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Mechanisms for regulation of excessive host responses to LPS

宿主对 LPS 过度反应的调节机制

基本信息

批准号：
17590397
负责人：
MATSUURA Motohiro
金额：
$ 2.24万
依托单位：
Jichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590397/
关键词：
lipopolysaccharide (LPS)endotoxin regulation of IL-12 expression LPS antagonist

项目摘要

Lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, is recognized by TLR4 on host immune cells to activate innate immunity leading to beneficial effects to the host. However, activation of immune reactions by LPS sometimes proceeds so strong that harmful effects are induced to the host. In the present study, regulatory mechanisms to prevent such over-activations were investigated.Activities of LPS are expressed via actions of various mediators. IL-12 is a representative LPS-mediator and, by itself, it exhibits beneficial effects when produced properly while harmful effects when produced too much. We have found a regulatory mechanism of LPS-induced IL-12 production that activate a repressor element, GA-12, in the promoter region of IL-12p40 gene. It was indicated that hyper-activation of ERK pathway via TLR4 is required prior to activation of GA-12. When mouse peritoneal exudate cells were stimulated with a high dose LPS (1,000 ng/ml), activation of this pathway was observed and production of IL-12p40 decreased from that of optimal LPS (10 ng/ml) stimulation. These results indicated that this regulatory mechanism is functioning generally to control excessive production of IL-12.We have also found a natural LPS-antagonist. LPS obtained from Yersinia cultured at 27℃ (optimal growth temperature) was active as LPS-agonist but LPS obtained from the bacteria cultured at 37℃ (host body temperature) was not active to human cells and showed strong antagonistic activity. Number of acyl groups in lipid A part of the LPS-37℃ was decreased from that of the LPS-27℃. This antagonistic type of the LPS-37℃ was likely to suppress all the signals downstream of TLR4 by interfering with the dimerization of TLR4.Investigations of suppressive mechanisms in both initiation steps of LPS signaling and down stream steps for production of each LPS-mediator may be useful for development of preventive measures against harmful LPS actions.

脂多糖 (LPS) 是革兰氏阴性细菌的细胞壁成分，可被宿主免疫细胞上的 TLR4 识别，从而激活先天免疫，从而对宿主产生有益影响。然而，脂多糖对免疫反应的激活有时会非常强烈，以致对宿主产生有害影响。在本研究中，研究了防止这种过度激活的调节机制。LPS 的活性通过各种介质的作用来表达。 IL-12 是一种代表性的 LPS 介体，其本身在适当产生时表现出有益作用，而在产生过多时表现出有害作用。我们发现了 LPS 诱导 IL-12 产生的调节机制，该机制激活 IL-12p40 基因启动子区域的阻遏元件 GA-12。这表明在激活 GA-12 之前需要通过 TLR4 过度激活 ERK 通路。当用高剂量 LPS (1,000 ng/ml) 刺激小鼠腹膜渗出液细胞时，观察到该途径被激活，并且 IL-12p40 的产生较最佳 LPS (10 ng/ml) 刺激有所减少。这些结果表明，这种调节机制总体上发挥着控制IL-12过量产生的作用。我们还发现了一种天然的LPS拮抗剂。从27℃（最适生长温度）培养的耶尔森氏菌中获得的LPS具有LPS激动剂活性，但从37℃（宿主体温）培养的细菌中获得的LPS对人体细胞没有活性，并表现出强烈的拮抗活性。 LPS-37℃的脂质A部分的酰基数比LPS-27℃有所减少。这种拮抗类型的 LPS-37℃ 很可能通过干扰 TLR4 的二聚化来抑制 TLR4 下游的所有信号。研究 LPS 信号传导的起始步骤和每个 LPS 介体产生的下游步骤中的抑制机制可能有助于制定针对有害 LPS 作用的预防措施。