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and Macrophage and Neutrophil Populations in the Heart1
* Department of Pathology and
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD 21205
Th1-type immune responses, mediated by IL-12-induced IFN-
, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12R
1 increases coxsackievirus B3 (CVB3)-induced 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 neutrophil populations were decreased. This decrease corresponded to reduced TNF-
and IFN- levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF- and IFN- 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- deficiency resulted in significantly increased viral replication and significantly reduced TNF- and IFN- levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN- production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN- 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.
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