Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages.
Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages.
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DOI：
10.1016/j.cellsig.2011.06.013
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发表时间：
2011-11
影响因子：
4.8
通讯作者：
Lee FY
中科院分区：
文献类型：
--
作者：
Minematsu H;Shin MJ;Celil Aydemir AB;Kim KO;Nizami SA;Chung GJ;Lee FY
活化T细胞核因子（NFAT）是T和B淋巴细胞中紧密控制获得性免疫的促炎细胞因子表达的关键转录因子。然而，关于NFAT在巨噬细胞中的先天免疫中的作用知之甚少。在这项研究中，我们报告说，NFAT是所需的Toll样受体（TLR）启动的先天性免疫反应在骨髓源性巨噬细胞（BCG）。所有TLR配体刺激，包括LPS，TLR 4配体，和Pam 3CSK 4，TLR 1/2配体，诱导TNF的表达，这是抑制VIVIT，NFAT特异性抑制剂肽。来自NFATc 4敲除小鼠的BCL 4表达比野生型更少的TNF。尽管NFAT和TNF之间存在明显的相关性，但基于NFAT-荧光素酶报告基因分析，LPS并不直接激活NFAT，而NF-κB被LPS诱导激活。相反，巨噬细胞表现出组成性NFAT活性，LPS不增加，VIVIT降低。NFATc 1 -4的免疫细胞化学检测显示NFATc 3/c4的核定位，无论LPS刺激。LPS刺激不引起NFATc 1/c2的核转位。VIVIT处理导致NFATc 3/c4的核输出并抑制TLR激活的TNF表达，表明NFATc的核驻留是TLR相关的先天免疫应答所必需的。使用抗RNA聚合酶II（PolII）抗体进行的染色质免疫沉淀（ChIP）试验表明，VIVIT降低了PolII与TNF基因位点的结合，这与VIVIT抑制LPS诱导的TNF mRNA表达一致。这项研究确定了一种新的模式，先天免疫调节所呈现的NFAT，这是一个众所周知的家庭的适应性免疫调节蛋白。
Nuclear factor of activated T cells (NFATs) are crucial transcription factors that tightly control proinflammatory cytokine expression for adaptive immunity in T and B lymphocytes. However, little is known about the role of NFATs for innate immunity in macrophages. In this study, we report that NFAT is required for Toll-like receptor (TLR)-initiated innate immune responses in bone marrow-derived macrophages (BMMs). All TLR ligand stimulation including LPS, a TLR4 ligand, and Pam3CSK4, a TLR1/2 ligand, induced expression of TNF which was inhibited by VIVIT, an NFAT-specific inhibitor peptide. BMMs from NFATc4 knock-out mouse expressed less TNF than wild type. Despite apparent association between NFAT and TNF, LPS did not directly activate NFAT based on NFAT-luciferase reporter assay, whereas NF-κB was inducibly activated by LPS. Instead, macrophage exhibited constitutive NFAT activity which was not increased by LPS and was decreased by VIVIT. Immunocytochemical examination of NFATc1-4 of BMMs exhibited nuclear localization of NFATc3/c4 regardless of LPS stimulation. LPS stimulation did not cause nuclear translocation of NFATc1/c2. Treatment with VIVIT resulted in nuclear export of NFATc3/c4 and inhibited TLR-activated TNF expression, suggesting that nuclear residence of NFATc is required for TLR-related innate immune response. Chromatin immunoprecipitation (ChIP) assay using anti-RNA Polymerase II (PolII) antibody suggested that VIVIT decreased PolII binding to TNF gene locus, consistent with VIVIT inhibition of LPS-induced TNF mRNA expression. This study identifies a novel paradigm of innate immune regulation rendered by NFAT which is a well known family of adaptive immune regulatory proteins.
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影响因子：
64.8
作者：
Arron, Joseph R.;Winslow, Monte M.;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
4.8
作者：
Adachi, S;Amasaki, Y;Iwata, M
通讯作者：
Iwata, M
DOI：
10.1083/jcb.200211104
发表时间：
2003-05-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Biswas G;Anandatheerthavarada HK;Zaidi M;Avadhani NG
通讯作者：
Avadhani NG
影响因子：
64.8
作者：
FLANAGAN, WM;CORTHESY, B;CRABTREE, GR
通讯作者：
CRABTREE, GR
DOI：
10.1073/pnas.250476497
发表时间：
2000-12-05
影响因子：
11.1
作者：
Ozinsky, A;Underhill, DM;Aderem, A
通讯作者：
Aderem, A