血小板内皮细胞粘附因子PECAM-1对巨噬细胞上TLR4的功能和信号转导的负调控作用
发布时间：2018-11-23 18:00
【摘要】：作为微生物细胞壁成分及一种病原体相关的分子模式,LPS可以激活先天免疫。LPS通过CD14与巨噬细胞上的Toll-like receptor(TLR)家族中的TLR4结合从而活化巨噬细胞。当TLR4识别LPS后,通过巨噬细胞内的MyD88依赖和非依赖途径,活化NF-κB和三种MAPK(ERK、INK和P38)从而产生一系列的细胞因子和趋化因子如TNF-α、IL-6、IFN-β和IL-1β等,参与免疫反应和炎症等多种生理病理过程。这些信号分子在不同的细胞因子的产生中发挥独立的作用。在这些信号分子缺陷的小鼠中,巨噬细胞对LPS触发的炎症反应是缺失的。而LPS刺激巨噬细胞所产生的炎症细胞因子在先天免疫的介导和获得性免疫的启动中起重要作用。 虽然先天免疫反应对控制病原体的生长发挥着重要作用,但是很明显对这种反应应该存在某种负调节机制,因为过度或者不适当的炎症反应会对机体造成一定伤害,如某些慢性炎症性疾病或者败血性休克,有时甚至是致命的。至今为止已经发现了很多TLR4的负调节因子,ST2就是其中的一个。这个分子同TLR4一样,也是属于Toll/IL-1受体家族蛋白。ST2缺陷小鼠的巨噬细胞在LPS刺激后产生高水平的细胞因子,而且过表达ST2抑制了TLR4介导的NF-κB活化。这些都提示着ST2在LPS反应中发挥着重要的负相调控作用。对ST2与其相互作用的分子共沉淀显示,ST2通过直接抑制MyD88依赖途径而发挥其负调节功能。SOCS1同样也是LPS反应的诱导性负调节子,SOCS1缺陷小鼠在LPS刺激后同样也产生高水平的细胞因子,并且对内毒素易感,但SOCS1和ST2不一样的是它的抑制作用是通过抑制MyD88非依赖途径来实现的。除了这些诱导性负调节子,组成性表达的负调节子在LPS反应的早期即可发挥抑制作用,可以更有效的减少炎症疾病的严重程度和病理程度。
[Abstract]:As a cell wall component and a pathogen-related molecular pattern, LPS activates innate immunity. LPS activates macrophages by binding CD14 to TLR4 in the Toll-like receptor (TLR) family on macrophages. When TLR4 recognizes LPS, it activates NF- 魏 B and three MAPK (ERK,INK and P38) via MyD88 dependent and non-dependent pathways in macrophages to produce a series of cytokines and chemokines such as TNF- 伪, IL-6,IFN- 尾 and IL-1 尾. Participate in various physiological and pathological processes such as immune response and inflammation. These signaling molecules play an independent role in the production of different cytokines. In mice with these signaling molecule deficiency, macrophages were deficient in the inflammatory response triggered by LPS. The inflammatory cytokines produced by macrophages stimulated by LPS play an important role in innate immunity and the initiation of acquired immunity. Although innate immune responses play an important role in controlling the growth of pathogens, it is clear that there should be some negative regulatory mechanism for such reactions, because excessive or inappropriate inflammatory responses can cause certain damage to the body. For example, some chronic inflammatory diseases or septic shock, sometimes even fatal. So far, many negative regulatory factors for TLR4 have been discovered, and ST2 is one of them. Like TLR4, macrophages belonging to the Toll/IL-1 receptor family of ST2 deficient mice produce high levels of cytokines after LPS stimulation, and overexpression of ST2 inhibits TLR4 mediated NF- 魏 B activation. These results suggest that ST2 plays an important role in the negative phase regulation of LPS reaction. The molecular coprecipitation of ST2 and its interaction shows that ST2 exerts its negative regulatory function by directly inhibiting the MyD88 dependent pathway. SOCS1 is also an inductive negative modulator of LPS reaction. SOCS1 deficient mice also produced high levels of cytokines after LPS stimulation and were susceptible to endotoxin. However, unlike ST2, the inhibitory effect of SOCS1 was achieved by inhibiting MyD88 independent pathway. In addition to these inducible negative regulators, constitutive negative regulators can play an inhibitory role in the early stage of LPS response, which can reduce the severity and pathological degree of inflammatory diseases more effectively.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R392
本文编号：2352314
[Abstract]:As a cell wall component and a pathogen-related molecular pattern, LPS activates innate immunity. LPS activates macrophages by binding CD14 to TLR4 in the Toll-like receptor (TLR) family on macrophages. When TLR4 recognizes LPS, it activates NF- 魏 B and three MAPK (ERK,INK and P38) via MyD88 dependent and non-dependent pathways in macrophages to produce a series of cytokines and chemokines such as TNF- 伪, IL-6,IFN- 尾 and IL-1 尾. Participate in various physiological and pathological processes such as immune response and inflammation. These signaling molecules play an independent role in the production of different cytokines. In mice with these signaling molecule deficiency, macrophages were deficient in the inflammatory response triggered by LPS. The inflammatory cytokines produced by macrophages stimulated by LPS play an important role in innate immunity and the initiation of acquired immunity. Although innate immune responses play an important role in controlling the growth of pathogens, it is clear that there should be some negative regulatory mechanism for such reactions, because excessive or inappropriate inflammatory responses can cause certain damage to the body. For example, some chronic inflammatory diseases or septic shock, sometimes even fatal. So far, many negative regulatory factors for TLR4 have been discovered, and ST2 is one of them. Like TLR4, macrophages belonging to the Toll/IL-1 receptor family of ST2 deficient mice produce high levels of cytokines after LPS stimulation, and overexpression of ST2 inhibits TLR4 mediated NF- 魏 B activation. These results suggest that ST2 plays an important role in the negative phase regulation of LPS reaction. The molecular coprecipitation of ST2 and its interaction shows that ST2 exerts its negative regulatory function by directly inhibiting the MyD88 dependent pathway. SOCS1 is also an inductive negative modulator of LPS reaction. SOCS1 deficient mice also produced high levels of cytokines after LPS stimulation and were susceptible to endotoxin. However, unlike ST2, the inhibitory effect of SOCS1 was achieved by inhibiting MyD88 independent pathway. In addition to these inducible negative regulators, constitutive negative regulators can play an inhibitory role in the early stage of LPS response, which can reduce the severity and pathological degree of inflammatory diseases more effectively.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R392
【共引文献】
相关硕士学位论文 前1条
1 周蕾;血小板对RA滑膜炎症和增生的影响及蛭元方干预研究[D];河北大学;2013年
，本文编号：2352314
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