發(fā)布時(shí)間：2018-07-28 15:03

【摘要】：第一部分:HMGB1刺激Kupper細(xì)胞后功能變化目的:觀察HMGB1刺激后Kupffer細(xì)胞(KCs)吞噬功能、膜蛋白表達(dá)及分泌功能變化。方法:分離大鼠KCs,鑒定KCs的純度,判斷KCs的活性及吞噬功能。將分離、純化的KCs以每孔3-4×106接種于培養(yǎng)板中,隨機(jī)分為2組:(1)HMGB1刺激組:給予500ng/ml HMGB1刺激;(2)對(duì)照組:給予PBS刺激。分別在處理24小時(shí)后收獲細(xì)胞。吞墨實(shí)驗(yàn)檢測(cè)KCs吞噬功能。流式細(xì)胞術(shù)檢測(cè)KCs膜蛋白表面分子F4/80,CD206表達(dá)情況。Western blot法檢測(cè)Arg-1,VEGF,TGF-β,MMP-9等蛋白表達(dá)水平。ELISA法檢測(cè)細(xì)胞培養(yǎng)上清液中IL-6,IL-8,IL-10分泌情況。Transwell小室法檢測(cè)共培養(yǎng)Walker256侵襲及遷移能力變化。重復(fù)上述檢測(cè)。結(jié)果:(1)所提取KCs純度大于91.0%,活力均在97.8%以上;(2)HMGB1組KCs M2表型表面分子CD206明顯高于對(duì)照組,Arg-1酶活性表達(dá)明顯高于對(duì)照組(P0.05)。HMGB1組細(xì)胞培養(yǎng)上清液IL-6水平明顯低于對(duì)照組;IL-10水平明顯高于對(duì)照組(P0.05)。HMGB1組Arg-1,TGF-β,MMP-9蛋白水平顯著高于對(duì)照組(P0.05);VEGF蛋白水平及IL-8分泌量差異不明顯(P0.05)。(3)HMGB1組共培養(yǎng)Walker256侵襲及遷移能力均顯著高于對(duì)照組(P0.05)。結(jié)論:HMGB1可激活KCs向M2表型極化,表現(xiàn)為吞噬功能下降,膜表達(dá)CD206增加,TGF-β、MMP-9蛋白表達(dá)增加,IL-10分泌升高,IL-6分泌減少,增強(qiáng)共培養(yǎng)大鼠肝癌細(xì)胞株遷移及侵襲能力。第二部分:抑制TREM-1對(duì)HMGB1誘導(dǎo)Kupffer細(xì)胞向M2型極化的影響目的:觀察特異抑制TREM-1后HMGB1刺激KCs細(xì)胞膜蛋白表達(dá)、吞噬功能及分泌功能變化。方法:將獲取的KCs以每孔3-4×106接種于培養(yǎng)板中,并隨機(jī)分為4組:(1)HMGB1組(500ng/ml,HMGB1);(2)LP17+HMGB1組(100μmol/L,LP17+500ng/ml,HMGB1);(3)sh RNA-TREM-1+HMGB1組(sh RNA-TREM-1+HMGB1);(4)sh RNA-NC+HMGB1組(sh RNA-NC+HMGB1)。熒光顯微鏡鑒定轉(zhuǎn)染效果。分別在處理后24小時(shí)收獲細(xì)胞。流式細(xì)胞術(shù)檢測(cè)KCs膜蛋白表面分子F4/80,CD206表達(dá)情況。Western blot法檢測(cè)VEGF,TGF-β,MMP-9等蛋白表達(dá)水平。ELISA法檢測(cè)細(xì)胞培養(yǎng)上清液中IL-6,IL-8,IL-10分泌情況。Transwell小室法檢測(cè)共培養(yǎng)Walker256侵襲及遷移能力變化。重復(fù)上述檢測(cè)。結(jié)果:(1)轉(zhuǎn)染sh RNA-TREM-1 24h后僅有少量綠色熒光蛋白表達(dá),48h后綠色熒光蛋白表達(dá)明顯增加,72h后達(dá)高峰,轉(zhuǎn)染率達(dá)83%。(2)HMGB1組、sh RNA-NC+HMGB1組KCs膜蛋白CD206比例顯著高于LP17+HMGB1組、sh RNA-TREM-1+HMGB1組(P0.05)。HMGB1組及sh RNA-NC+HMGB1組TGF-β、MMP-9蛋白表達(dá)水平顯著高于LP17+HMGB1組、sh RNA-TREM-1+HMGB1組(P0.05);LP17+HMGB1組與sh RNA-TREM-1+HMGB1組間無(wú)顯著性差異(P0.05),HMGB1組與sh RNA-TREM-1+HMGB1組間無(wú)顯著性差異(P0.05)。HMGB1組IL-6水平明顯低于LP17+HMGB1組及sh RNA-TREM1組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05);而與sh RNA-NC組無(wú)顯著性差異(P0.05)。HMGB1組IL-10蛋白水平(528.6±14.3pg/ml)明顯高于LP17+HMGB1組及sh RNA-TREM1組,(P0.05);而與sh RNA-NC組,但差異不明顯(P0.05)。(3)HMGB1組共培養(yǎng)Walker256遷移力和侵襲顯著高于LP17+HMGB1組和sh RNA-TREM1組(P0.05);而與sh RNA-NC組無(wú)顯著性差異(P0.05)。結(jié)論:HMGB1可引起KCs向M2型極化;沉默或特異性拮抗KCs TREM-1可阻斷該作用。提示HMGB1是通過(guò)結(jié)合KCs上TREM-1發(fā)揮胞內(nèi)信號(hào)傳導(dǎo)作用的。第三部分:JAK-STAT信號(hào)通路在HMGB1/TREM-1激活Kupffer細(xì)胞向M2型極化中的作用目的:研究JAK-STAT信號(hào)通路在HMGB1/TREM-1誘導(dǎo)KCs向M2型極化中的作用。方法:選取2014年6月至2015年2月到重慶醫(yī)科大學(xué)附屬第二醫(yī)院就診的HCC行HIFU治療后患者145例。根據(jù)納入及排除標(biāo)準(zhǔn),入組HCC行HIFU治療后患者15例,設(shè)立15例健康對(duì)照人群,測(cè)定外周血HMGB1及s TREM1水平。免疫組化法檢測(cè)3例HCC行HIFU治療后再手術(shù)切除病灶的腫瘤組織及癌旁組織中HMGB1、TREM-1、DAP12、STAT6、PPARg表達(dá)情況。將獲取的大鼠KCs以每孔3-4×106接種于培養(yǎng)板中,隨機(jī)分為以下四組:(1)HMGB1組:(500ng/ml,HMGB1);(2)LP17+HMGB1組:(100μmol/L,LP17+500ng/ml,HMGB1);(3)HMGB1+GW9662組:(25μmol/L,GW9662+HMGB1);(4)對(duì)照組(Control組)。各組于處理24h后收獲細(xì)胞。流式細(xì)胞術(shù)檢測(cè)膜蛋白表面分子F4/80,CD206表達(dá)情況;Western blot檢測(cè)DAP12、STAT6、VEGF、TGF-β、MMP-9蛋白表達(dá)水平變化;ELISA檢測(cè)細(xì)胞上清液中IL-6、IL-8及IL-10的含量變化。重復(fù)上述檢測(cè)。結(jié)果:(1)HCC組外周血HMGB1及s TREM1水平顯著高于健康人群組(P0.05)。(2)與癌旁組織相比較,腫瘤組織內(nèi)HMGB1、TREM1、DAP12、STAT6及PPARγ表達(dá)均明顯增高(P0.05)。(3)體外細(xì)胞實(shí)驗(yàn)HMGB1組細(xì)胞培養(yǎng)上清液IL-10水平顯著高于LP17+HMGB1組、Control組及GW9662+HMGB1組(P0.05);IL-6水平顯著低于LP17+HMGB1組、Control組及GW9662+HMGB1組(P0.05)。流式細(xì)胞檢測(cè)結(jié)果顯示:HMGB1組KCs膜蛋白CD206比例顯著高于LP17+HMGB1組、GW9662+HMGB1組及Control組(P0.05)。HMGB1組、GW9662+HMGB1組DAP12蛋白表達(dá)量均顯著高于Control組、LP17+HMGB1組(P0.05);HMGB1組DAP12蛋白表達(dá)量稍高于GW9662+HMGB1組,但差異不明顯(P0.05);Control組、LP17+HMGB1組DAP12蛋白表達(dá)量,但差異不明顯(P0.05)。HMGB1組、GW9662+HMGB1組STAT6蛋白表達(dá)量顯著均高于Control組、LP17+HMGB1組(P0.05);HMGB1組STAT6蛋白表達(dá)量高于HMGB1組STAT6蛋白表達(dá)量高于GW9662+HMGB1組,但差異不明顯(P0.05);Control組、LP17+HMGB1組STAT6蛋白表達(dá)量,但差異不明顯(P0.05)。HMGB1組MMP-9、TGF-β蛋白表達(dá)量顯著均高于Control組、LP17+HMGB1組及GW9662+HMGB1組(P0.05);Control組、LP17+HMGB1組及GW9662+HMGB1組三組間MMP-9、TGF-β蛋白表達(dá)量,但差異不明顯(P0.05)。結(jié)論:(1)肝癌HIFU治療后外周血存在HMGB1及s TREM1蛋白水平顯著升高;癌組織中HMGB1、TREM1、DAP12、STAT6及PPARγ較癌旁組織表達(dá)明顯增高;(2)刺激KCs 24小時(shí)后,KCS向M2型極化;LP17,GW9662可明顯抑制HMGB1的刺激作用。(3)HMGB1與TREM-1結(jié)合,是通過(guò)JAK-STAT6途徑激活PPARg,引起KCs向M2型極化。
[Abstract]:The first part: HMGB1 stimulation of Kupper cell post function change objective: To observe the phagocytic function, membrane protein expression and secretory function of Kupffer cell (KCs) after HMGB1 stimulation. Methods: isolate rat KCs, identify the purity of KCs, judge the activity and phagocytosis of KCs, and inoculate the purified KCs with 3-4 x per pore in the culture plate and divide them into 2 groups randomly. (1) HMGB1 stimulation group: 500ng/ml HMGB1 stimulation was given; (2) control group was given PBS stimulation. The cells were harvested after 24 hours of treatment. The phagocytosis of KCs was detected by ink swallowing experiment. Flow cytometry was used to detect the F4/80 of the surface molecule of KCs membrane protein, and the.Western blot method of CD206 expression was tested for Arg-1, VEGF, beta, and other protein expression levels were detected. The secretion of IL-6, IL-8, IL-10 in the supernatant of cell culture was detected by.Transwell cell method, and the changes of the invasion and migration of Walker256 were detected. The results were as follows: (1) the purity of the extracted KCs was more than 91% and the activity was above 97.8%; (2) the M2 phenotypic surface subdivision of KCs in HMGB1 group was obviously higher than that of the control group, and the activity expression of Arg-1 enzyme was obviously higher than that of the control group. The level of IL-6 in cell culture supernatant of control group (P0.05).HMGB1 was significantly lower than that of control group, and the level of IL-10 was significantly higher than that of control group (P0.05).HMGB1 group Arg-1, TGF- beta, MMP-9 protein level was significantly higher than that of control group (P0.05), VEGF protein level and IL-8 secretion difference was not obvious. (3) the invasion and migration ability of the group was significantly higher than that of the control group. Higher than the control group (P0.05). Conclusion: HMGB1 can activate the phenotypic polarization of KCs to M2, showing the decrease of phagocytosis, the increase of membrane expression CD206, the increase of TGF- beta, the increase of MMP-9 protein, the increase of IL-10 secretion, and the decrease of IL-6 secretion. The second part: inhibiting TREM-1 to HMGB1 inducible Kupffer cells Polarization effect Objective: To observe the HMGB1 stimulation of KCs cell membrane protein expression, phagocytic function and secretory function after specific inhibition of TREM-1. Methods: the obtained KCs was inoculated in the culture plate with 3-4 x 106 per pore, and randomly divided into 4 groups: (1) HMGB1 group (500ng/ml, HMGB1); (2) LP17+HMGB1 group (100 mu mol/L, LP17+500ng/ml, HMGB1); (3) sh Group (SH RNA-TREM-1+HMGB1); (4) sh RNA-NC+HMGB1 group (SH RNA-NC+HMGB1). The transfection effect was identified by fluorescence microscope. The cells were harvested at 24 hours after treatment. Flow cytometry was used to detect the surface molecule F4/80 of KCs membrane protein. CD206 expression was detected by.Western blot method. The secretion of IL-6, IL-8 and IL-10 in the liquid was detected by.Transwell chamber method. The changes of the invasion and migration of Walker256 were detected. The results were as follows: (1) only a small amount of green fluorescent protein was expressed after transfection of SH RNA-TREM-1 24h, and the expression of green fluorescent protein was obviously increased after 48h, and the peak was reached after 72h, and the transfection rate reached 83%. (2) HMGB1 group. The ratio of KCs membrane protein CD206 was significantly higher than that of group LP17+HMGB1, and sh RNA-TREM-1+HMGB1 group (P0.05).HMGB1 group and sh RNA-NC+HMGB1 group TGF- beta, MMP-9 protein expression level was significantly higher than that of LP17+HMGB1 group. No significant difference (P0.05) in group.HMGB1 was significantly lower than that in group LP17+HMGB1 and sh RNA-TREM1 (P0.05), but there was no significant difference between group sh RNA-NC (P0.05).HMGB1 group (P0.05).HMGB1 group (528.6 +). (P0.05) (3) (3) the migration force and invasion of co culture of group HMGB1 were significantly higher than that in group LP17+HMGB1 and sh RNA-TREM1 group (P0.05), but there was no significant difference from sh RNA-NC group (P0.05). Conclusion: HMGB1 can cause KCs to polarization polarization; silence or specific antagonism can prevent this effect. The third part: the third part: the role of JAK-STAT signaling pathway in HMGB1/TREM-1 activation of Kupffer cells to M2 polarization: the study of the role of JAK-STAT signaling pathway in HMGB1/TREM-1 induced KCs to M2 polarization. Method: HCC line HIFU treatment from June 2014 to February 2015 According to the inclusion and exclusion criteria, according to the inclusion and exclusion criteria, 15 patients were treated with HCC after HIFU treatment, and 15 healthy controls were set up to determine the level of HMGB1 and s TREM1 in the peripheral blood. 3 cases of HCC were examined for HMGB1, TREM-1, DAP12, STAT6, PPARg expression in the tumor tissues and adjacent tissues after HIFU treatment. The rat KCs was inoculated with 3-4 * 106 per pore in the culture plate, randomly divided into four groups: (1) group HMGB1: (500ng/ml, HMGB1); (2) group LP17+HMGB1: (100 mol/L, LP17+500ng/ml, HMGB1); (3) HMGB1+GW9662 group: (25 micron mol/L, GW9662+HMGB1); (4) the control group (Control group). Flow cytometry was used to detect the surface protein of membrane protein. F4/80, CD206 expression, Western blot detection of DAP12, STAT6, VEGF, TGF- beta, and MMP-9 protein expression levels; ELISA detection of IL-6, IL-8, and concentrations in cell supernatants. Repeat the above tests. (1) the level of peripheral blood and the levels of the peripheral blood were significantly higher than those in the healthy group. (2) compared with the paracancerous tissue, the tumor group was compared. The expression of HMGB1, TREM1, DAP12, STAT6 and PPAR increased significantly in the weave (P0.05). (3) the level of IL-10 in the cell culture supernatant was significantly higher than that in the LP17+HMGB1 group, Control and GW9662+HMGB1 group (P0.05) in the HMGB1 group in vitro, and the level of flow cytometry showed that the level of cell culture was significantly lower than that in the group and GW9662+HMGB1 group. The ratio of KCs membrane protein CD206 was significantly higher than that in group LP17+HMGB1, and the expression of DAP12 protein in group GW9662+HMGB1 and Control group (P0.05) was significantly higher than that in Control group and LP17+HMGB1 group (P0.05). In group GW9662+HMGB1, the expression of STAT6 protein in group GW9662+HMGB1 was significantly higher than that in group Control and group LP17+HMGB1 (P0.05), and the expression of STAT6 protein in HMGB1 group was higher than that of STAT6 protein in HMGB1 group, but the difference was not obvious, but the difference was not obvious. 5) MMP-9, TGF- beta protein expression in group.HMGB1 was significantly higher than that in group Control, LP17+HMGB1 and GW9662+HMGB1 group (P0.05); Control, LP17+HMGB1 and GW9662+HMGB1 groups were MMP-9, TGF- beta protein expression, but the difference was not obvious. The expression of HMGB1, TREM1, DAP12, STAT6 and PPAR in the tissue was significantly higher than that in the para cancerous tissues. (2) after 24 hours of KCs stimulation, KCS was polarized to M2 type; LP17, GW9662 could obviously inhibit HMGB1 stimulation. (3) the combination of HMGB1 and HMGB1 is activated by the pathway.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R730.5

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4 魯沛;造血干細(xì)胞對(duì)小鼠Kupffer細(xì)胞池的維持作用[D];首都醫(yī)科大學(xué);2015年

5 徐正婕;Kupffer細(xì)胞在非酒精性脂肪性肝炎發(fā)病中的作用[D];復(fù)旦大學(xué);2003年

6 姚輝華;Kupffer細(xì)胞功能對(duì)大鼠肝移植急性排斥反應(yīng)的影響[D];四川大學(xué);2004年

7 李盈科;小鼠肝臟Kupffer細(xì)胞α_7-ACh受體在膽堿能性抗炎通路中的作用[D];第二軍醫(yī)大學(xué);2009年

8 高小鵬;RvE_1對(duì)肝缺血再灌注損傷中Kupffer細(xì)胞活化調(diào)控作用的研究[D];第四軍醫(yī)大學(xué);2010年

9 謝小軍;Kupffer 細(xì)胞調(diào)控Th17細(xì)胞分化及其在大鼠肝移植急性排斥反應(yīng)中的作用研究[D];浙江大學(xué);2011年

10 魏思東;Kupffer細(xì)胞中GITRL促進(jìn)肝臟炎癥與移植排斥反應(yīng)機(jī)制的實(shí)驗(yàn)研究[D];重慶醫(yī)科大學(xué);2011年

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4 趙玉瑩;Kupffer細(xì)胞的活化在急性酒精性脂肪肝發(fā)病中的作用[D];山東大學(xué);2017年

5 姜楠;肝臟缺血再灌注損傷對(duì)Kupffer細(xì)胞SOC的影響及藥物拮抗[D];同濟(jì)大學(xué);2006年

6 黃海t;非酒精性脂肪性肝病中Kupffer細(xì)胞激活方式的研究[D];浙江大學(xué);2013年

7 黃漢飛;Kupffer細(xì)胞在血紅素氧合酶-1保護(hù)大鼠移植肝缺血再灌注損傷中的作用研究[D];昆明醫(yī)學(xué)院;2009年

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10 朱強(qiáng);SD大鼠肝細(xì)胞、Kupffer細(xì)胞分離與培養(yǎng)/共同培養(yǎng)的實(shí)驗(yàn)研究[D];昆明醫(yī)學(xué)院;2005年

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