Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition.
Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition.
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DOI：
10.1371/journal.pone.0169531
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Knoell DL
中科院分区：
文献类型：
--
作者：
Pyle CJ;Akhter S;Bao S;Dodd CE;Schlesinger LS;Knoell DL
先天免疫系统的两个重要功能是启动炎症和重新分配有利于宿主的微量营养素。锌是一种必需的微量营养素，用于宿主的防御。锌输入子ZIP 8通过LPS刺激单核细胞中的NF-κB通路而被独特地诱导，并且以锌依赖性方式发挥调节炎症的功能。在此，我们确定了锌代谢的影响后，LPS诱导的炎症在人类巨噬细胞。我们观察到ZIP 8在静息巨噬细胞中组成型表达，并且在LPS暴露后显著升高，与其他13种已知的锌输入蛋白相比，这种反应是独特的。在LPS暴露期间，生理范围内的细胞外锌浓度显著降低IL-10 mRNA表达和蛋白释放，但增加TNFα、IL-8和IL-6的mRNA表达。ZIP 8敲低抑制LPS驱动的细胞锌积累，并防止IL-10释放的锌依赖性减少。此外，补充锌可以降低C/EBPβ的核定位和活性，C/EBPβ是一种已知驱动IL-10表达的转录因子。这些研究首次证明，锌以ZIP 8依赖性方式调节LPS介导的人巨噬细胞的免疫活化，减少IL-10。基于这些发现，我们预测，巨噬细胞锌代谢是重要的宿主防御病原体。
Two vital functions of the innate immune system are to initiate inflammation and redistribute micronutrients in favor of the host. Zinc is an essential micronutrient used in host defense. The zinc importer ZIP8 is uniquely induced through stimulation of the NF-κB pathway by LPS in monocytes and functions to regulate inflammation in a zinc-dependent manner. Herein we determined the impact of zinc metabolism following LPS-induced inflammation in human macrophages. We observed that ZIP8 is constitutively expressed in resting macrophages and strikingly elevated following LPS exposure, a response that is unique compared to the 13 other known zinc import proteins. During LPS exposure, extracellular zinc concentrations within the physiological range markedly reduced IL-10 mRNA expression and protein release but increased mRNA expression of TNFα, IL-8, and IL-6. ZIP8 knockdown inhibited LPS-driven cellular accumulation of zinc and prevented zinc-dependent reduction of IL-10 release. Further, zinc supplementation reduced nuclear localization and activity of C/EBPβ, a transcription factor known to drive IL-10 expression. These studies demonstrate for the first time that zinc regulates LPS-mediated immune activation of human macrophages in a ZIP8-dependent manner, reducing IL-10. Based on these findings we predict that macrophage zinc metabolism is important in host defense against pathogens.
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影响因子：
15.3
作者：
D'Andrea, A;Aste-Amezaga, M;Valiante, N M;Ma, X;Kubin, M;Trinchieri, G
通讯作者：
Trinchieri, G
影响因子：
3.7
作者：
Asakawa S;Kishimoto Y;Takano T;Okita K;Takakuwa S;Sato T;Hiratsuka M;Takeuchi O;Hirasawa N
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Hirasawa N
影响因子：
4.4
作者：
Haase, Hajo;Ober-Bloebaum, Julia L.;Rink, Lothar
通讯作者：
Rink, Lothar
影响因子：
3.4
作者：
Hardyman, J. E. J.;Tyson, J.;Ford, D.
通讯作者：
Ford, D.
影响因子：
29
作者：
Jantsch J;Schatz V;Friedrich D;Schröder A;Kopp C;Siegert I;Maronna A;Wendelborn D;Linz P;Binger KJ;Gebhardt M;Heinig M;Neubert P;Fischer F;Teufel S;David JP;Neufert C;Cavallaro A;Rakova N;Küper C;Beck FX;Neuhofer W;Muller DN;Schuler G;Uder M;Bogdan C;Luft FC;Titze J
通讯作者：
Titze J