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，TLR4在宿主免疫核管上识别出激活先天免疫的宿主免疫，从而对宿主产生有益的影响。但是，LPS的免疫反应激活有时会如此强大，以至于诱导了宿主的有害作用。在本研究中，研究了预防这种过度激活的调节机制。LPS的活性通过各种介体的作用表达。 IL-12是代表性的LPS-介绍者，并且本身会在正确产生过多时产生适当而有害效应时会表现出有益的效果。我们发现了LPS诱导的IL-12产生的调节机制，该机制在IL-12P40基因的启动子区域中激活了复制元件Ga-12。据表明，在激活Ga-12之前，需要通过TLR4过度激活ERK途径。当小鼠腹膜渗出液用高剂量LP（1,000 ng/ml）刺激时，观察到该途径的激活，并且IL-12P40的产生与最佳LP（10 ng/ml）刺激的产生减少。这些结果表明，这种调节机制通常起着控制IL-12的过量产生的作用。从在27℃（最佳生长）温度下培养的耶尔森氏菌获得的LPs活跃为LPS-激动剂，但从37℃培养的细菌获得的LPS（宿主体温）对人类细胞没有活性，并且表现出强拮抗活性。 LPS-37℃的一部分脂质中的酰基数量从LPS-27℃℃℃提高。这种拮抗类型的LPS-37℃可能通过干扰LPS信号传导的抑制机制的二聚化来抑制TLR4下游的所有信号，并且在LPS信号的两个启动步骤中进行了抑制机制的评估，并且用于生产每个LPS的流程步骤可能有助于预防措施，以开发针对有害的LPS LPS动作的预防措施。