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Cited by 198Viral Infections and Immunology ResearchCardiac Fibrosis and Remodelinginterferon and immune responses

Interferon-γ Protects against Chronic Viral Myocarditis by Reducing Mast Cell Degranulation, Fibrosis, and the Profibrotic Cytokines Transforming Growth Factor-β1, Interleukin-1β, and Interleukin-4 in the Heart

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Fairweather, DeLisa, Frisancho-Kiss, Sylvia, Yusung, Susy A., Barrett, Masheka A., Davis, Sarah E., Gatewood, Shannon J.L., Njoku, Dolores B., Rose, Noel R.·2004·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)63241-5PMC PMC1618717
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Abstract

Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-gamma, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12R beta 1 and IFN-gamma deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the hearts of IFN-gamma-deficient mice. All mice infected with CB3 developed DCM, but IFN-gamma-deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12R beta 1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN-gamma protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the heart.

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  • IFNs reduce viral replication and prevent remodeling and fibrosis and thereby progression to DCM.

    “However, IFNs reduce viral replication and prevent remodeling and fibrosis and thereby progression to DCM. 128,169,170”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [128]

    The Discussion (page unavailable) says IFN-γ reduces CB3 viral replication and cardiac fibrosis, supporting those parts of the claim. But the DCM Results (page unavailable) report that all infected mouse strains developed DCM, including wild-type mice; IFN-γ reduced severe DCM rather than preventing progression to DCM. The paper studies IFN-γ specifically, not IFNs generally. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • cMRI cannot identify specific cellular components of inflammation and may be less accurate in early stages of myocarditis because fibrosis typically develops weeks after acute myocarditis.

    “cMRI cannot identify specific cellular components of inflammation and may be less accurate in the early stages of myocarditis because fibrosis typically develops weeks after acute myocarditis. 128-130”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [128]

    The introduction describes acute myocarditis in infected mice on days 7–14, and the cardiac-fibrosis results report fibrosis at day 35 during chronic myocarditis (page numbers unavailable). This supports a later association with fibrosis in this mouse model, but does not establish when fibrosis first develops or that it typically develops weeks later. The paper does not address cMRI’s ability to identify inflammatory cells or its accuracy in early myocarditis. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Type I and II IFNs are a dominant immune response in CVB3 myocarditis models and EAM, where inhibition of these pathways leads to increased viral replication, pericardial and myocardial inflammation, and DCM.

    “Type I and II IFNs are a dominant immune response in CVB3 myocarditis models (and EAM) where inhibition of these pathways leads to increased viral replication, pericardial and myocardial inflammation, and DCM. 124,128,152,169,170”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [128]

    The Discussion (page not provided) says IFN-γ protects against viral replication in acute CB3 infection and against fibrosis in chronic disease; it also describes worse inflammation in an experimental autoimmune myocarditis model when IFN-γ is absent or neutralized. The chronic-myocarditis results report increased pericarditis and more severe DCM in IFN-γ-deficient mice. The paper does not establish the claim about type I IFNs or that both IFN pathways are a dominant response; it also says infectious virus is absent during chronic myocarditis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Fairweather, D., Frisancho-Kiss, S., Yusung, S. A., Barrett, M. A., Davis, S. E., Gatewood, S. J. L., Njoku, D. B., & Rose, N. R.
Affiliations
  • Johns Hopkins University (US)
  • Johns Hopkins Medicine (US)
Corresponding author
Rose, Noel R.
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2004-12
Volume
165
Issue
6
Pages
1883-1894
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/s0002-9440(10)63241-5
PMC
PMC1618717
OpenAlex
W2157962982
Cited by
198
References
78
Citations by year
2026: 7 · 2025: 6 · 2024: 14 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 5 · 2019: 7 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 6 · 2014: 7 · 2013: 12 · 2012: 19
FWCI
6.33
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (HL67290, HL70729, AI51835)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
interferon-gamma, mast cell degranulation, myocardial fibrosis, dilated cardiomyopathy, pericarditis, TGF-β1, IL-1β, IL-4, histamine, Th1 response, profibrotic cytokines
MeSH terms
Animals, Cardiomyopathy, Dilated, Chronic Disease, Enterovirus Infections, Heart, Histamine, Interferon-gamma, Interleukin-1, Mast Cells, Mice, Inbred BALB C, Myocarditis, Myocardium, Cell Degranulation, Interleukin-4, Transforming Growth Factor beta, Receptors, Interleukin, Mice, Knockout, Enterovirus B, Human, Mice, Receptors, Interleukin-12, Transforming Growth Factor beta1

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