Proinflammatory consequences of transgenic Fas ligand expression in the heart

Expression of Fas ligand (FasL) renders certain tissues immune privileged, but its expression in other tissues can result in severe neutrophil infiltration and tissue destruction. The consequences of enforced Fast expression in striated muscle is particularly controversial. To create a stable reproducible pattern of cardiomyocyte-specific Fast expression, transgenic (Tg) mice were generated that express murine Fast specifically in the heart, where it is not normally expressed. Tg animals are healthy and indistinguishable from nontransgenic littermates. Fast expression in the heart does result in mild leukocyte infiltration, but despite coexpression of Fas and Fast in Tg hearts, neither myocardial tissue apoptosis nor necrosis accompanies the leukocyte infiltration. Instead of tissue destruction, Fast Tg hearts develop mild interstitial fibrosis, functional changes, and cardiac hypertrophy, with cot responding molecular changes in gene expression. Induced expression of the cytokines TNF-alpha, IL-1 beta, IL-6, and TGF-beta accompanies these proinflammatory changes. The histologic, functional, and molecular proinflammatory consequences of cardiac Fast expression are transgene-dose dependent. Thus, coexpression of Fas and Fast in the heart results in leukocyte infiltration and hypertrophy, but without the severe tissue destruction observed in other examples of FasL-directed proinflammation. The data suggest that the Fast expression level and other tissue-specific microenvironmental factors can modulate the proinflammatory consequences of FasL.