IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication.
Th1-type immune responses, mediated by IL-12-induced IFN-gamma, protect the host from most viral infections. To investigate the role of IL-12 and IFN-gamma on the development of Coxsackievirus B3 (CB3)-induced myocarditis, we examined the level of inflammation, viral replication, and cytokine production in IL-12Rbeta1- and IFN-gamma-deficient mice following CB3 infection. We report that IL-12Rbeta1 deficiency results in decreased viral replication and inflammation in the heart, while IFN-gamma deficiency exacerbates CB3 replication. Importantly, decreased IL-1beta and IL-18 levels in IL-12Rbeta1-deficient hearts correlated directly with decreased myocardial inflammation. Because IL-1beta 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-1beta/IL-18, just as we had observed in IL-12Rbeta1-deficient mice. This is the first report that TLR4 influences CB3 replication. These results show that IL-12Rbeta1 and TLR4 exacerbate CB3 infection and myocarditis while IFN-gamma protects against viral replication. The remarkable similarities between the effects of IL-12Rbeta1 and TLR4 suggest that these receptors share common downstream pathways that directly influence IL-1beta and IL-18 production, and confirm that IL-1beta 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.
Fairweather
DeLisa
D
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Yusung
Susan
S
Frisancho
Sylvia
S
Barrett
Masheka
M
Gatewood
Shannon
S
Steele
Ronelle
R
Rose
Noel R
NR
D000208:Acute Disease; D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D029822:Enterovirus B, Human / Q000254:growth & development / Q000276:immunology*; D006321:Heart / Q000821:virology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000276:immunology / Q000821:virology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053707:Receptors, Interleukin-12; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
D007375:Interleukin-1; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors