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肥大细胞内毒素耐受及其对 IgE 介导信号转导的影响，以及 BCL3 缺乏的作用。

Endotoxin tolerance in mast cells, its consequences for IgE-mediated signalling, and the effects of BCL3 deficiency.

机构信息

Institute of Biochemistry and Molecular Immunology, Medical School, RWTH Aachen University, Aachen, Germany.

Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany.

出版信息

Sci Rep. 2017 Jul 3;7(1):4534. doi: 10.1038/s41598-017-04890-4.

DOI:10.1038/s41598-017-04890-4
PMID:28674400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5495797/
Abstract

Stimulation with lipopolysaccharide (LPS; endotoxin) not only causes rapid production of proinflammatory cytokines, but also induces a state of LPS hypo-responsiveness to a second LPS stimulation (endotoxin tolerance (ET)). Murine bone marrow-derived MCs (BMMCs) and peritoneal MCs (PMCs) developed ET as shown by an abrogated production of Il6/Tnf RNAs and IL-6/TNF-α proteins. In naive BMMCs, LPS stimulation induced a transient decline in the trimethylation of lysine 9 of the core histone H3 (H3K9me3), a suppressive chromatin mark, at the Il6/Tnf promoters, which correlated with p50(NFκB) and p65(NFκB) binding. Both demethylation and NFκB binding were abrogated in tolerant cells. In addition, cytosolic NFκB activation was suppressed in tolerant BMMCs. Intriguingly, antigen stimulation of naive and tolerant MCs induced comparable production of Il6/Tnf and IL-6/TNF-α, although ET also affected antigen-triggered activation of NFκB; pharmacological analysis indicated the importance of Ca-dependent transcription in this respect. In macrophages, the IκB member BCL3 is induced by LPS and known to be involved in ET, which was not corroborated comparing wild-type and Bcl3-deficient BMMCs. Interestingly, Bcl3-deficient PMCs produce markedly increased amounts of IL-6/TNF-α after LPS stimulation. Collectively, ET in MCs is BCL3-independent, however, in PMCs, BCL3 negatively regulates immediate LPS-induced cytokine production and quantitatively affects ET.

摘要

脂多糖（LPS；内毒素）刺激不仅会导致促炎细胞因子的快速产生，还会导致对第二次 LPS 刺激的 LPS 低反应状态（内毒素耐受（ET））。正如 Il6/Tnf RNA 和 IL-6/TNF-α 蛋白的产生被废除所表明的那样，鼠骨髓来源的 MC（BMMC）和腹腔 MC（PMC）产生了 ET。在幼稚的 BMMC 中，LPS 刺激诱导核心组蛋白 H3 的赖氨酸 9 三甲基化（H3K9me3）的瞬时下降，这是一种抑制性染色质标记，与 p50（NFκB）和 p65（NFκB）结合相关。在耐受细胞中，去甲基化和 NFκB 结合均被废除。此外，耐受 BMMC 中的细胞质 NFκB 激活受到抑制。有趣的是，幼稚和耐受 MC 的抗原刺激诱导可比的 Il6/Tnf 和 IL-6/TNF-α产生，尽管 ET 也影响抗原触发的 NFκB 激活；药理学分析表明 Ca 依赖性转录在这方面的重要性。在巨噬细胞中，IκB 成员 BCL3 被 LPS 诱导，并且已知参与 ET，这在比较野生型和 Bcl3 缺陷型 BMMC 时没有得到证实。有趣的是，BCL3 缺陷型 PMC 在 LPS 刺激后产生明显增加的 IL-6/TNF-α量。总之，MC 中的 ET 与 BCL3 无关，但是在 PMC 中，BCL3 负调节即刻 LPS 诱导的细胞因子产生，并定量影响 ET。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/ef033f53aca7/41598_2017_4890_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/6a12c69c5a49/41598_2017_4890_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/d12b3c89362d/41598_2017_4890_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/a161c27807d5/41598_2017_4890_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/1139536e43ac/41598_2017_4890_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/7d9c66ef6c48/41598_2017_4890_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/063b0e399921/41598_2017_4890_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/45ce05804371/41598_2017_4890_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/ef033f53aca7/41598_2017_4890_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/6a12c69c5a49/41598_2017_4890_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/d12b3c89362d/41598_2017_4890_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/a161c27807d5/41598_2017_4890_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/1139536e43ac/41598_2017_4890_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/7d9c66ef6c48/41598_2017_4890_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/063b0e399921/41598_2017_4890_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/45ce05804371/41598_2017_4890_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5062/5495797/ef033f53aca7/41598_2017_4890_Fig8_HTML.jpg

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