Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets.
Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets.
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DOI：
10.1177/1753425910369020
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发表时间：
2011-02
期刊：
影响因子：
3.2
通讯作者：
Peri F
中科院分区：
文献类型：
--
作者：
Piazza M;Damore G;Costa B;Gioannini TL;Weiss JP;Peri F
血红素是大量必需蛋白中的一个假基，在氧的运输、储存和电子穿梭中起着关键作用。大量的游离血红素与病理状态有关。近年来，有研究认为toll样受体4 （TLR4）的激活是检测游离血红素“危险信号”的途径之一。在这里，我们研究了血红素（铁(III)-原卟啉IX）及其代谢氧化衍生物血原血红素（铁(III)-原卟啉I）对TLR4通路调节的生化基础。高浓度hemin（50µM）触发TLR4介导的人HEK293/TLR4细胞系在缺乏共受体CD14和MD-2的情况下产生IL-8，后者是内毒素激活TLR4的必要共受体。Hemin和内毒素共同作用于HEK/TLR4细胞时具有叠加效应，提示Hemin和内毒素通过不同的机制激活TLR4。与血红素相反，血原血红素不能触发TLR4依赖性的HEK/TLR4细胞激活，而是引起内毒素刺激的IL-8产生的剂量依赖性抑制。coprohemin的抑制作用与内毒素对MD-2（·TLR4）的传递减少是平行的，这是内毒素激活TLR4所必需的。因此，尽管它们的化学结构相似，hemin和coprohemin对TLR4通路的作用却截然不同，前者作为TLR4的轻度激动剂，后者作为选择性靶向内毒素- md -2相互作用的拮抗剂。
Heme is a prosthetic group in a large number of essential proteins that have a pivotal role in oxygen transport, storage and electron shuttling. High amounts of free heme are associated with pathological states,. Recently, it has been suggested that activation of Toll-like receptor 4 (TLR4) is one of the ways in which the “danger signal” of free heme is detected. Here we examine the biochemical basis of the modulation of the TLR4 pathway by hemin (iron(III)-protoporphyrin IX) and its metabolic, oxidated derivative coprohemin (iron(III)-coproporphyrin I). High concentrations of hemin (50 µM) triggered TLR4-mediated IL-8 production in human HEK293/TLR4 cell line in the absence of the co-receptors CD14 and MD-2, the latter an essential co-receptor for TLR4 activation by endotoxin. Hemin and endotoxin have additive effects when co-administrated to HEK/TLR4 cells, suggesting that hemin and endotoxin activate TLR4 by different mechanisms. Coprohemin, in contrast to hemin, is unable to trigger TLR4-dependent activation of HEK/TLR4 cells, but instead causes dose-dependent inhibition of endotoxin-stimulated IL-8 production. The inhibitory effect of coprohemin is paralleled by reduced delivery of endotoxin to MD-2(·TLR4) that is necessary for activation of TLR4 by endotoxin. Thus, despite their similar chemical structure, hemin and coprohemin have very different effects on the TLR4 pathway, the former acting as a mild agonist of TLR4, the latter as an antagonist selectively targeting the endotoxin-MD-2 interaction.
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Toll样受体9介导疟疾色素血液唑素的先天免疫激活。
DOI：
10.1084/jem.20041836
发表时间：
2005-01-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Coban C;Ishii KJ;Kawai T;Hemmi H;Sato S;Uematsu S;Yamamoto M;Takeuchi O;Itagaki S;Kumar N;Horii T;Akira S
通讯作者：
Akira S
影响因子：
20.3
作者：
Wagener, FADTG;Eggert, A;Figdor, CG
通讯作者：
Figdor, CG
影响因子：
37.8
作者：
Oyama, J;Blais, C;Bourcier, T
通讯作者：
Bourcier, T
影响因子：
4.4
作者：
Gioannini, Theresa L.;Weiss, Jerrold P.
通讯作者：
Weiss, Jerrold P.
影响因子：
20.3
作者：
Balla, J;Balla, G;Vercellotti, GM
通讯作者：
Vercellotti, GM