral myocarditis resulting from encephalomyocarditis virus (EMCV) infection.9 10 11 12 These reports suggested that modulation of cytokines could be a successful approach in the treatment of the disease.
This study was designed to examine the effects of IL-10 in a murine experimental model of acute viral myocarditis caused by EMCV.
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Methods |
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Interleukin-10
A rat IgG1 designated JES 2A5 monoclonal antibody specific for murine IL-10 (
IL-10 Ab), an isotype-matched control antibody
(control Ab) designated GL113 (IgG1), and recombinant murine IL-10
(rmIL-10) were prepared as described
previously.13 14 Recombinant human IL-10 (rhIL-10),
which was fully active on mouse cells,15 was kindly
provided by Schering-Plow Research Institute, Kenilworth, NJ. rmIL-10,
rhIL-10, IL-10 Ab, and control Ab were mixed in 0.1 mL of PBS for
the purpose of the experiments.
Experimental Infection
Four-week-old inbred male DBA/2 mice were inoculated with 0.1 mL
IP of the M variant of EMCV diluted in Eagle's modified essential
medium (Nissui Pharmaceutical Co) to a concentration of 100
pfu/mL.7
The day of virus inoculation was defined as day 0.
Time Course of IL-10 Levels in the Heart
The time course of IL-10 mRNA and protein levels in the heart of
surviving infected animals were examined. IL-10 mRNA and protein levels
in the heart of uninfected mice are indicated as "day 0" values.
Treatment Protocols
Protocol 1: Dose-Dependent Effects of rhIL-10
rhIL-10 was administered in a dose of 1 or 10 µg ·
mouse-1 · d-1 SC
for 6 or 14 consecutive days, starting on day 0.
Protocol 2: Effects of Timing of rhIL-10 Administration
rhIL-10 (10 µg · mouse-1
· d-1 SC) was administered daily consecutively
to day 6 or 14, starting on day 0, 1, or 3.
Protocol 3: Effects of rmIL-10
rmIL-10 was administered in a dose of 3 µg ·
mouse-1 · d-1 SC
for 6 consecutive days, starting on day 0.
All recombinant IL-10 was administered once daily, while control mice received vehicle only.
Protocol 4: Effects of IL-10 Ab
IL-10 Ab was administered in a dose of 500 µg ·
mouse-1 · d-1 IP
on alternate days starting on day 0, 1, or 3, while control mice
received control Ab on equivalent days. All antibodies were
administered once daily.
Histological Examination
The hearts were fixed in 10% formalin, embedded in paraffin,
sectioned, and stained with hematoxylin and eosin. The extent of
cellular infiltration and myocardial necrosis was graded blindly by 2
observers and scored as follows: 0, no lesions; 1+, lesions involving
<25% of the myocardium; 2+, lesions involving 25% to
50%; 3+, lesions involving 50% to 75%; and 4+, lesions involving
75% to 100%.
Assay of Cytokine Levels in the Heart
Cytokine levels in the heart were measured as previously
described.16 Briefly, the hearts of surviving animals were
homogenized with PBS at 4°C and centrifuged, and
the resultant supernatants were collected to measure cytokine
levels with an ELISA kit (Genzyme Co for IL-4, IL-6, IL-10, IL-12, and
tumor necrosis factor- [TNF-]; BioSource International for
IL-1ß; and Endogen Inc for IL-2 and interferon-
[IFN-]). The
sensitivity of the kit is 5 pg/mL for IL-4 and IL-6; 15 pg/mL for
IL-10, TNF-, and IFN-; and 7 pg/mL for IL-1ß. Cytokine
levels were expressed as pg/mg heart.
RNA Preparation and cDNA Synthesis
Total RNA was isolated by the guanidinium
thiocyanate–phenol-chloroform–isoamyl alcohol procedure from hearts
of surviving animals. Total RNA (10 µg) was used for first-strand
cDNA synthesis as described.10 Water (60 µL) was added
to each sample.
Primer Construction for Polymerase Chain Reaction
For polymerase chain reaction (PCR), a sense primer (A)
and an antisense primer (B) were synthesized as previously described
(IL-10 and ß-actin)10 11 and by use of the published
cDNA sequences for inducible nitric oxide synthase
(iNOS).17 Actual sequences of iNOS primers were as
follows: iNOS gene-specific primer A, 5'-CCCTTCCGAAGTTTCTGGCAGCAGC-3';
iNOS gene-specific primer B, 5'-GGCTGTCAGAGCCTCGTGGCTTTGG-3'; iNOS
competitive DNA fragment primer-A,
5'-CCCTTCCGAAGTTT-CTGGCAGCAGCCGCAAGTGAAATCTCCTCCG-3'; and iNOS
competitive DNA fragment primer-B,
5'-GGCTGTCAGAGCCT-CGTGGCTTTGGGGGACAAGATACTCATCTGC-3'.
Semiquantitative PCR Analysis for Time Course of IL-10
mRNA
The semiquantitative analysis of IL-10 and ß-actin
mRNA was performed as described.10 11 Briefly, cDNA was
amplified for 24 cycles (for IL-10) or 21 cycles (for ß-actin). The
PCR products were resolved by electrophoresis and analyzed
by the Southern blotting method with a Fujix (Japan) bioimaging
analyzer BAS 2000. The amounts of IL-10 PCR products were
normalized to ß-actin. The results are expressed as arbitrary
units.
Quantification of Murine iNOS mRNA in the Heart by Competitive
PCR
The expression of iNOS mRNA in the heart was measured by a
modification of the methods described by Li et al.18 The
350-bp iNOS competitor DNA construct was created for the quantification
of iNOS mRNA by PCR with a PCR MIMIC construction kit (Clontech
Laboratories, Inc). A constant amount of the cDNA (2 µL) was then
coamplified with known concentrations of the competitor DNA construct
(2 µL) for 35 cycles of 94°C for 45 seconds, 50°C for 45 seconds,
and 72°C for 90 seconds with 0.2 µmol/L of iNOS gene-specific
primer pairs in a reaction mixture (46 µL) containing 0.25 U AmpliTaq
Gold polymerase (Roche Molecular Systems, Inc). The PCR products
were resolved by 2% agarose gel electrophoresis, visualized by
ethidium bromide staining, and photographed. The negatives of the
photographs were analyzed by an image analyzing system (NIH
Image) (Figure 1
). The concentration of
mRNA was expressed as amol iNOS mRNA/mg total RNA.
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174 HaeIII. B,
Quantitative analysis of competitive PCR experiment shown in A.
Log of ratio of absorbance of target and MIMIC (350-bp iNOS competitor
and 497-bp iNOS) was plotted against log of (molecules MIMIC) added to
PCR reaction. Line was drawn from a linear regression analysis
of data points. Amount of target molecule was determined as point of an
equimolar ratio between internal control and target.
Assay of Myocardial Virus Concentration
The hearts of surviving animals were homogenized in
PBS and centrifuged. The supernatant was assayed by FL plaque
assay.19 The myocardial virus concentration was expressed
as log pfu/mg of heart.
Statistical Analysis
Survival was analyzed by the Kaplan-Meier method.
Statistical comparisons were performed by ANOVA with Bonferroni's
multiple-comparison correction. Measurements of myocardial virus
concentration were tested by the Kruskal-Wallis test. Values are
expressed as mean±SEM. A value of P<0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Time Course of IL-10 Levels in the Heart
Both IL-10 mRNA and protein levels were detectable in the hearts of control mice (Figure 2
, day 0). These
cytokine levels increased 1 day after virus inoculation to
reach peak levels 7 days after inoculation and had decreased
significantly by day 14 after inoculation, although they remained
significantly higher than in uninfected controls. IL-10 mRNA levels on
days 3, 7, and 14 were significantly higher than those on day 0
(P<0.05), and IL-10 protein levels on day 7 were
significantly higher than those on day 0 (P<0.05). Compared
with the value of 48.2±17.8 U measured in infected mice on day 7, mean
IL-10 mRNA level was 2.1±5.4% in the uninfected control, 3.9±8.3%
on day 1 after infection, 12.2±8.1% on day 3, and 14.7±7.9% on day
14 (n=5 each, Figure 2B). Compared with the value of 2.8±0.5
pg/mg heart measured in infected mice on day 7, IL-10 protein levels
were 52.5±10.6% in the uninfected control, 73.9±22.4% on day 1
after infection, 81.5±18.1% on day 3, and 56.5±12.6% on day 14 (n=5
each, Figure 2C).
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Dose-Dependent Effects of rhIL-10
Survival Rate
The 14-day survival rate was significantly higher in the
10-µg/mouse group (80%) than in the control group (30%, n=10 each,
P<0.05, Figure 3). The 14-day
survival rate in the 1-µg/mouse group was intermediate (6 of 10,
60%).
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indicates control group; 
,
1-µg/mouse rhIL-10 group; and 
, 10-µg/mouse rhIL-10 group.
*P<0.05 vs control.
HW/BW Ratio and Myocardial Histology on Day 6
The ratio of heart weight to body weight (HW/BW) and the
pathological scores were lower in the low-dose rhIL-10 group and
significantly lower in the high-dose rhIL-10 group than in the control
group (Table 1 and Figure 4).
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Cytokine Levels in the Heart on Day 6
The differences in TNF- and IL-2 levels measured between the
high-dose rhIL-10 group and the control group were statistically
significant (P<0.05, Figure 5). On day 6, compared with a mean
control value of 125.6±13.2 pg/mg heart, rhIL-10 had suppressed
TNF- levels by 81.8±4.8% in the low-dose rhIL-10 group and by
76.1±5.1% in the high-dose rhIL-10 group (n=5 each). Likewise,
compared with a mean control measurement of 15.4±1.0 pg/mg heart,
rhIL-10 had suppressed IL-2 levels by 82.4±4.2% and 72.9±10.4% in
the low- and high-dose groups, respectively (n=5 each). No such effects
were measured with respect to IL-1ß, IL-4, IL-6, IL-12, and IFN-
production (n=5 each, Table 2).
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iNOS mRNA Levels in the Heart on Day 6
The difference in iNOS mRNA levels measured between the high-dose
rhIL-10 group (8.6±4.7 amol/mg total RNA) and the control group
(26.5±7.1 amol/mg total RNA) was statistically significant
(P<0.05, Figure 6). On day 6,
iNOS mRNA in the low-dose rhIL-10 group was 16.9±4.1 amol/mg total RNA
(n=5 each).
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Myocardial Virus Concentration on Day 6
On day 6, the myocardial virus concentration was unchanged by
rhIL-10. Myocardial virus concentration was 2.8±0.4 log pfu/mg heart
in the high-dose rhIL-10 group, 3.0±0.4 log pfu/mg heart in the
low-dose rhIL-10 group, and 2.9±0.5 log pfu/mg heart in the control
group (n=5 in each).
Effects of Timing of rhIL-10 Administration
Survival Rate
The 14-day survival rate increased significantly in the rhIL-10
groups treated from day 0 (80%) or from day 1 (80%) compared with the
control group (30%, n=10 each, P<0.05, Figure 7). The 14-day survival rate was not
changed by rhIL-10 in the group treated from day 3 (4 of 10, 40%).
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, from day 3 group. *P<0.05 vs
control.
HW/BW Ratio and Myocardial Histology on Day 6
The HW/BW ratio and the pathological scores were significantly
lower in the mice treated with rhIL-10 from day 0 or from day 1 than in
the control group. The scores were not changed in the group actively
treated from day 3 (Table 3).
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Effects of rmIL-10
The HW/BW ratio and the pathological scores were significantly
lower in the rmIL-10 group than in the control group (Table 4).
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Effects of IL-10 Ab
Survival Rate
The 14-day survival rate was significantly lower in the IL-10
Ab groups treated from day 0 (0%) and from day 1 (0%) than in the
group treated from day 3 (30%) or the control group (30%, n=10 each,
P<0.05, Figure 8).
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HW/BW Ratio and Myocardial Histology on Day 6
The HW/BW ratio and the pathological scores were higher in the
IL-10 Ab groups than in the control group, but no significant
differences were found between the 4 groups in the HW/BW ratio and the
pathological scores (Table 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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IL-10 improved the survival and attenuated myocardial lesions in mice suffering from acute myocarditis induced by EMCV. On the basis of previous reports, several mechanisms may explain this favorable effect of the cytokine. First, IL-10 can suppress TNF-
release by
macrophages and lymphocytes. In our murine model of viral
myocarditis, immunohistochemical studies have shown that TNF-
immunostaining in the heart is localized to
macrophages, lymphocytes, and endothelial
cells.10 The effect of rhIL-10 on TNF-
production in heart tissue homogenates is probably
due to inhibition of TNF- production by macrophages
and lymphocytes. We have reported that pretreatment with anti–TNF-
antibody reduces myocardial damage and prolongs survival in the same
murine model.9 In addition, TNF- appears to be an
important element in the pathophysiology of congestive heart
failure.16 20 21 22 These findings suggest that, in this
model of viral myocarditis, IL-10 may prolong survival and attenuate
myocardial lesions by inhibiting TNF-. Second, IL-10 can inhibit IL-2 production by lymphocytes.2 In a murine model of coxsackievirus B3–induced myocarditis, survival was prolonged and myocardial injury was lessened by the exogenous administration of IL-2 during the first week after viral inoculation.23 In contrast, administration of IL-2 during the second week exacerbated the course of the disease.23 In another report, exogenous treatment by IL-2 accentuated the myocardial damage caused by murine coxsackievirus B3–induced myocarditis.24 These findings suggest that in this model of viral myocarditis, IL-10 may prolong survival and attenuate myocardial injury in part by inhibiting IL-2.
Third, IL-10 can reduce NO production by inhibiting
macrophage function.3 In our animal model of viral
myocarditis, NO production was enhanced in response to EMCV
infection, and
NG-monomethyl-L-arginine,
an inhibitor of NO synthesis, attenuated myocardial
lesions.25 We reported that the third-generation
calcium channel blocker amlodipine had beneficial effects and decreased
iNOS-positive macrophages by immunohistochemistry in the same
model.25 In this study, rhIL-10 may inhibit the excessive
production of NO by suppression of iNOS mRNA. In addition,
TNF- and IL-2 are strong inducers of iNOS.26 Thus,
rhIL-10 may indirectly suppress iNOS gene expression by inhibiting
production of TNF- and IL-2. NO is a mediator of the
negative inotropic effects of cytokines, including TNF- and
IL-2.26 IL-10 may also suppress the negative inotropic
effects of NO by directly and indirectly inhibiting iNOS gene
expression.
In this study, treatment with IL-10 reduced mortality and myocardial injury when begun on the day of virus inoculation or 1 day later. However, when administered later, the cytokine did not influence the survival rate or prevent the development of myocardial lesions. In a murine model of fatal group B streptococcus sepsis, IL-10 improved survival when administered 20 or 4 hours before inoculation but had no effect on mortality if given at later times.27 Mortality and inflammation were increased in IL-10 knockout mice with virus-induced encephalomyelitis.28 Collectively, these data suggested that IL-10 plays a major role in the early commitment of the immune response in vivo. In our animal model of viral myocarditis, the amplitude of increase in cytokine mRNA suggests that the early responses, including growth and differentiation of T cells, may occur as early as 24 hours after inoculation.10 The immune responses enter the next stage by 3 days after infection. IL-10 may represent an important regulator of the early immune response to viral infection.
This study showed that IL-10 administration suppressed inflammation
without altering virus replication. These results suggest that IL-10
does not impair the host defense against intracellular pathogens in
vivo. In this model of viral myocarditis, administration of
IL-1211 and IFN-12 also decreased
mortality and myocardial injury. However, from the results and data
presented here, we could not determine whether the beneficial
effects on viral myocarditis were associated with a predominant
response of Th1 or Th2. At this point, these results merely point to
the important role of these cytokines in the immune responses
and to their potential clinical applications. Exogenous
cytokines or neutralizing antibodies influence many effectors
of immune responses in vivo, including the induction or suppression of
the other endogenous cytokines. In addition, it has
been reported that IL-10 acts in a Th-subset–independent
fashion.29 A simple Th1-Th2 dichotomy may not explain the
mechanisms of viral myocarditis. It has been recognized that the immune
system may be inherently toxic to the host and that the negative
regulation of an immune response prevents the toxicity caused by
excessive inflammatory responses. This study shows that IL-10 may be a
key regulatory cytokine to protect the organism against
dangerous inflammatory responses.
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Acknowledgments |
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This work was supported in part by a research grant from the Japanese Ministry of Health and Welfare and a grant-in-aid for General Scientific Research from the Japanese Ministry of Education, Science, and Culture. We thank Drs K. Ono, A. Iwasaki, M. Okada, T. Miyamoto, and A. Nakano for their valuable assistance in this study.
Received February 23, 1999; revision received April 15, 1999; accepted April 26, 1999.
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K. Yamamoto, T. Shioi, K. Uchiyama, T. Miyamoto, S. Sasayama, and A. Matsumori Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice J. Am. Coll. Cardiol., December 3, 2003; 42(11): 2000 - 2006. [Abstract] [Full Text] [PDF]
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R. Nishio, T. Shioi, S. Sasayama, and A. Matsumori Carvedilol increases the production of interleukin-12 and interferon-{gamma} and improves the survival of mice infected with the encephalomyocarditis virus J. Am. Coll. Cardiol., January 15, 2003; 41(2): 340 - 345. [Abstract] [Full Text] [PDF]
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R. Nishio, S. Sasayama, and A. Matsumori Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1506 - 1514. [Abstract] [Full Text] [PDF]
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T. Miyamoto, A. Matsumori, M.-W. Hwang, R. Nishio, H. Ito, and S. Sasayama Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1713 - 1718. [Abstract] [Full Text] [PDF]
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 M. A. Exley, N. J. Bigley, O. Cheng, S. M. A. Tahir, S. T. Smiley, Q. L. Carter, H. F. Stills, M. J. Grusby, Y. Koezuka, M. Taniguchi, et al. CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus J. Leukoc. Biol., May 1, 2001; 69(5): 713 - 718. [Abstract] [Full Text]
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 I. Hamanaka, Y. Saito, H. Yasukawa, I. Kishimoto, K. Kuwahara, Y. Miyamoto, M. Harada, E. Ogawa, N. Kajiyama, N. Takahashi, et al. Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involved in gp130 Resistance in Cardiovascular System in Rat Treated With Cardiotrophin-1 In Vivo Circ. Res., April 13, 2001; 88(7): 727 - 732. [Abstract] [Full Text] [PDF]
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