Regular Article
Effect of Interleukin-18 on Viral Myocarditis: Enhancement of Interferon- γ and Natural Killer Cell Activity

https://doi.org/10.1006/jmcc.2000.1242Get rights and content

Abstract

Encephalomyocarditis virus causes viral myocarditis with myocyte necrosis and inflammatory cell infiltration in mice. Because previous studies have shown that some cytokines prevent the sequelae of myocarditis, we assessed the effect of a newly identified cytokine, interleukin-18 (IL-18), in preventing the sequelae of myocarditis. Murine IL-18 (10μ g/day/mouse) was given peritoneally for 10 days in C3H mice infected with EMC virus. Mice were divided into group IL-18 (infected-treated), saline group (infected-untreated), group IL-18-2 (treatment started on day 2), group IL-18-5 (treatment started on day 5). Although the 14-day survival rate in saline group was 20%, that in the group IL-18 increased to 80% (P<0.05). Either mice in group IL-18-2 or in group IL-18-5 did not survive longer than saline group. The viral titer of the heart on day 3 was lower in group IL-18 compared to the saline group (1.00±0.20 log10tissue culture infected dose (TCID)50/mg wet weight v 1.42±0.12 log10TCID50/mg,n =3 of each). Mice in group IL-18 had less myocardial necrosis and cellular infiltration than the saline group. The myocardial expression of interferon- γ (IFN- γ) mRNA in group IL-18 was significantly (P<0.05) greater than the saline group on days 1 and 3 after viral inoculation. Circulating IFN- γ was significantly elevated on days 1, 5, and 7, but significantly reduced on day 3. The natural killer cell activities in the spleen on days 1, 3, and 5 were significantly (P<0.05) greater in group IL-18 than in the saline group (41±9%v 10±6% on day 3, 4 of each). We conclude that IL-18 reduces the severity of EMC viral myocarditis by inducing cardiac expression of IFN- γ mRNA and increasing splenic natural killer cell activity.

References (20)

  • R Kandolf et al.

    Coxsackie B3 virus can relicate in cultured human foetal heart cells and is inhibited by interferon

    J Mol Cell Cardiol

    (1985)
  • MA Lucchiari et al.

    A major role of macrophage activation by interferon-gamma during mouse hepatitis virus type 3 infection. I. Genetically dependent resistance

    Immunobiology

    (1989)
  • NG Ilback et al.

    Effects of the immunomodulator LS 2616 on lymphocyte subpopulations in murine Coxsackievirus B3 myoÍcarditis

    J Immunol

    (1989)
  • T Yokoyama et al.

    Combination therapy of OK432 and recombinant human interferon alpha A/D on viral myocarditis in mice starting after infection

    J Pharmacol Exp Ther

    (1991)
  • T Kanda et al.

    Effect of combination therapy with OK432 and recombinant human interferon-alpha A/D on atrial natriuretic peptide gene expression in mice with viral myocarditis

    J Pharmacol Exp Ther

    (1995)
  • C Kishimoto et al.

    Cytokine and murine coxsackievirus B3 myocarditis. Interleukin-2 suppresses myocarditis in the acute stage, but enhanced the condition in the subsequent stage

    Circulation

    (1994)
  • T Kanda et al.

    Modification of viral myocarditis in mice by interleukin-6

    Circ Res

    (1996)
  • N Yamamoto et al.

    Effects of intranasal administration of recombinant murine interferon- γ on murine acute myocarditis caused by encephalomyocarditis virus

    Circulation

    (1998)
  • M Miric et al.

    Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy

    Eur Heart J

    (1995)
  • H Okamura et al.

    Cloning of a new cytokine that induces IFN- γ production by T cells

    Nature

    (1995)
There are more references available in the full text version of this article.

Cited by (36)

  • Innate and adaptive immunity in acute myocarditis

    2024, International Journal of Cardiology
  • Natural killer cells in inflammatory heart disease

    2017, Clinical Immunology
    Citation Excerpt :

    The ability of NK cells to limit viral infections is important in cardiac biology [105–108]. NK cells are required for protection against mouse models of CBV and MCMV-mediated myocarditis in an IFNγ-dependent manner [90,109,110]. Clinically, rare individuals with NK cell deficiencies have an increased susceptibility to viral infections, though not specifically cardiac infections [111–114].

  • Regulatory effects of IL-18 on cytokine profiles and development of myocarditis during Trypanosoma cruzi infection

    2014, Microbes and Infection
    Citation Excerpt :

    In fact, there is an intense inflammatory response in the heart, which is differently modulated and dependent on the parasite strain [6,23,24]. IL-18 is a proinflammatory cytokine induced during T. cruzi infection in mice [3,19] and humans [25] which also induces the production of IFN-γ [11–15] and other pro-inflammatory cytokines including IL-1β and TNF-α [26]. However, to this date, the role of IL-18 in T. cruzi infection has remained unclear.

  • Inflammation in viral myocarditis: Friend or foe?

    2012, Trends in Molecular Medicine
    Citation Excerpt :

    Dose and time dependency were also observed for IL-6, as transgenic overexpression of IL-6 aggravates the course of EMCV myocarditis [51], whereas recombinant IL-6 administration in the acute, but not subacute, phase is protective [52]. Similarly, beneficial effects of IL-18 treatment (involving enhanced NK cell activity) were only observed from treatment at the time of infection, whereas initiation of treatment at day 2 post-infection failed to provide cardioprotection [53]. Detrimental roles have been ascribed to two other proinflammatory cytokines, IL-1 and IL-12.

  • Cardiac Cell-specific Apoptotic and Cytokine Responses to Reovirus Infection: Determinants of Myocarditic Phenotype

    2009, Journal of Cardiac Failure
    Citation Excerpt :

    IL-10 treatment in an EMCV mouse model resulted in increased survival, decreased myocardial lesions and decreased levels of TNF-α, but had no effect on myocardial virus concentration.56 IL-18 has been demonstrated to have similar beneficial attributes: increased survival, decreased viral titer, decreased myocardial necrosis, increased IFN- γ expression in the heart, and increased natural killer cell activity in the spleen.57 Specific to reovirus associated myocarditis, Sherry et al have identified IFN-β and the resulting cascade of effects as important factors in the control of viral replication.39,42,58,59

View all citing articles on Scopus

Please address all correspondence to: Tsugiyasu Kanda, MD, Department of Laboratory Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi 371, Japan. Fax: +81 272 20 7720. E-mail: [email protected]

View full text