[摘要]：We recently described a model of inflammatory cardiomyopathy in interferon (IFN)-gamma overexpressing transgenic mice stably circulating IFN-gamma in the serum referred to as SAP IFN-gamma mice. SAP-IFN-gamma transgenic mice show cardiac infiltration by mononuclear leukocytes, culminating in dilated cardiomyopathy characterized by an increase of left ventricular end diastolic diameter and reduction of fractional shortening. We hypothesized that the pathological mechanism underlying SAP-IFN-gamma cardiomyopathy might be mediated by (auto)immune processes or tumor necrosis factor (TNF)-alpha synthesis from IFN-gamma-activated macrophages. To verify these hypotheses, we crossed SAP-IFN-gamma transgenic mice with immunodeficient Rag1(-/-) or TNF-alpha(-/-) knockout mice and analyzed the cardiac phenotype of the resulting double-mutant offspring. Immunodeficient Rag1(-/-) SAP-IFN-gamma mice had a decreased impaired life span and intensive cardiac inflammatory reactions, showing that the cardiotoxic IFN-gamma effect operative in SAP-IFN-gamma mice was not mediated by an adaptive immune mechanism. SAP-IFN-gamma TNF-alpha(-/-) hearts showed virtually no histopathological alterations, a significant reduction of cardiac infiltration by CD11c(+) dendritic cells and F4/80(+) macrophages, almost complete normalization of cardiac troponin T levels in serum and of left ventricular end diastolic diameter and fractional shortening, and a dramatic increase of life span, compared with SAP-IFN-gamma transgenic controls. Thus, myocarditis and cardiomyopathy developing in IFN-gamma-overexpressing transgenic mice is, to a significant degree, mediated by TNF-alpha. TNF-alpha-mediated cardiotoxicity in SAP-IFN-gamma transgenic mice is independent of changes of apoptosis. (Am J Pathol 2012, 180:73-81; DOI: 10.1016/j.ajpath.2011.09.006)
