© 1996 American Heart Association, Inc.
Articles |
Modification of Viral Myocarditis in Mice by Interleukin-6
From the Department of Laboratory Medicine (T.K., I.K.) and the Second Department of Internal Medicine (R.N., S.I.), Gunma University School of Medicine, and the College of Medical Care and Technology (T.S.), Gunma University, Maebashi, Japan, and the Department of Pathology and Laboratory Medicine (J.E.W.M., D.Y., B.M.M.), University of British Columbia, St. Paul's Hospital, Vancouver, Canada.
Correspondence to Tsugiyasu Kanda, MD, Department of Laboratory Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi 371, Japan.
Abstract Inflammatory cytokines play a key role in
the myocardial injury produced by viral myocarditis. Although
interleukin-6 (IL-6) reportedly possesses antiviral properties, its
effect in viral myocarditis is unclear. To investigate the role of IL-6
in viral myocarditis induced by encephalomyocarditis virus (EMCV) in
mice, we evaluated (1) the survival rate following IL-6 administration,
(2) the viral titer in the heart, (3) viral replication in the heart by
in situ hybridization, (4) histopathological changes using
immunohistochemical staining, (5) neutralizing antibody against EMCV,
(6) circulating interferon and tumor necrosis factor-
(TNF-), (7)
viral suppression in vitro by IL-6, and (8) natural killer (NK)–cell
activity. Eight-week-old C3H/HeJ mice were injected
intraperitoneally with EMCV (day 0) and were also
injected subcutaneously twice daily for 4 consecutive days with 10
µg/0.1 mL of human IL-6 on day -4 (group A), day 0 (group B), or day
+4 (group D) for 4 days. As a control, 0.1 mL PBS instead of IL-6 was
injected on day 0 for 4 days (group C). Certain mice were killed on day
4. The myocardial virus titers, viral replication in situ, and NK-cell
activity in the spleen were determined. Decreased viral titer and viral
replication in the heart reduced the titer of circulating TNF-, and
lower NK-cell activity was observed in group B versus group C (control
group). The titer of neutralizing antibodies against EMCV was
significantly (P<.05) increased in group B compared with
group C. The remaining mice were killed on days 10 and 30 after
infection. The ratio of heart weight (HW) to body weight (BW) and
myocardial injury in group B were reduced versus group C on days 10 and
30. The HW of group B on day 30 did not differ from the normal control
group. The ratio of splenic weight to BW and the ratio of thymic weight
to BW of group B increased on day 10, with expanded follicles observed
in the spleen and enlargement of the medulla observed in the thymus.
Immunohistochemical study revealed an increased percentage of
macrophages in the heart and spleen of group B. In summary,
IL-6 reduces myocardial damage in mice with viral myocarditis.
Modification of immune responses together with reduction in viral
replication appears to be the mechanism of the IL-6 effect. Although
IL-6 is likely important in the process of viral antigen
presentation, early activation of immune responses and
attenuation of viral replication appear most significant, as reflected
in the limited time window during which IL-6 is effective in
myocarditis.
Key Words: myocarditis • interleukin-6 • host immunity • in situ hybridization
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