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Cited by 229Viral Infections and Immunology ResearchImmune Response and InflammationCardiac Fibrosis and Remodeling

IL-12 Receptor β1 and Toll-Like Receptor 4 Increase IL-1β- and IL-18-Associated Myocarditis and Coxsackievirus Replication

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Fairweather, DeLisa, Yusung, Susan, Frisancho, Sylvia, Barrett, Masheka, Gatewood, Shannon, Steele, Ronelle, Rose, Noel R·2003·The Journal of Immunology
DOI 10.4049/jimmunol.170.9.4731
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Abstract

Th1-type immune responses, mediated by IL-12-induced IFN-γ, protect the host from most viral infections. To investigate the role of IL-12 and IFN-γ on the development of Coxsackievirus B3 (CB3)-induced myocarditis, we examined the level of inflammation, viral replication, and cytokine production in IL-12Rβ1- and IFN-γ-deficient mice following CB3 infection. We report that IL-12Rβ1 deficiency results in decreased viral replication and inflammation in the heart, while IFN-γ deficiency exacerbates CB3 replication. Importantly, decreased IL-1β and IL-18 levels in IL-12Rβ1-deficient hearts correlated directly with decreased myocardial inflammation. Because IL-1β and IL-18 were associated with myocardial inflammation, we examined the effect of TLR4 deficiency on CB3 infection and myocarditis. We found that TLR4-deficient mice also had significantly reduced levels of myocarditis, viral replication, and IL-1β/IL-18, just as we had observed in IL-12Rβ1-deficient mice. This is the first report that TLR4 influences CB3 replication. These results show that IL-12Rβ1 and TLR4 exacerbate CB3 infection and myocarditis while IFN-γ protects against viral replication. The remarkable similarities between the effects of IL-12Rβ1 and TLR4 suggest that these receptors share common downstream pathways that directly influence IL-1β and IL-18 production, and confirm that IL-1β and IL-18 play a significant role in the pathogenesis of CB3-induced myocarditis. These findings have important implications not only for the pathogenesis of myocarditis, but for other autoimmune diseases triggered by viral infections.

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  • Inhibition of TLR4 and NLRP3 pathways reduces myocarditis in mouse models.

    “Importantly, inhibition of TLR4 and NLRP3 pathways reduces myocarditis in mouse models. 161,168”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [161]

    The section “TLR4 deficiency reduces myocarditis” reports significantly less myocarditis in TLR4-deficient mice 12 days after Coxsackievirus B3 infection. The paper does not report NLRP3 inhibition or its effect on myocarditis (searched: NLRP3, inflammasome, Nalp3). Passage page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • The TLR4, caspase-1, and NLRP3 pathways are upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3-only models and increase IL-1β and IL-18 levels in the heart.

    “Another key pathway upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3only models is the TLR4, caspase-1, and NLRP3 pathways that increase IL-1 β and IL-18 levels in the heart. 124,146,152,156,161-164”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [161]

    The study’s CB3-infected mouse results report that TLR4 deficiency reduced IL-1β and IL-18 in the heart, supporting the TLR4 portion of the claim (TLR4 deficiency results; page not provided). The Discussion mentions an EAM study but says its IL-1β finding came from splenocyte cultures and that IL-18 was not examined. Our copy does not establish upregulation of caspase-1 or NLRP3 in myocarditis patients or across the listed models. (LLM, conf=0.88)

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Authors
Fairweather, D., Yusung, S., Frisancho, S., Barrett, M., Gatewood, S., Steele, R., & Rose, N. R.
Affiliations
  • Johns Hopkins University (US)
  • Department of Pathology, Johns Hopkins Medical Institutions , Baltimore, MD 21205
ORCID
Fairweather, DeLisa
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2003-05-01
Volume
170
Issue
9
Pages
4731-4737
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.170.9.4731
OpenAlex
W1917885467
Cited by
229
References
40
Citations by year
2026: 5 · 2025: 4 · 2024: 9 · 2023: 10 · 2022: 12 · 2021: 8 · 2020: 11 · 2019: 6 · 2018: 10 · 2017: 3 · 2016: 11 · 2015: 7 · 2014: 10 · 2013: 4 · 2012: 17
FWCI
8.56
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL 67290, R01HL067290, HL 70729, R01HL070729)
  • National Institute of Allergy and Infectious Diseases (AI 51835, R21AI051835)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
coxsackievirus B3, viral myocarditis, TLR4, IL-1β, IL-18, interferon-gamma, Th1 response, viral replication, myocarditis, autoimmunity
MeSH terms
Acute Disease, Animals, Heart, Interleukin-1, Male, Membrane Glycoproteins, Mice, Inbred BALB C, Mice, Inbred C3H, Myocarditis, Myocardium, Pancreas, Receptors, Cell Surface, Virus Replication, Down-Regulation, Up-Regulation, Receptors, Interleukin, Mice, Knockout, Interleukin-18, Enterovirus B, Human, Toll-Like Receptors, Toll-Like Receptor 4, Mice, Receptors, Interleukin-12

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