161: IL6 promotes the progression of experimental autoimmune myocarditis to dilated cardiomyopathy.

We have recently reported that IL17A−/− animals are protected from progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM) as determined by echocardiography on day 54. IL17A−/− mice had lower IL6 levels in their heart compared with wildtype (WT) BALB/c animals. This was the only cytokine found to differ significantly between the two groups at both days 14 and 21. To investigate the IL6 requirement for DCM development we used two experimental approaches. First, we over-expressed IL6 in WT and IL17A−/− animals through hydrodynamic gene delivery (HGD) on days −1 or 7 of EAM. Mice over-expressing IL6 showed worsening of heart function compared to controls. Second, we blocked IL6R signaling using an anti-IL6R monoclonal antibody (mAb) in WT mice with EAM. Mice administered the anti-IL6R mAb on days 7 and 14 or 14 and 21 of EAM were protected from heart failure and DCM development by day 54 of disease. At day 14 of EAM there was reduced STAT3 phosphorylation in the heart after anti-IL6R mAb administration and increased STAT3 phosphorylation following HGD of IL6. In the mice receiving anti-IL6R mAb there was a significant decrease in the total number of CD45+ cells infiltrating the heart as measured by flow cytometry with similar composition in controls. Mice over-expressing IL6, both WT and IL17A−/− genotypes, had more CD11b+F4/80+ macrophages as well as CD11b+Ly6G+ neutrophils in the heart. IL6R mAb treated mice had lower circulating complement C3 levels where over-expressing mice had higher C3 levels than controls. Our data suggest that in EAM IL6 promotes the development of DCM during early events around day 7. [ABSTRACT FROM AUTHOR]