Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium
Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium
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DOI：
10.1172/jci6709
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发表时间：
1999-08-01
影响因子：
15.9
通讯作者：
Kelly, RA
中科院分区：
文献类型：
--
作者：
Frantz, S;Kobzik, L;Kelly, RA
先天免疫反应蛋白的表达，包括IL-1β、肿瘤坏死因子和细胞因子诱导的一氧化氮合酶(INOS)亚型，已在人类和实验动物的心脏中得到证明，无论病因如何，尽管导致它们表达的近期事件尚不清楚。注意到果蝇Toll的人类同源物，一种在果蝇体内的近端先天免疫跨膜信号蛋白，现在被称为人类Toll样受体4(HTLR4)，在心脏中的表达似乎相对较高，我们检测了心肌的分离细胞成分以及正常和异常的小鼠、大鼠和人的心肌中TLR4mRNA和蛋白质的丰度。TLR4在心肌细胞和冠脉微血管内皮细胞的表达水平可被内毒素或IL-1β所增强，这种作用可被氧自由基清除剂PDTC抑制。在心肌细胞中，转染有活性的TLR4结构，即CD4/hTLR4，可以激活核因子-kappaB报告结构，但不能激活AP-1或iNOS报告结构。在正常小鼠、大鼠和人心肌中，TLR4在心肌细胞中呈弥漫性表达，并且可能是胞浆表达。然而，在远离缺血损伤部位的重塑小鼠心肌和特发性扩张型心肌病患者的心脏组织中，TLR4在2个或更多相邻心肌细胞的并列区域可见局部强染色，而在对照心肌中未见此染色。TLR4和其他Toll同源物的表达和信号增强可能有助于激活受损心肌的先天免疫。
Expression of innate immune response proteins, including IL-1 beta, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1 beta, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-kappa B reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.