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 infiltr ation and tissue destruction. The consequences of enforced Fast expression in striated muscle is particularly controversial. To create a stable reprod ucible pattern of cardiomyocyte-specific Fast expression, transgenic (Tg) m ice were generated that express murine Fast specifically in the heart, wher e it is not normally expressed. Tg animals are healthy and indistinguishabl e 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 th e leukocyte infiltration. Instead of tissue destruction, Fast Tg hearts dev elop mild interstitial fibrosis, functional changes, and cardiac hypertroph y, with cot responding molecular changes in gene expression. Induced expres sion of the cytokines TNF-alpha, IL-1 beta, IL-6, and TGF-beta accompanies these proinflammatory changes. The histologic, functional, and molecular pr oinflammatory consequences of cardiac Fast expression are transgene-dose de pendent. Thus, coexpression of Fas and Fast in the heart results in leukocy te infiltration and hypertrophy, but without the severe tissue destruction observed in other examples of FasL-directed proinflammation. The data sugge st that the Fast expression level and other tissue-specific microenvironmen tal factors can modulate the proinflammatory consequences of FasL.