TY - JOUR
T1 - IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-γ and macrophage and neutrophil populations in the heart
AU - Fairweather, De Lisa
AU - Frisancho-Kiss, Sylvia
AU - Yusung, Susy A.
AU - Barrett, Masheka A.
AU - Davis, Sarah E.
AU - Steele, Ronelle A.
AU - Gatewood, Shannon J.L.
AU - Rose, Noel R.
PY - 2005/1/1
Y1 - 2005/1/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.174.1.261
DO - 10.4049/jimmunol.174.1.261
M3 - Article
C2 - 15611248
AN - SCOPUS:10844234013
SN - 0022-1767
VL - 174
SP - 261
EP - 269
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -