血浆 L-胱氨酸/L-谷氨酸失衡增加晚期肝硬化患者循环 CD14+单核细胞中的肿瘤坏死因子-α。

Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.

机构信息

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan.

出版信息

PLoS One. 2011;6(8):e23402. doi: 10.1371/journal.pone.0023402. Epub 2011 Aug 17.

DOI:10.1371/journal.pone.0023402

PMID:21858100

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3157377/

Abstract

BACKGROUND AND AIMS

The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys) and secrete substantial amounts of L-Glutamate (L-Glu) via the transport system Xc- (4F2hc+xCT), and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes.

METHODS

We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM), and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha.

RESULTS

The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19), the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio.

CONCLUSIONS

A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.

摘要

背景与目的

失代偿期肝硬化患者的固有免疫细胞通常无法对病原体产生正常反应。先前的研究报道，抗原呈递细胞通过 Xc-（4F2hc+xCT）转运系统摄取 L-胱氨酸（L-Cys）并大量分泌 L-谷氨酸（L-Glu），这种交换会影响免疫反应。本研究旨在探讨晚期肝硬化患者血浆 L-Cys/L-Glu 失衡对循环单核细胞功能的影响。

方法

我们使用一种与晚期肝硬化患者血浆氨基酸平均浓度一致的无血清培养基（ACM），并在含有 0-300nmol/ml L-Cys 的 ACM 中用 LPS 检测 CD14+单核细胞或 THP-1 的功能。在晚期肝硬化患者中，我们实际测定了单核细胞的 TNF-α和 xCTmRNA，并评估了血浆 L-Cys/L-Glu 比值与 TNF-α之间的相关性。

结果

L-Cys 的加入显著增加了 ACM 下单核细胞 TNF-α的产生。LPS 和 THP-1 作用下的单核细胞表达 xCT，细胞外高浓度 L-Cys 增强了 L-Cys/L-Glu 反向转运，细胞内 GSH/GSSG 比值降低。过量的 L-Glu 抑制了 L-Cys 的转运。在晚期肝硬化患者（n=19）中，根据 Child-Pugh 分级，单核细胞的 TNF-α和 xCTmRNA 增加。高 L-Cys/L-Glu 比值组单核细胞 TNF-αmRNA 明显高于低比值组，血浆 TNF-α与 L-Cys/L-Glu 比值显著相关。