Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone attenuates lipopolysaccharide-induced inflammation by activating the unfolded protein response.
Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone attenuates lipopolysaccharide-induced inflammation by activating the unfolded protein response.
复制标题
DOI：
10.3892/br.2014.225
复制
发表时间：
2014-03
影响因子：
2.3
通讯作者：
Jiang-guo Zhang;Fengyun Gong;Ling Li;Manzhi Zhao;Jianxin Song
中科院分区：
文献类型：
--
作者：
Jiang-guo Zhang;Fengyun Gong;Ling Li;Manzhi Zhao;Jianxin Song
N-3-氧代十二烷酰高丝氨酸内酯(3-oxo-C12-Hsl)是铜绿假单胞菌(Pseudomonas铜绿假单胞菌)产生的一种群体感应信号分子，通过直接干扰核因子-κB(NF-κB)信号转导和诱导细胞凋亡，参与细菌毒力因子的表达和宿主免疫反应的调节。内质网应激引起的未折叠蛋白反应可能通过阻断NF-κB的激活而抑制炎症反应的后期。最近研究表明，3-oxo-C12-HSL可诱导人主动脉内皮细胞(HAECs)的UPR。因此，3-oxo-C12-HSL还可能通过激活UPR来抑制NF-κB的激活，从而抑制炎症反应。然而，可能的潜在机制尚未完全阐明。因此，我们研究了3-oxo-C12-HSL对RAW264.7小鼠巨噬细胞系的细胞存活率、uPR活化、脂多糖诱导的NF-κB活化和炎症反应的影响。6.25μM3-oxo-C12-HSL对RAW264.7细胞的存活率无明显影响。而用6.25μM3-oxo-C12-HSL处理RAW264.7细胞可有效地触发UPR，并增加靶基因CCAAT/增强子结合蛋白β(C/EBPβ)和CCAAT/增强子结合蛋白同源蛋白(CHOP)的表达。C/EBPβ和CHOP的表达与内毒素诱导的NF-κB活化呈负相关。3-oxo-C12-HSL预处理也能抑制内毒素刺激的促炎细胞因子的产生。因此，3-oxo-C12-HSL可能通过抑制UPR介导的NF-κB而减轻内毒素诱导的炎症反应，而不影响细胞活力。这可能是铜绿假单胞菌逃避宿主免疫系统并维持持续感染的另一种机制。
N-3-oxododecanoyl homoserine lactone (3-oxo-C12-HSL), a quorum-sensing signal molecule produced by Pseudomonas aeruginosa (P. aeruginosa), is involved in the expression of bacterial virulence factors and in the modulation of host immune responses by directly disrupting nuclear factor-κB (NF-κB) signaling and inducing cell apoptosis. The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress may suppress inflammatory responses in the later phase by blocking NF-κB activation. It was recently demonstrated that 3-oxo-C12-HSL may induce UPR in human aortic endothelial cells (HAECs). Therefore, 3-oxo-C12-HSL may also inhibit NF-κB activation and suppress inflammatory responses by activating UPR. However, the possible underlying mechanism has not been fully elucidated. Accordingly, we investigated the effects of 3-oxo-C12-HSL on cellular viability, UPR activation, lipopolysaccharide (LPS)-induced NF-κB activation and inflammatory response in the RAW264.7 mouse macrophage cell line. Treatment with 6.25 μM 3-oxo-C12-HSL was not found to affect the viability of RAW264.7 cells. However, pretreating RAW264.7 cells with 6.25 μM 3-oxo-C12-HSL effectively triggered UPR and increased the expression of UPR target genes, such as CCAAT/enhancer-binding protein β (C/EBP β) and CCAAT/enhancer-binding protein-homologous protein (CHOP). The expression of C/EBP β and CHOP was found to be inversely correlated with LPS-induced NF-κB activation. 3-Oxo-C12-HSL pretreatment was also shown to inhibit LPS-stimulated proinflammatory cytokine production. Hence, 3-oxo-C12-HSL may attenuate LPS-induced inflammation via UPR-mediated NF-κB inhibition without affecting cell viability. This may be another mechanism through which P. aeruginosa evades the host immune system and maintains a persistent infection.