(Circulation. 2001;103:743.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Tumor Necrosis Factor-
(TNF-) Plays a Protective Role in Acute Viral Myocarditis in Mice
A Study Using Mice Lacking TNF-
From the Department of Laboratory Medicine (H.W., K. Saito, H. Fujii, S.F., N.M., M.S.) and Second Department of Internal Medicine (H.T., H. Fujiwara), Gifu University School of Medicine, Gifu; Department of Laboratory Medicine, Gunma University School of Medicine, Gunma (T.K., I.K.); and Department of Immunology, National Institute of Animal Health (K. Sekikawa), Japan.
Correspondence to Hisayasu Wada, MD, PhD, Department of Laboratory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. E-mail wadah{at}cc.gifu-u.ac.jp
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Abstract |
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Background—It has been reported that tumor necrosis factor-
(TNF-) is expressed
in the heart with viral myocarditis and that its expression aggravates
the condition. The pathophysiological effects of TNF- on viral
myocarditis, however, have not been fully
elucidated.
Methods and Results—To
investigate the role of TNF- in the progression of viral
myocarditis, we used TNF- gene–deficient mice
(TNF--/-) and induced acute
myocarditis by infection with encephalomyocarditis virus (EMCV). The
survival rate of TNF--/- mice after
EMCV infection was significantly lower than that of
TNF-+/+ mice (0% versus 67% on day 14).
Injection of recombinant human TNF- (0.2 to 4.0 µg/mouse IV)
improved the survival of TNF--/- mice
in a dose-dependent manner, indicating that TNF- is essential for
protection against viral myocarditis. The levels of viral titer and
viral genomic RNA of EMCV in the myocardium were significantly higher
in TNF--/- than in
TNF-+/+ mice. Histopathological
examination showed that the inflammatory changes of the myocardium were
less marked in TNF--/- than in
TNF-+/+ mice. Immunohistochemical
analysis revealed that the levels of immunoreactivity of intercellular
adhesion molecule-1 and vascular cell adhesion molecule-1 in the
myocardium were decreased in TNF--/-
mice compared with TNF-+/+
mice.
Conclusions—These
observations suggested that TNF- is necessary for adhesion molecule
expression and to recruit leukocytes to inflammatory sites, and thus,
the lack of this cytokine resulted in failure of elimination of
infectious agents. We concluded that TNF- plays a protective role in
the acute stage of viral
myocarditis.
Key Words: tumor necrosis factor- • myocarditis • viruses • cell adhesion molecules
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Tumor necrosis factor-
(TNF-) is considered to be a proinflammatory
cytokine1 and to play a
crucial role in the initiation and continuation of inflammation and
immunity. In this regard, this cytokine may be implicated in the
pathogenesis of cardiovascular diseases, especially in viral
myocarditis. In fact, elevated plasma levels of TNF- have been
reported in patients with acute
myocarditis.2 The enhanced
expression of TNF- mRNA was also reported in a mouse model of viral
myocarditis.3 4 It
is still unclear, however, whether the expression of TNF- is
beneficial to the host. Administration of TNF- has been reported to
aggravate viral myocarditis,5
and neutralization of this cytokine with selective antibodies
ameliorates viral5 and
autoimmune myocarditis.6
These findings indicated that endogenous TNF- is deleterious to
myocarditis. Conversely, it has also been reported that TNF- has
antiviral activity,7 and mice
lacking TNF- show a high degree of susceptibility to infectious
agents8 9 and
impaired clearance of adenoviral
vectors.10 These
observations suggest that TNF- has a protective role against viral
infection. The pathophysiological effects of endogenous TNF- in
viral myocarditis, therefore, are still controversial and remain to be
elucidated. To directly examine the role of endogenous TNF- in viral
myocarditis, we used mice with a targeted disruption of the gene
encoding TNF-11 and
induced acute myocarditis by infection with encephalomyocarditis virus
(EMCV). Our results indicate that TNF- plays an essential role in
protection against viral infection in the acute stage of viral
myocarditis. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animals
TNF-
gene–deficient
(TNF--/-) mice were produced by gene
targeting as described
previously.11 Briefly, a
TNF-–targeting vector was constructed from a 7-kb DNA fragment
isolated from a 129 mouse 
FIXII genomic library. The
HincII-HindIII
fragment containing exon 3 and part of exon 4 was replaced with a
neomycin-resistant gene cassette. This targeting vector was introduced
into TT2 ES cells by electroporation. Resistant clones were screened,
and homologous recombination events were confirmed by Southern blotting
analysis. Three clones were injected into 8-cell–stage C57BL/6J
embryos, which were transferred into the uteri of pseudopregnant ICR
females. Chimeric mice derived from 1 clone transmitted the mutation to
offspring.
TNF-+/-
heterozygotes were backcrossed with C57BL/6J mice, and the F8
generation was used for preparation of
TNF--/- homozygotes. The H2 haplotype
of homozygotes was determined to be H2b. C57BL/6J mice obtained from
Japan SLC (Shizuoka, Japan) were used as wild-type controls
(TNF-+/+).
Viral Inoculation
A myocarditic variant of EMCV was generously provided
by Dr Seto (Keio University, Tokyo, Japan). The virus stock was stored
at -80°C in Hanks’ balanced salt solution with 0.1% BSA until
use. Mice were inoculated intraperitoneally with 50 or 500
plaque-forming units (pfu) of EMCV in 0.1 mL of saline. Eight-week-old
male mice were used for inoculation and housed in an isolated room. The
day of virus inoculation was defined as day 0 in the following studies.
The experiments were performed according to the institutional
guidelines of Gifu University.
Tumor Necrosis Factor-
Recombinant human TNF- (rhTNF-) produced in
Escherichia coli by recombinant
DNA technology was provided by Dainippon Pharmaceutical Co
Ltd.12 rhTNF- (0.2 to 4.0
µg) was dissolved in 0.1 mL of saline and injected
intravenously.
Measurement for Plasma TNF-
Concentration
Plasma TNF- levels were determined with a
solid-phase sandwich ELISA (BioSource International). Ninety-six–well
microplates were coated with an antibody specific for mouse TNF-.
Fifty microliters of each sample was added in duplicate to the
microplates, and 50 µL of biotinylated anti–TNF- antibody
solution was pipetted into each well. After 1.5-hour incubation at room
temperature, the microplates were washed 5 times, and 100 µL of
streptavidin–horseradish peroxidase conjugate solution was added to
each well. Standard curves were made with mouse TNF- used as a
standard. The minimum detectable concentration of TNF- was <3
pg/mL.
RNA Extraction and Reverse
Transcription–Polymerase Chain Reaction Analysis
Total RNA was extracted from the heart with Isogen
(Nippon Gene) and determined by the absorbance at 260 nm. Reverse
transcription–polymerase chain reaction (RT-PCR) was carried out with
mRNA Selective PCR Kits (Takara Biochemicals). The following
oligonucleotide primer pairs were synthesized: EMCV sense,
5'-GTCGTG-AAGGAAGCAGTTCC-3'; antisense,
5'-CACGTGGCTTTTGGC-CGCAGAGGC-3'; ß-actin sense,
5'-GGACTCCTATGTGGGTGA- CGAGG-3'; antisense,
5'-GGGAGAGCATAGCCCTCGTAGAT-3'.
The PCR products were analyzed by agarose gel electrophoresis with ethidium bromide staining. The optimum number of cycles was determined experimentally for each gene product and to verify uniform amplification.
Viral Titer
The viral titers in the hearts of infected mice on
day 7 were measured as described
previously.13 Briefly, the
heart was weighed and homogenized in 2 mL of Eagle’s MEM. After
centrifugation, the supernatant was added to 96-well microtiter plates
containing human amnion (FL) cells in MEM with 10% FCS. The microtiter
plates were examined daily for 5 days for the appearance of any
cytopathic effect. The viral titers were expressed as the 50% tissue
culture infectious doses
(TCID50).
Histopathological Study
One half of the heart was fixed in 10% buffered
formalin and embedded in paraffin. Transverse sections of the
ventricles were stained with hematoxylin and eosin (HE) and observed by
microscopy at x200 magnification. The extent of cellular infiltration
and myocardial necrosis was graded blindly by 2 experienced
pathologists who had no knowledge of the study design and was scored as
follows13 : 0, no lesions;
1+, lesions involving <25%; 2+, lesions involving 25% to 50%; 3+,
lesions involving 50% to 75%; and 4+, lesions involving 75% to
100%.
The other half of the heart was embedded in OCT compound (Miles Laboratory), snap-frozen in liquid nitrogen, and cut into sections 5 µm thick. Sections were air-dried and fixed in cold acetone for 10 minutes. The primary antibodies used were hamster anti-mouse intercellular adhesion molecule-1 (ICAM-1, clone 3E2, PharMingen, diluted 1:20) and rat anti-mouse vascular cell adhesion molecule-1 (VCAM-1, clone 429, PharMingen, diluted 1:10). Secondary antibodies were biotinylated goat anti-hamster IgG (EY Laboratories, diluted 1:300) and rabbit anti-rat IgG (Dako, diluted 1:300). The streptavidin-peroxidase complex (Dako) and 3,3'-diaminobenzidine were used for visualization. The sections were counterstained with methyl green (Sigma). The levels of immunoreactivities of ICAM-1 and VCAM-1 were examined by 2 experienced pathologists in a blinded fashion.
Measurement of Plasma Creatine Kinase, Lactate
Dehydrogenase, Alanine Aminotransferase, and Blood Urea
Nitrogen
Activities of creatine kinase (CK), LDH, and ALT and
concentrations of BUN in the plasma were measured with commercially
available kits and an automatic analyzer Hitachi
736.
Statistical Analysis
Results are expressed as mean±SEM. Survival rates of
mice were analyzed by the Kaplan-Meier method. Comparisons between 2
groups were performed by Student’s
t test, and those among 3
groups were performed by 1-way ANOVA. Histopathological scores were
examined by the Mann-Whitney test. StatView 4.5 and Super ANOVA
software were used for statistical analyses on a Power Macintosh G3
(Apple Computer). Results were considered statistically significant at
a value of
P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Survival After Inoculation of EMCV
Figure 1
shows the survival rates of
TNF-+/+ and
TNF--/- mice. The survival rates of
TNF-+/+ mice on day 14 after inoculation
with 50
(Figure 1A) or 500
(Figure 1B) pfu of EMCV were 95% and 67%, respectively. All
TNF--/- mice died within 14 days
after inoculation of either dose of EMCV.
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RT-PCR Analysis of Viral Genomic RNA and Viral
Titer in the Heart
The cardiac viral genomic RNA levels on day 7 after
inoculation with 50 or 500 pfu of EMCV in
TNF--/- mice quantified by RT-PCR
analysis were significantly increased compared with those in
TNF-+/+ mice
(Figure 2B). The cardiac viral titer in
TNF--/- mice was also significantly
higher than that in TNF-+/+ mice
(Figure 2C). These results suggested that
TNF--/- mice have impaired viral
elimination.
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Changes in Plasma TNF- Levels in
EMCV-Treated Mice
As shown in
Figure 3, plasma TNF- levels of
TNF-+/+ mice were significantly elevated
6 hours after inoculation with 500 pfu of EMCV and reached the maximal
value 24 hours after inoculation. Plasma TNF- levels on day 7 were
still higher than before inoculation. Plasma TNF- could not be
detected in TNF--/-
mice.
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Survival of EMCV-Treated
TNF--/- Mice Supplemented With
rhTNF-
Because a significant increase in plasma TNF- level
was observed 6 hours after inoculation of EMCV in
TNF-+/+ mice, rhTNF- (0.2 to 4.0
µg/mouse IV) was injected through the tail vein into
TNF--/- mice 6 hours after
inoculation with 500 pfu of EMCV. As shown in
Figure 4, intravenous injection of rhTNF- improved the
survival of TNF--/- mice in a
dose-dependent manner. Survival of
TNF--/- mice receiving rhTNF- at a
dose of 
2.0 µg was equivalent to that of
TNF-+/+ mice. These findings indicated
that TNF- is required for protection against acute viral
myocarditis.
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Immunohistochemical Findings
As shown in
Figure 5, TNF-+/+ mice showed
apparent cellular infiltration of the heart on day 7 after inoculation
with 500 pfu of EMCV. Interestingly, the cellular infiltration in
TNF--/- mice was suppressed compared
with that in TNF-+/+ mice.
Histopathological scores of cellular infiltration and myocardial
necrosis were significantly decreased in
TNF--/- mice
(Table).
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Figure 6 shows the results of immunostaining for ICAM-1 and
VCAM-1 in the infected heart on day 7. The levels of ICAM-1 and VCAM-1
immunoreactivity in TNF--/- mice were
diminished compared with those in TNF-+/+
mice.
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Plasma CK, LDH, ALT, and BUN
Plasma CK and LDH activities of
TNF--/- mice were significantly
higher than those of TNF-+/+ mice
(Figure 7), suggesting that severe myocardial damage occurred
in TNF--/- mice despite the slight
changes in histopathological findings compared with
TNF-+/+ mice. There were no significant
differences in plasma ALT or BUN levels, however, between
TNF--/- and
TNF-+/+ mice
(Figure 7).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, EMCV was used to induce myocarditis in mice. EMCV is a member of the Picornaviridae family, which includes the Enterovirus genus. EMCV can cause acute myocarditis in various animal species, including mice. This is an established mouse model for viral myocarditis leading to dilated cardiomyopathy and congestive heart failure.14 On entry of EMCV into the host cell, the single-positive-strand viral RNA is released from the capsid, and viral proteins are synthesized by the host cell translational machinery. One of the viral proteins is an RNA-dependent RNA polymerase that allows replication of viral genomic RNA. Replicated positive-strand viral RNAs are encapsidated and released by host cell lysis.15 EMCV infection is thus usually cytopathic.
TNF- plays a crucial role in the progression of
inflammatory responses in the heart as well as other vital organs. In
fact, it has been reported that plasma TNF- levels are elevated in
patients with various cardiac diseases, including acute
myocarditis,2 and that the
cardiac expression of TNF- mRNA is enhanced in mice with viral
myocarditis.3 4 The
production of TNF- is generally considered to be harmful to the
cardiovascular system, because systemic administration of TNF-
results in myocardial
depression16 and
cardiomyopathy.17
Cardiac-specific overexpression of TNF- has been reported to cause
severe myocarditis in
mice.18 19
Moreover, the neutralization of TNF- with selective antibodies
ameliorates viral5 and
autoimmune6 myocarditis and
prevents myocardial dysfunction induced by
lipopolysaccharide.20 In
marked contrast, TNF- has also been proposed to have beneficial
actions. TNF- production might enhance contractility, mediate
compensatory hypertrophy, or be involved in cardiac adaptation to
stress.21 22
Furthermore, TNF- has been reported to have antiviral
activity.7 Mice lacking
TNF- show a high degree of susceptibility to infectious
agents8 9 and
impaired clearance of adenoviral
vectors,10 suggesting that
TNF- has a protective role against viral infection. Thus, the
precise role of TNF- in the pathogenesis of viral myocarditis is
still unclear. To directly address this issue, we induced acute viral
myocarditis in TNF--/-
mice11 by infection with
EMCV.
In the present study, EMCV caused severe, lethal
myocarditis in TNF--/- mice. The
survival rate of TNF--/- mice after
EMCV infection was significantly lower than that of
TNF-+/+ mice
(Figure 1
). Intravenous administration of rhTNF- (0.2 to
4.0 µg/mouse) improved the survival of
TNF--/- mice in a dose-dependent
manner
(Figure 4). Moreover, the myocardial viral titer and the
level of viral genomic RNA in TNF--/-
mice were significantly higher than those in
TNF-+/+ mice
(Figure 2). These observations indicated that lack of TNF-
resulted in failure to eliminate infecting viruses, showing that
TNF- is essential for protection from viral myocarditis in the acute
stage. A recent study using knockout mice demonstrated that the
effectors most important for elimination of adenovirus vectors from
infected hepatocytes are TNF- > Fas >
perforin.10 The antiviral
effect of TNF- has already been demonstrated both in vitro and in
vivo.7 23
Administration of TNF-, however, is unable to cause elimination of
the adenovirus vectors in severe combined immunodeficient
mice,10 suggesting that
TNF- does not act directly on infectious agents. TNF- is thought
to exert its antiviral effects via activation of the immune system.
Chisari24 reported that
hepatitis B virus (HBV)–specific cytotoxic T lymphocytes can abolish
HBV gene expression and replication noncytopathically by secreting
TNF- and interferon-
. TNF- delivers noncytopathic antiviral
signals to the hepatocytes to degrade the cytoplasmic transcript and
the nucleocapsid particles of
HBV.25 TNF-, therefore,
is thought to be an important immune mediator in host
defense.
Conversely, the observation that intravenous administration
of rhTNF- 6 hours after inoculation with EMCV improved the survival
of TNF--/- mice
(Figure 4) indicates that TNF- is necessary only in the
early stage of infection to protect against viral myocarditis. The
plasma TNF- level on day 7 after inoculation in
TNF-+/+ mice, however, was still higher
than the basal level
(Figure 3), suggesting that TNF- production is excessively
prolonged. The persistent expression of TNF- in the chronic stage of
viral myocarditis in mice has been
reported,3 4 and
TNF- expression was more pronounced in susceptible C3H.HeJ mice, in
which marked myocardial depression was
observed.4 These findings
suggest that persistent expression of TNF- in the chronic stage of
viral myocarditis may be harmful to the cardiovascular system, whereas
TNF- expression in the acute stage of viral myocarditis is
beneficial for elimination of infectious viruses. The persistent
expression of TNF- may cause chronic infiltration of
leukocytes,18 19
resulting in myocardial damage. Interleukin-2 has been reported to have
a similar action26 in that
interleukin-2 suppressed viral myocarditis in the acute stage but
exacerbated the condition in the chronic stage. As in the cases of
norepinephrine and angiotensin II, sustained production of TNF-
might be a maladaptive response to chronic heart
diseases.27 28
Histopathological analysis revealed that myocardial cellular
infiltration in TNF--/- mice was
markedly suppressed compared with TNF-+/+
mice
(Figure 5). Similar findings have been reported, in that
TNF--/- mice showed significant
reduction in the number of infiltrating lymphocytes in the liver
infected with adenoviral vectors and impaired clearance of adenoviral
vectors from the liver.10
TNF- is a potent inducer of the expression of adhesion
molecules,29 30
which are necessary to recruit immune cells to sites of inflammation.
Immunohistochemical analysis
(Figure 6) showed that the levels of adhesion molecule
immunoreactivity (ICAM-1, VCAM-1) in the myocardium were reduced in
TNF--/- mice compared with
TNF-+/+ mice, suggesting that TNF-
could recruit leukocytes to inflammatory sites through the upregulation
of adhesion molecules. The lack of leukocyte recruitment may be a major
factor responsible for impaired clearance of infectious agents in
TNF--/-
mice.10 In contrast, the
leukocyte recruitment in autoimmune myocarditis is thought to be
harmful, because there is no infectious agent to be eliminated, and
leukocyte infiltration merely causes myocardial damage in autoimmune
myocarditis. For this reason, TNF- receptor p55–deficient mice do
not develop autoimmune
myocarditis,31 and
anti–TNF- antibodies ameliorate autoimmune
myocarditis.6
The minimal histopathological changes raised suspicions that
myocarditis may not have been the actual cause of death in
TNF--/- mice. No detectable
inflammation was observed, however, in extracardiac organs, such as the
brain, spinal cord, liver, pancreas, and kidney, in
TNF--/- mice (data not shown).
Furthermore, the myocardial viral titer
(Figure 2) and the plasma CK and LDH levels
(Figure 7) of TNF--/- mice
were markedly increased. EMCV is thought to be a cytopathic
virus,15 and persistent
picornavirus infection has been reported to induce cytopathic effects
on myocytes.32 33
Thus, we considered myocarditis to be the cause of death in
TNF--/- mice infected with EMCV.
Because EMCV is thought to bind to VCAM-1 as the first step in viral
entry,34 the mechanism by
which EMCV injures myocytes with suppressed VCAM-1 expression in
TNF--/- mice is unknown, and the
exact cause of death in TNF--/- mice
remains to be elucidated. On the basis of our data, however, it is
obvious that the presence of TNF-, particularly at an early stage of
infection, is critical to protection from lethal EMCV
infection.
In conclusion, TNF- plays a protective role in acute
viral myocarditis, possibly through leukocyte
recruitment.
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Acknowledgments |
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This work was supported in part by a Grant-in-Aid for General Scientific Research from the Japanese Ministry of Education, Science, and Culture (10670641). We thank S. Maeda, M. Takemura, N. Furuta, A. Morise, C. Togashi, and A. Saito for excellent technical assistance.
Received June 9, 2000; revision received August 15, 2000; accepted August 15, 2000.
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M. Li, D. Georgakopoulos, G. Lu, L. Hester, D. A. Kass, J. Hasday, and Y. Wang p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart Circulation, May 17, 2005; 111(19): 2494 - 2502. [Abstract] [Full Text] [PDF]
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 A. Matsumori, Y. Nunokawa, A. Yamaki, K. Yamamoto, M.-W. Hwang, T. Miyamoto, M. Hara, R. Nishio, K. Kitaura-Inenaga, and K. Ono Suppression of cytokines and nitric oxide production, and protection against lethal endotoxemia and viral myocarditis by a new NF-{kappa}B inhibitor Eur J Heart Fail, March 1, 2004; 6(2): 137 - 144. [Abstract] [Full Text] [PDF]
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 Y. CHEN, Q. KE, Y. YANG, J. S. RANA, J. TANG, J. P. MORGAN, and Y.-F. XIAO Cardiomyocytes overexpressing TNF-{alpha} attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase FASEB J, December 1, 2003; 17(15): 2231 - 2239. [Abstract] [Full Text] [PDF]
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A. Martire, B. Fernandez, A. Buehler, C. Strohm, J. Schaper, R. Zimmermann, P. E Kolattukudy, and W. Schaper Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice mimics ischemic preconditioning through SAPK/JNK1/2 activation Cardiovasc Res, February 1, 2003; 57(2): 523 - 534. [Abstract] [Full Text] [PDF]
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R. M Smith, S. Lecour, and M. N Sack Innate immunity and cardiac preconditioning: a putative intrinsic cardioprotective program Cardiovasc Res, August 15, 2002; 55(3): 474 - 482. [Abstract] [Full Text] [PDF]
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R. M Smith, N. Suleman, J. McCarthy, and M. N Sack Classic ischemic but not pharmacologic preconditioning is abrogated following genetic ablation of the TNF{alpha} gene Cardiovasc Res, August 15, 2002; 55(3): 553 - 560. [Abstract] [Full Text] [PDF]
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D. L. Mann Tumor Necrosis Factor and Viral Myocarditis: The Fine Line Between Innate and Inappropriate Immune Responses in the Heart Circulation, February 6, 2001; 103(5): 626 - 629. [Full Text] [PDF]
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