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 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-alpha, IL-1beta, IL-6, and TGF-beta 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.
Nelson
D P
DP
Division of Molecular Cardiovascular Biology, and. Division of Cardiology, Department of Pediatrics, The Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Setser
E
E
Hall
D G
DG
Schwartz
S M
SM
Hewitt
T
T
Klevitsky
R
R
Osinska
H
H
Bellgrau
D
D
Duke
R C
RC
Robbins
J
J
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000473:pathology; D048429:Cell Size; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D018628:Gene Dosage; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000032:analysis; D019014:fas Receptor / Q000032:analysis
D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D019014:fas Receptor