IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart.
Th1-type immune responses, mediated by IL-12-induced IFN-gamma, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12Rbeta1 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-alpha and IFN-gamma levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF-alpha and IFN-gamma 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-gamma deficiency resulted in significantly increased viral replication and significantly reduced TNF-alpha and IFN-gamma levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN-gamma production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN-gamma 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.
Fairweather
DeLisa
D
Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Frisancho-Kiss
Sylvia
S
Yusung
Susy A
SA
Barrett
Masheka A
MA
Davis
Sarah E
SE
Steele
Ronelle A
RA
Gatewood
Shannon J L
SJ
Rose
Noel R
NR
D000818:Animals; D003384:Coxsackievirus Infections / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency; D029822:Enterovirus B, Human / Q000276:immunology; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency* / Q000276:immunology; D053765:Interleukin-12 Subunit p35; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009205:Myocarditis / Q000276:immunology / Q000821:virology*; D009504:Neutrophils / Q000276:immunology*; D021122:Protein Subunits / Q000172:deficiency* / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D004268:DNA-Binding Proteins; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D021122:Protein Subunits; D047888:Receptors, Tumor Necrosis Factor, Type I; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma