血小板內皮細胞粘附因子PECAM-1對巨噬細胞上TLR4的功能和信號轉導的負調控作用
發(fā)布時間：2018-11-23 18:00
【摘要】：作為微生物細胞壁成分及一種病原體相關的分子模式,LPS可以激活先天免疫。LPS通過CD14與巨噬細胞上的Toll-like receptor(TLR)家族中的TLR4結合從而活化巨噬細胞。當TLR4識別LPS后,通過巨噬細胞內的MyD88依賴和非依賴途徑,活化NF-κB和三種MAPK(ERK、INK和P38)從而產生一系列的細胞因子和趨化因子如TNF-α、IL-6、IFN-β和IL-1β等,參與免疫反應和炎癥等多種生理病理過程。這些信號分子在不同的細胞因子的產生中發(fā)揮獨立的作用。在這些信號分子缺陷的小鼠中,巨噬細胞對LPS觸發(fā)的炎癥反應是缺失的。而LPS刺激巨噬細胞所產生的炎癥細胞因子在先天免疫的介導和獲得性免疫的啟動中起重要作用。 雖然先天免疫反應對控制病原體的生長發(fā)揮著重要作用,但是很明顯對這種反應應該存在某種負調節(jié)機制,因為過度或者不適當的炎癥反應會對機體造成一定傷害,如某些慢性炎癥性疾病或者敗血性休克,有時甚至是致命的。至今為止已經發(fā)現了很多TLR4的負調節(jié)因子,ST2就是其中的一個。這個分子同TLR4一樣,也是屬于Toll/IL-1受體家族蛋白。ST2缺陷小鼠的巨噬細胞在LPS刺激后產生高水平的細胞因子,而且過表達ST2抑制了TLR4介導的NF-κB活化。這些都提示著ST2在LPS反應中發(fā)揮著重要的負相調控作用。對ST2與其相互作用的分子共沉淀顯示,ST2通過直接抑制MyD88依賴途徑而發(fā)揮其負調節(jié)功能。SOCS1同樣也是LPS反應的誘導性負調節(jié)子,SOCS1缺陷小鼠在LPS刺激后同樣也產生高水平的細胞因子,并且對內毒素易感,但SOCS1和ST2不一樣的是它的抑制作用是通過抑制MyD88非依賴途徑來實現的。除了這些誘導性負調節(jié)子,組成性表達的負調節(jié)子在LPS反應的早期即可發(fā)揮抑制作用,可以更有效的減少炎癥疾病的嚴重程度和病理程度。
[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- 偽, 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.
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2006
【分類號】：R392
本文編號：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- 偽, 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.
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2006
【分類號】：R392
【共引文獻】
相關碩士學位論文 前1條
1 周蕾;血小板對RA滑膜炎癥和增生的影響及蛭元方干預研究[D];河北大學;2013年
，本文編號：2352314
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