Proinflammatory consequences of transgenic Fas ligand expression in the heart
Proinflammatory consequences of transgenic Fas ligand expression in the heart
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DOI：
10.1172/jci8212
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发表时间：
2000-05-01
影响因子：
15.9
通讯作者：
Robbins, J
中科院分区：
文献类型：
--
作者：
Nelson, DP;Setser, E;Robbins, J
Fas配体（FasL）的表达使某些组织具有免疫特权，但其在其他组织中的表达可导致严重的中性粒细胞浸润和组织破坏。横纹肌强制快速表达的后果尤其有争议。为了创建心肌细胞特异性Fast表达的稳定可复制模式，产生了转基因（Tg）小鼠，在正常情况下不表达的心脏中特异性表达小鼠Fast。Tg动物是健康的，与非转基因的幼崽没有区别。Fast在心脏中的表达确实会导致轻微的白细胞浸润，但尽管Fas和Fast在Tg心脏中共同表达，心肌组织没有凋亡和坏死伴随白细胞浸润。而不是组织破坏，快速Tg心脏发展为轻度间质纤维化，功能改变和心脏肥厚，cot响应基因表达的分子变化。诱导的细胞因子tnf - α、IL-1 β、IL-6和tgf - β的表达伴随着这些促炎变化。心肌Fast表达的组织学、功能和分子促炎后果是转基因剂量依赖性的。因此，Fas和Fast在心脏中的共表达导致白细胞浸润和肥大，但没有在其他fasl导向的促炎中观察到的严重组织破坏。这些数据表明，Fast表达水平和其他组织特异性微环境因素可以调节FasL的促炎后果。
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.