A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation.
A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation.
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DOI：
10.1371/journal.pone.0016945
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发表时间：
2011-02-08
期刊：
影响因子：
3.7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Li W;Zhu S;Li J;Huang Y;Zhou R;Fan X;Yang H;Gong X;Eissa NT;Jahnen-Dechent W;Wang P;Tracey KJ;Sama AE;Wang H
一种肝脏衍生的蛋白质——胎球蛋白 - A于1944年首次从小牛胎儿血清中纯化出来，但其在致死性全身性炎症中的潜在作用此前并不为人所知。本研究旨在阐明致死性全身性炎症（LSI）期间肝脏胎球蛋白 - A表达调控的分子机制，并探究胎球蛋白 - A水平的改变是否影响动物存活以及是否影响一种晚期介质——高迁移率族蛋白B1（HMGB1）的全身性蓄积。
在胎球蛋白 - A基因敲除小鼠或野生型小鼠中，通过内毒素血症或盲肠结扎穿孔（CLP）诱导LSI，并比较动物存活率。在有或无胎球蛋白 - A的情况下，用外源性（内毒素）或内源性（干扰素 - γ）刺激物刺激小鼠腹腔巨噬细胞，并评估HMGB1的表达和释放。在内毒素血症或脓毒症发作后，循环中的胎球蛋白 - A水平以时间依赖性方式降低，在26小时之间开始下降，在24 - 48小时左右达到最低点，并在大约72小时后恢复至基线水平。这些动态变化与早期细胞因子干扰素 - γ介导的肝脏胎球蛋白 - A表达抑制（高达50 - 70%）相吻合。胎球蛋白 - A表达的破坏使动物更易患LSI，而补充胎球蛋白 - A（20 - 100毫克/千克）可剂量依赖性地提高动物存活率。这种保护作用与体内全身性HMGB1蓄积的显著减少以及体外干扰素 - γ或脂多糖诱导的HMGB1释放的平行抑制相关。
这些实验数据表明，胎球蛋白 - A对致死性全身性炎症具有保护作用，部分是通过抑制活性HMGB1的释放实现的。
A liver-derived protein, fetuin-A, was first purified from calf fetal serum in 1944, but its potential role in lethal systemic inflammation was previously unknown. This study aims to delineate the molecular mechanisms underlying the regulation of hepatic fetuin-A expression during lethal systemic inflammation (LSI), and investigated whether alterations of fetuin-A levels affect animal survival, and influence systemic accumulation of a late mediator, HMGB1. LSI was induced by endotoxemia or cecal ligation and puncture (CLP) in fetuin-A knock-out or wild-type mice, and animal survival rates were compared. Murine peritoneal macrophages were challenged with exogenous (endotoxin) or endogenous (IFN-γ) stimuli in the absence or presence of fetuin-A, and HMGB1 expression and release was assessed. Circulating fetuin-A levels were decreased in a time-dependent manner, starting between 26 h, reaching a nadir around 24–48 h, and returning towards base-line approximately 72 h post onset of endotoxemia or sepsis. These dynamic changes were mirrored by an early cytokine IFN-γ-mediated inhibition (up to 50–70%) of hepatic fetuin-A expression. Disruption of fetuin-A expression rendered animals more susceptible to LSI, whereas supplementation of fetuin-A (20–100 mg/kg) dose-dependently increased animal survival rates. The protection was associated with a significant reduction in systemic HMGB1 accumulation in vivo, and parallel inhibition of IFN-γ- or LPS-induced HMGB1 release in vitro. These experimental data suggest that fetuin-A is protective against lethal systemic inflammation partly by inhibiting active HMGB1 release.
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