發(fā)布時間：2018-02-03 05:38

  本文關(guān)鍵詞： 神經(jīng)肽 天然免疫 神經(jīng)內(nèi)分泌 CRH UCN 腹腔巨噬細(xì)胞 吞噬作用 F-actin 細(xì)胞骨架重塑 RhoA Rac1 CRH受體 PKA PKC ERK1/2　出處：《第三軍醫(yī)大學(xué)》2009年博士論文　論文類型：學(xué)位論文

【摘要】： 神經(jīng)內(nèi)分泌與免疫功能的相互滲透作用和關(guān)聯(lián)作用,對機(jī)體在不同條件下穩(wěn)態(tài)的維持起有決定性的作用,尤其在創(chuàng)傷與感染的病理生理條件下。神經(jīng)內(nèi)分泌與免疫系統(tǒng)之間相互關(guān)系的研究已經(jīng)成為神經(jīng)免疫內(nèi)分泌學(xué)(Neuroimmun-endocrinology)的一個重要研究熱點。研究發(fā)現(xiàn),下丘腦分泌的神經(jīng)肽可參與外周免疫功能的調(diào)節(jié)機(jī)制,如促腎上腺皮質(zhì)激素釋放激素(Corticotropin-releasing hormone,CRH)及其結(jié)構(gòu)相關(guān)肽urocortin(UCN)經(jīng)過下丘腦-垂體-腎上腺(hypothalamicpituitary-adrenal,HPA)軸發(fā)揮間接地免疫/炎癥調(diào)節(jié)作用,但是外周局部的CRH與UCN可以自分泌或旁分泌的方式直接參與免疫/炎癥的調(diào)節(jié)。嚴(yán)重創(chuàng)傷或感染后機(jī)體免疫功能出現(xiàn)失調(diào),尤其是巨噬細(xì)胞免疫功能改變可導(dǎo)致機(jī)體防御感染的免疫功能紊亂,導(dǎo)致全身性炎癥反應(yīng)綜合征(systemic inflammatory response syndrome,SIRS)、多器官功能衰竭(multiple organ failure,MOF)的易感性增加。巨噬細(xì)胞功能紊亂的機(jī)制很復(fù)雜,可能與微環(huán)境中神經(jīng)內(nèi)分泌激素等有關(guān)。因此,深入探討神經(jīng)肽CRH與UCN對細(xì)胞免疫功能影響及機(jī)制有利于維持機(jī)體內(nèi)環(huán)境的穩(wěn)態(tài),豐富創(chuàng)傷或感染后免疫功能紊亂的免疫平衡調(diào)控策略。CRH與UCN,以及它們的受體在機(jī)體中樞神經(jīng)系統(tǒng)與外周組織與器官分布非常廣泛。CRH與UCN通過與其受體結(jié)合,激活多種G蛋白,從而可能激活下游多種信號通路,發(fā)揮不同的生物學(xué)效應(yīng)。目前關(guān)于CRH在調(diào)節(jié)機(jī)體行為、內(nèi)分泌、自律性以及應(yīng)激免疫等方面的研究已積累了很多資料。越來越多的證據(jù)表明外周CRH與UCN在調(diào)節(jié)免疫炎癥反應(yīng)過程發(fā)揮著重要的作用。吞噬清除作用作為巨噬細(xì)胞重要的天然免疫功能,在機(jī)體嚴(yán)重創(chuàng)傷后感染后往往受到抑制。盡管對巨噬細(xì)胞吞噬機(jī)制已有廣泛的認(rèn)識,但是關(guān)于CRH與UCN,在巨噬細(xì)胞天然吞噬功能中的調(diào)節(jié)作用,目前知之甚少。 本研究通過采用原代培養(yǎng)大鼠腹腔巨噬細(xì)胞,觀察CRH與UCN對巨噬細(xì)胞吞噬熒光微球的吞噬率以及平均熒光強(qiáng)度的影響、及其對巨噬細(xì)胞在吞噬過程中細(xì)胞骨架蛋白重塑與解聚的動態(tài)影響,明確CRH與UCN對巨噬細(xì)胞天然吞噬功能的調(diào)節(jié)作用。接著深入研究CRH與UCN調(diào)控巨噬細(xì)胞骨架蛋白調(diào)節(jié)因子Rho GTPases亞家族蛋白RhoA、Rac1磷酸化的量效關(guān)系和時效關(guān)系,進(jìn)而利用信號分子阻斷策略探討CRH與UCN調(diào)控巨噬細(xì)胞RhoA、Rac1磷酸化的受體途徑和信號轉(zhuǎn)導(dǎo)通路,旨在揭示CRH與UCN調(diào)控巨噬細(xì)胞天然吞噬功能的信號轉(zhuǎn)導(dǎo)機(jī)制。 主要研究內(nèi)容與結(jié)果: 1.通過流式細(xì)胞技術(shù)結(jié)合熒光微球分析了CRH與UCN對巨噬細(xì)胞吞噬功能的調(diào)節(jié)作用。結(jié)果顯示CRH在10-8M水平可顯著增強(qiáng)巨噬細(xì)胞吞噬微球功能。UCN在10-10~10-7濃度均能夠明顯增強(qiáng)巨噬細(xì)胞吞噬功能。 2.正常巨噬細(xì)胞的骨架蛋白均勻分布在胞核與胞漿,在胞膜周邊有輕度的集中。在CRH孵育細(xì)胞1h后,F-actin骨架蛋白向細(xì)胞周邊聚集,膜上出現(xiàn)單層絲狀偽足。UCN刺激后F-actin改變與CRH刺激后相似,吞噬30min時骨架蛋白重塑更明顯, 60min時骨架蛋白表達(dá)量卻下降。這種動態(tài)變化現(xiàn)象與CRH與UCN刺激后巨噬細(xì)胞吞噬改變相一致。 3.CRH以10-8M濃度孵育巨噬細(xì)胞30min后Rac1磷酸化水平明顯增加,60min后RhoA磷酸化水平達(dá)到峰值。UCN在10-10~10-7M濃度孵育細(xì)胞時均可顯著增強(qiáng)RhoA、Rac1磷酸化水平。其中10-8M的UCN孵育細(xì)胞30min后Rac1磷酸化水平增加最明顯,但是RhoA磷酸化水平呈現(xiàn)雙峰狀增加,持續(xù)時間更長。 4.Rho-ROCK的特異性抑制劑W56、選擇性Rac1抑制劑Y27632預(yù)孵育細(xì)胞后,可明顯抑制CRH、UCN對巨噬細(xì)胞的促吞噬作用。Y27632、W56預(yù)孵育后細(xì)胞周邊絲狀偽足量少,周邊聚集不明顯,絲狀、板狀偽足伸展變短,可阻礙F-actin重塑。 5.CRHR1的特異性拮抗劑Antalarmin、CRHR1/R2非特異性拮抗劑Astressin預(yù)處理后,CRH與UCN孵育細(xì)胞對熒光微球的吞噬率明顯下降。在Antalarmin預(yù)孵育后, CRH所致的RhoA磷酸化可被完全抑制,而對由CRH所致的Rac1磷酸化抑制的程度與Astressin預(yù)孵育后的效應(yīng)接近。Antalarmin預(yù)孵育后,對由UCN所致的RhoA磷酸化水平?jīng)]有影響,Rac1磷酸化水平輕微降低,但是在Astressin預(yù)孵育后, UCN孵育所致的RhoA、Rac1磷酸化水平均明顯降低。 6.CRH與UCN孵育靜息狀態(tài)下的大鼠腹腔巨噬細(xì)胞,PKA活性增強(qiáng)非常顯著。PKA活性在CRH作用后15min達(dá)到高峰,而在UCN作用后的10min至60min呈逐漸增加趨勢。PKC活性在CRH與UCN孵育細(xì)胞后增加比較迅速,在15min時到達(dá)高峰。MDL-12330A預(yù)孵育細(xì)胞阻斷PKA后,CRH、UCN對細(xì)胞RhoA磷酸化的影響均顯著下降。在應(yīng)用CR預(yù)孵育細(xì)胞后CRH對RhoA磷酸化增強(qiáng),對Rac1磷酸化水平?jīng)]有明顯影響。但是CR預(yù)孵育細(xì)胞后UCN對RhoA磷酸化影響下降約63%,對Rac1磷酸化影響顯著下降。 7.CRH以10-8M的濃度刺激巨噬細(xì)胞后ERK1/2磷酸化增強(qiáng),5min時最顯著,持續(xù)到15min。UCN孵育巨噬細(xì)胞后ERK1/2磷酸化水平5-30min持續(xù)高水平。在PD98059預(yù)處理后可完全抑制CRH對RhoA的表達(dá)升高作用,預(yù)處理后UCN對RhoA磷酸化升高完全被逆轉(zhuǎn),對Rac1的表達(dá)影響的抑制率達(dá)47.7% 結(jié)論 1.CRH與UCN可明顯增強(qiáng)巨噬細(xì)胞的吞噬功能,UCN的促吞噬作用強(qiáng)于CRH。CRH對吞噬作用的影響具有濃度依賴性,其中在10-8M濃度時對細(xì)胞吞噬效應(yīng)最強(qiáng);UCN在10-10~10-7濃度時均能夠明顯增強(qiáng)巨噬細(xì)胞吞噬功能。 2.CRH與UCN可增強(qiáng)巨噬細(xì)胞骨架蛋白重塑,這與CRH與UCN增強(qiáng)吞噬作用相一致。表現(xiàn)為CRH與UCN孵育后的巨噬細(xì)胞F-actin骨架蛋白向細(xì)胞周邊聚集,膜上出現(xiàn)粘附斑以及偽足增加,尤其UCN刺激后細(xì)胞出現(xiàn)板狀偽足延伸。 3.Rho GTPases在CRH與UCN調(diào)節(jié)巨噬細(xì)胞天然吞噬免疫中起到重要作用。CRH與UCN可通過增強(qiáng)巨噬細(xì)胞Rho GTPases中的RhoA、Rac1磷酸化水平,以促進(jìn)巨噬細(xì)胞骨架蛋白的重塑,從而增強(qiáng)巨噬細(xì)胞的吞噬功能。 4.CRH與UCN通過不同的信號轉(zhuǎn)導(dǎo)機(jī)制,最后由Rho特異性的通路調(diào)節(jié)大鼠腹腔巨噬細(xì)胞骨架蛋白重塑。CRH通過與CRHR1結(jié)合,激活cAMP-PKA/ERK1/2信號通路,促進(jìn)RhoA、Rac1磷酸化;UCN主要與CRHR2結(jié)合,通過PKC/ERK1/2信號通路促進(jìn)RhoA、Rac1磷酸化。 5.CRH與UCN是結(jié)構(gòu)相關(guān)肽,對巨噬細(xì)胞天然吞噬功能的作用相似,但是信號通路不同。這種差異性反映了它們在調(diào)節(jié)巨噬細(xì)胞吞噬過程中對吞噬活性以及細(xì)胞骨架蛋白重塑的影響有所不同。這些肽可能決定了微環(huán)境中由外源性刺激引發(fā)的細(xì)胞吞噬功能改變的程度。
[Abstract]:The mutual infiltration and interaction between neuroendocrine and immune function, maintenance of the body under different conditions of steady state plays a decisive role in pathophysiological conditions in trauma and infection. Study on the relationship between the neuroendocrine and immune system has become neuroimmunoendocrinology (Neuroimmun-endocrinology) is an important research topic. The study found that the hypothalamus neuropeptide can regulate the mechanism involved in the peripheral immune function, such as corticotropin releasing hormone (Corticotropin-releasing hormone, CRH) and urocortin (UCN) peptide structure through the hypothalamic pituitary adrenal axis (hypothalamicpituitary-adrenal, HPA) regulate inflammation / immune indirectly, but peripheral local CRH and UCN can be directly involved in autocrine or paracrine immune / inflammatory regulation of severe trauma. After infection or immune function imbalance, especially the change of macrophage immunity can lead to immune dysfunction of defense against infection, resulting in systemic inflammatory response syndrome (systemic inflammatory response syndrome, SIRS), multiple organ failure (multiple organ failure, MOF). The mechanism of the increased susceptibility of macrophage dysfunction is very complex. May be associated with nerve endocrine hormone in the micro environment. Therefore, to further explore the effect of neuropeptide CRH and UCN on cell immune function and mechanism of steady state to maintain the internal environment, rich in immune dysfunction after trauma or inflammation of the immune balance and control strategy of.CRH and UCN, and their receptors in the central nervous system and peripheral the tissues and organs is widely distributed and UCN.CRH binding with its receptor activation of G protein, which may activate multiple downstream channel Signaling pathway plays different biological effects. At about CRH in the regulation of the body's behavior, endocrine, immune and stress on self-discipline and other aspects have accumulated a lot of information. More and more evidence that peripheral CRH and UCN play an important role in regulating the immune inflammatory reaction process. The phagocytosis of macrophages as a natural immune function importantly, in the body after infection of severe trauma often suppressed. Although there has been broad understanding of the mechanisms of phagocytosis of macrophages, but on the CRH and UCN in macrophages phagocytic function in the natural regulation, is poorly understood.
This study by using primary cultured rat peritoneal macrophages, phagocytosis rate effect observation of CRH and UCN on macrophage phagocytosis of fluorescent microspheres and the average fluorescence intensity, and dynamic effect on macrophage cells in the phagocytic process of cytoskeletal remodeling and depolymerization, clear CRH and UCN natural function of macrophage phagocytosis regulation. Then we study CRH and UCN regulate macrophage cytoskeleton regulator Rho GTPases subfamily protein RhoA, dose and time effect relationship of Rac1 phosphorylation, and then use the signal blocking strategy of CRH and UCN molecules regulate macrophage RhoA receptor pathway and signal transduction pathway of Rac1 phosphorylation, signal transduction mechanism of CRH and UCN to reveal the natural control of macrophage phagocytosis function.
The main research contents and results are as follows:
1., the regulation effect of CRH and UCN on macrophage phagocytosis was analyzed by flow cytometry combined with fluorescent microspheres. Results showed that CRH could significantly enhance macrophage phagocytosis function at 10-8M level, and.UCN could significantly enhance macrophage phagocytosis in 10-10~10-7 concentration.
2. normal cytoskeletal protein macrophages homogeneously distributed in the nucleus and cytoplasm, with slight concentration in the membrane surrounding. Incubated in CRH cells after 1h, F-actin to the cell skeleton protein gathered around, single filopodia after.UCN stimulation of F-actin change and CRH stimulate the emergence of the membrane after similar, phagocytic 30min cytoskeleton remodeling obviously, 60min skeleton protein expression was decreased. The dynamic changes of CRH and UCN after stimulation with macrophage consistent change.
The phosphorylation level of Rac1 3.CRH in 10-8M 30min concentration increased significantly after incubation of macrophages, 60min phosphorylation of RhoA and.UCN reached the peak in the 10-10~10-7M concentration of incubating the cells significantly enhanced RhoA phosphorylation of Rac1. The 10-8M UCN 30min after Rac1 cells were incubated in the phosphorylation level increased obviously, but the phosphorylation of RhoA the level of present Shuangfeng increases lasted longer.
The specific inhibitor of W56 4.Rho-ROCK, a selective inhibitor of Rac1 preincubation of Y27632 cells, can inhibit CRH and UCN on macrophage phagocytosis promoting.Y27632, pretreatment of W56 cells after peripheral filopodia less, gathered around is not obvious, filiform, lamellipodia extension becomes shorter, can hinder F-actin remodeling.
Specific antagonist Antalarmin 5.CRHR1, CRHR1/R2 specific antagonist after pretreatment with Astressin, CRH and UCN cells were incubated on the fluorescent microspheres phagocytosis rate decreased significantly. At Antalarmin after preincubation, phosphorylation of RhoA induced by CRH can be inhibited completely, and close to the effect degree of inhibition by phosphorylation of Rac1 induced by CRH the preincubation with Astressin after pretreatment of.Antalarmin, by the influence on the phosphorylation of RhoA induced by UCN, slightly reduced the phosphorylation level of Rac1, but in Astressin after preincubation, incubated in UCN induced RhoA and Rac1 phosphorylation were significantly reduced.
6.CRH and UCN were incubated with rat peritoneal macrophages in resting state, PKA activity was significantly increased the activity of.PKA in 15min after CRH reached the peak, increasing the activity of.PKC in CRH and UCN increased quickly after the cells were incubated in UCN after 10min to 60min, reached a peak of.MDL-12330A pre incubation cells PKA in 15min, CRH, the effect of UCN on the phosphorylation of RhoA significantly decreased. In CRH on RhoA phosphorylation enhanced by CR preincubation of cells, has no obvious effect on the phosphorylation of Rac1. But CR pre incubation decreased by about 63% the effect of UCN on the phosphorylation of RhoA cells and the effect on Rac1 phosphorylation decreased significantly.
Enhanced ERK1/2 phosphorylation of 7.CRH at a concentration of 10-8M stimulated macrophages, 5min was most significant, until the sustained phosphorylation of ERK1/2 5-30min 15min.UCN were incubated with macrophages after high level. Can completely inhibit the expression of CRH of RhoA increased in PD98059 after pretreatment, pretreatment of UCN increased the phosphorylation of RhoA was completely reversed, inhibited the expression of Rac1 on the rate of 47.7%
conclusion
1.CRH and UCN can significantly enhance the phagocytic function of macrophage, promoting phagocytosis of UCN is stronger than the effect of CRH.CRH on phagocytosis in a dose-dependent manner, which had the strongest effect on phagocytic cells in concentration of 10-8M; UCN can significantly enhance the phagocytic function of macrophages in 10-10~10-7 concentration.
2.CRH and UCN can induce cytoskeletal remodeling in macrophages, and the CRH and UCN enhanced phagocytosis. Consistent performance for CRH and UCN after incubation of macrophages to F-actin cytoskeleton surrounding cells aggregation, membrane appeared focal adhesion and pseudopodia increased, especially after the stimulation of UCN cells showed lamellipodia extension.
3.Rho GTPases plays an important role in regulating the natural phagocytosis of macrophages in CRH and UCN..CRH and UCN can enhance the phosphorylation level of macrophages in Rho GTPases by promoting the remodeling of macrophage skeleton protein, thereby enhancing the phagocytosis of macrophages.
4.CRH and UCN through different signal transduction pathways, and finally by Rho specific regulation of rat peritoneal macrophage protein skeleton remodeling in.CRH combined with CRHR1, cAMP-PKA/ERK1/2 signal pathway to promote RhoA phosphorylation of Rac1; UCN and CRHR2 combining RhoA PKC/, through the promotion of ERK1/2 signaling pathway, phosphorylation of Rac1.
5.CRH and UCN are related to the structure of natural peptide on the immune function of macrophage is similar, but different signaling pathway. This difference reflects in the regulation of macrophage phagocytosis of phagocytic activity and the cytoskeletal remodeling are different. These peptides may determine caused by exogenous stimuli in the microenvironment of phagocytic cells the function of the degree of change.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2009
【分類號】：R392.1

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8 張春虎;李云輝;王素娥;邱娟;胡隨瑜;肖桂林;唐濤;范榮;熊新貴;王楊;黃熙;;柴胡疏肝散對慢性應(yīng)激抑郁模型大鼠行為及血漿CRH、ACTH的影響[A];第六屆全國中西醫(yī)結(jié)合基礎(chǔ)理論研究學(xué)術(shù)研討會暨第二屆湖南省中西醫(yī)結(jié)合學(xué)會肝病專業(yè)學(xué)術(shù)年會論文集[C];2010年

9 胡隨瑜;李云輝;張春虎;王素娥;肖桂林;邱娟;;柴胡疏肝散對慢性應(yīng)激抑郁模型大鼠行為及血漿CRH、ACTH的影響[A];中國中西醫(yī)結(jié)合學(xué)會精神疾病專業(yè)委員會第十屆學(xué)術(shù)會議論文集[C];2010年

10 包愛民;周江寧;;HPA軸與HPG軸的相互作用與抑郁癥[A];中國神經(jīng)科學(xué)學(xué)會第六屆學(xué)術(shù)會議暨學(xué)會成立十周年慶祝大會論文摘要匯編[C];2005年

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3 記者 朱大明;高廣濱會見愛爾蘭CRH公司高管[N];長春日報;2010年

4 吳文坤;欲購中條山水泥國際建材巨頭CRH進(jìn)晉之謀[N];中華建筑報;2010年

5 證券時報記者 李瑞鵬;商務(wù)部放行 亞泰集團(tuán)聯(lián)手CRH成真[N];證券時報;2008年

6 記者 徐光勝;張少良會見愛爾蘭客人[N];哈爾濱日報;2009年

7 本報記者 高文力;高溢價收購 CRH眼光決定價值[N];上海證券報;2008年

8 記者朱大明 董馨 連雅婕;市領(lǐng)導(dǎo)會見愛爾蘭等地客人[N];長春日報;2009年

9 記者楊洪倫 通訊員吳方;亞泰集團(tuán)與CRH公司完成股權(quán)交割[N];長春日報;2009年

10 記者 高超;王福生會見CRH集團(tuán)經(jīng)貿(mào)考察團(tuán)[N];延邊日報;2010年

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2 郭艷琳;下丘腦室旁核CRH神經(jīng)元激活在慢性充血性心力衰竭中的交感興奮作用及機(jī)制研究[D];山西醫(yī)科大學(xué);2011年

3 張悅;內(nèi)質(zhì)網(wǎng)應(yīng)激介導(dǎo)的CRH誘導(dǎo)大鼠海馬神經(jīng)元凋亡[D];河北醫(yī)科大學(xué);2012年

4 羅琦;基于心胃相關(guān)理論組方中藥對IBS模型大鼠腦腸軸CRH及肥大細(xì)胞的干預(yù)作用[D];廣州中醫(yī)藥大學(xué);2012年

5 楊榮;先天性缺損型心臟病的心內(nèi)封堵材料表面內(nèi)皮細(xì)胞生長和介入封堵治療研究[D];南京醫(yī)科大學(xué);2003年

6 游興姬;CRH及內(nèi)源性H_2S對臨產(chǎn)前后子宮肌收縮性的不同調(diào)節(jié)作用[D];第二軍醫(yī)大學(xué);2011年

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8 朱忠寧;Urocortin正性頻率和正性肌力作用以及心臟CRF-R2β mRNA表達(dá)的研究[D];河北醫(yī)科大學(xué);2006年

9 胡凱莉;乳鐵蛋白修飾生物可降解納米粒的腦內(nèi)遞藥研究[D];復(fù)旦大學(xué);2009年

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4 馬文彬;下丘腦CRH預(yù)處理對電針調(diào)整慢性疲勞大鼠疲勞狀態(tài)的影響研究[D];成都中醫(yī)藥大學(xué);2011年

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7 王山;雌激素增強(qiáng)Urocortin舒血管作用的機(jī)制[D];第二軍醫(yī)大學(xué);2011年

8 趙夢杰;大鼠束縛—浸水應(yīng)激對丘腦、延髓、骶髓中CRH信號通路活動的影響[D];山東師范大學(xué);2011年

9 戴龍芳;妊娠期高血壓疾病患者血漿中E、NE和CRH含量與季節(jié)型氣候的關(guān)系及臨床意義[D];南昌大學(xué);2012年

10 劉杰;CRH對妊娠子宮肌炎性因子生成的影響[D];第二軍醫(yī)大學(xué);2012年

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