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Proinflammatory consequences of transgenic Fas ligand expression in the heart
David P. Nelson, … , Richard C. Duke, Jeffrey Robbins
David P. Nelson, … , Richard C. Duke, Jeffrey Robbins
Published May 1, 2000
Citation Information: J Clin Invest. 2000;105(9):1199-1208. https://doi.org/10.1172/JCI8212.
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Article

Proinflammatory consequences of transgenic Fas ligand expression in the heart

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Abstract

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 FasL expression in striated muscle is particularly controversial. To create a stable reproducible pattern of cardiomyocyte-specific FasL expression, transgenic (Tg) mice were generated that express murine FasL specifically in the heart, where it is not normally expressed. Tg animals are healthy and indistinguishable from nontransgenic littermates. FasL expression in the heart does result in mild leukocyte infiltration, but despite coexpression of Fas and FasL in Tg hearts, neither myocardial tissue apoptosis nor necrosis accompanies the leukocyte infiltration. Instead of tissue destruction, FasL Tg hearts develop mild interstitial fibrosis, functional changes, and cardiac hypertrophy, with corresponding molecular changes in gene expression. Induced expression of the cytokines TNF-α, IL-1β, IL-6, and TGF-β accompanies these proinflammatory changes. The histologic, functional, and molecular proinflammatory consequences of cardiac FasL expression are transgene-dose dependent. Thus, coexpression of Fas and FasL 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 FasL expression level and other tissue-specific microenvironmental factors can modulate the proinflammatory consequences of FasL.

Authors

David P. Nelson, Elizabeth Setser, D. Greg Hall, Steven M. Schwartz, Timothy Hewitt, Raisa Klevitsky, Hanna Osinska, Don Bellgrau, Richard C. Duke, Jeffrey Robbins

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Figure 1

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Murine FasL transgene construct and mRNA transcript analysis. (a) Murine...
Murine FasL transgene construct and mRNA transcript analysis. (a) Murine FasL cDNA was isolated by RT-PCR, sequenced, ligated to the α-MyHC promoter, and used to produce Tg animals (30). (b) Representative RNase protection assay showing that cardiac FasL expression corresponds to transgene copy number. (c) Total RNA was isolated from ventricles of NTg and Tg mice 8–12 weeks old with the transgene copy numbers indicated (n = 6 for each line). FasL and Fas transcripts were determined by multiplex RNase protection. Signal intensities were quantified on a PhosphorImager and standardized by comparison to GAPDH signals. FasL expression is undetectable in NTg hearts, whereas steady-state FasL transcript levels correspond to the transgene copy number of each Tg line. Constitutive expression of Fas mRNA is detectable in NTg and Tg hearts. Fas and FasL transcripts are coexpressed in Tg hearts.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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