IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-γ and macrophage and neutrophil populations in the heart

De Lisa Fairweather, Sylvia Frisancho-Kiss, Susy A. Yusung, Masheka A. Barrett, Sarah E. Davis, Ronelle A. Steele, Shannon J.L. Gatewood, Noel R. Rose

Research output: Contribution to journalArticle

Abstract

Th1-type immune responses, mediated by IL-12-induced IFN-γ, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12Rβ1 increases coxsackievirus B3 (CVB3)-indaced myocarditis. In this study, we examined the role of IL-12 on the development of CVB3-induced myocarditis using mice deficient in IL-12p35 that lack IL-12p70. We found that IL-12 deficiency did not prevent myocarditis, but viral replication was significantly increased. Although there were no changes in the total percentage of inflammatory cells in IL-12-deficient hearts compared with wild-type BALB/c controls by FACS analysis, macrophage and neotrophil populations were decreased. This decrease corresponded to reduced TNF-α and IFN-α levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF-α and IFN-γ during acute CVB3 myocarditis. Increased viral replication in IL-12-deficient mice was not mediated by reduced TNFRp55 signaling, because viral replication was unaltered in TNFRp55-deficient mice. However, STAT4 or IFN-γ deficiency resulted in significantly increased viral replication and significantly reduced TNF-α and IFN-γ levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN-γ production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN-γ deficiency also increased chronic CVB3 myocarditis, indicating that therapeutic strategies aimed at reducing Th1-mediated autoimmune diseases may exacerbate common viral infections such as CVB3 and increase chronic inflammatory heart disease.

Original languageEnglish (US)
Pages (from-to)261-269
Number of pages9
JournalJournal of Immunology
Volume174
Issue number1
DOIs
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Fairweather, D. L., Frisancho-Kiss, S., Yusung, S. A., Barrett, M. A., Davis, S. E., Steele, R. A., Gatewood, S. J. L., & Rose, N. R. (2005). IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-γ and macrophage and neutrophil populations in the heart. Journal of Immunology, 174(1), 261-269. https://doi.org/10.4049/jimmunol.174.1.261