【摘要】：研究背景巨噬細(xì)胞是人體免疫系統(tǒng)中一種具有多種特性的細(xì)胞群體,在機(jī)體防御細(xì)菌、病毒和寄生蟲感染方面發(fā)揮著重要作用。隨著研究的深入,巨噬細(xì)胞在腫瘤發(fā)生發(fā)展的作用也越來越被重視。浸潤在腫瘤微環(huán)境中的巨噬細(xì)胞常被稱為腫瘤相關(guān)巨噬細(xì)胞(TAMs)。TAM是外周循環(huán)的單核細(xì)胞在局部CCL2、巨噬細(xì)胞集落刺激因子(M-CSF)和血管內(nèi)皮生長(zhǎng)因子(VEGF)等細(xì)胞因子的刺激下聚集分化形成的。巨噬細(xì)胞主要有兩個(gè)表型即M1和M2型。M1型巨噬細(xì)胞可由LPS或IFN-γ誘導(dǎo)分化產(chǎn)生;IL-4和IL-13可促進(jìn)巨噬細(xì)胞向M2型極化。M1型巨噬細(xì)胞是強(qiáng)有力的效應(yīng)細(xì)胞,能殺死微生物,產(chǎn)生炎性細(xì)胞因子,如腫瘤壞死因子(TNF-α)和IL-12,并在清除細(xì)菌、病毒和真菌感染中起重要作用。相反,M2型巨噬細(xì)胞通過產(chǎn)生IL-10和轉(zhuǎn)化生長(zhǎng)因子(TGF-β)等,抑制炎癥反應(yīng)。M2型巨噬細(xì)胞在組織重塑、寄生蟲感染、血管生成和腫瘤進(jìn)展中也發(fā)揮著重要作用。白細(xì)胞介素-6具有多效性,其可以影響人體多方功能,如血管疾病、脂質(zhì)代謝、胰島素抵抗和神經(jīng)心理行為。IL-6是STAT3信號(hào)通路的一個(gè)強(qiáng)有力的激活因子,活化的P-STAT3信號(hào)蛋白迅速易位到細(xì)胞核中,并結(jié)合到靶基因如細(xì)胞周期蛋白D1、c-myc、和VEGF的啟動(dòng)子的識(shí)別序列,從而增加這些靶基因的轉(zhuǎn)錄和表達(dá)。大量研究發(fā)現(xiàn)IL-6引起的STAT3的活化在腫瘤的進(jìn)展中起著十分重要的作用。在前期研究中,我們發(fā)現(xiàn)在胃癌患者的腫瘤組織中IL-6的表達(dá)高于非腫瘤組織。同時(shí),在癌組織中M2型巨噬細(xì)胞浸潤數(shù)量也增加。為了探索IL-6是否與M2巨噬細(xì)胞的極化有關(guān),我們建立了IL-6誘導(dǎo)巨噬細(xì)胞體外分化的細(xì)胞培養(yǎng)模型,通過檢測(cè)IL-6刺激誘導(dǎo)后的巨噬細(xì)胞的表型特點(diǎn),我們發(fā)現(xiàn)IL-6能誘導(dǎo)正常巨噬細(xì)胞分化為M2樣巨噬細(xì)胞,主要表現(xiàn)為IL-10和TGF-β的表達(dá)升高,IL-12p35的表達(dá)降低。為此,進(jìn)一步對(duì)該誘導(dǎo)分化的機(jī)制進(jìn)行了探討,同時(shí)也對(duì)誘導(dǎo)的M2樣巨噬細(xì)胞的功能做了進(jìn)一步的研究。目的:1.建立IL-6體外誘導(dǎo)巨噬細(xì)胞分化的細(xì)胞模型,探究IL-6對(duì)巨噬細(xì)胞分化的影響及誘導(dǎo)分化的具體信號(hào)機(jī)制。2.探討IL-6誘導(dǎo)而來的M2樣巨噬細(xì)胞對(duì)胃癌腫瘤細(xì)胞的生物學(xué)功能的影響。方法:1、采用陽性磁珠分選法分選健康成人外周血(PBMC)中的CD14+單核細(xì)胞,流式細(xì)胞儀檢測(cè)CD14+單核的純度后,在重組人巨噬細(xì)胞集落刺激因子(M-CSF)的刺激下誘導(dǎo)分化5天,使其分化為巨噬細(xì)胞,再經(jīng)過IL-6的誘導(dǎo)刺激,使巨噬細(xì)胞進(jìn)一步向M2表型分化。提取RNA,通過實(shí)時(shí)熒光定量PCR檢測(cè)M2型巨噬細(xì)胞的分子標(biāo)志(IL-10、TGF-β)。2、IL-6可以激活JAK—STAT3信號(hào)通路,活化的STAT3(即p-stat3)可以進(jìn)入胞核,作用其下游靶基因,參與轉(zhuǎn)錄調(diào)控。本實(shí)驗(yàn)擬采用Westen blot和免疫熒光證實(shí)IL-6通過激活STAT3—p-STAT3這一信號(hào)通路而介導(dǎo)巨噬細(xì)胞的M2型極化。同時(shí),采用小干擾RNA(si RNA)干擾STAT3目的基因,預(yù)先沉默巨噬細(xì)胞內(nèi)STAT3的表達(dá),再采取實(shí)時(shí)熒光定量PCR檢測(cè)IL-10、TGF-β的表達(dá),進(jìn)一步探究STAT3在IL-6誘導(dǎo)巨噬細(xì)胞分化這一過程的調(diào)節(jié)作用。3、采用細(xì)胞侵襲及細(xì)胞增殖實(shí)驗(yàn)(CCK8)對(duì)誘導(dǎo)而來的巨噬細(xì)胞進(jìn)行生物學(xué)功能的研究。采用胃癌細(xì)胞(AGS、SGC-7901)與IL-6誘導(dǎo)的M2樣巨噬細(xì)胞上清液共培養(yǎng),研究誘導(dǎo)的巨噬細(xì)胞對(duì)胃癌細(xì)胞的侵襲能力及增殖能力的影響。結(jié)果:1、經(jīng)過M-CSF誘導(dǎo)的CD14+單核細(xì)胞分化為巨噬細(xì)胞后,在IL-6的刺激下,巨噬細(xì)胞表現(xiàn)出IL-10表達(dá)升高,TGF-β表達(dá)升高,IL-12p35表達(dá)降低,并且,隨著IL-6刺激濃度的提高,巨噬細(xì)胞表達(dá)的IL-10和TGF-β也隨著增高,而IL-12p35的表達(dá)量卻隨IL-6濃度的升高而降低。2、Western blot檢測(cè)STAT3和p-STAT3的表達(dá)量,結(jié)果顯示在加入IL-6刺激的巨噬細(xì)胞組,細(xì)胞總STAT3的表達(dá)量沒有升高,而活化的磷酸化STAT3即p-STAT3表達(dá)量顯著升高;提高IL-6的刺激濃度,細(xì)胞中總STAT3表達(dá)量保持不變,而活化的p-STAT3的表達(dá)量卻隨IL-6刺激濃度的升高而增加。免疫熒光檢測(cè)顯示,加入IL-6刺激的巨噬細(xì)胞組,細(xì)胞內(nèi)見大量的活化形式的p-STAT3熒光信號(hào),且活化的p-STAT3都分布在細(xì)胞核。在si RNA預(yù)沉默STAT3表達(dá)后,定量PCR檢測(cè)IL-10、TGF-β和IL-12p35分子的表達(dá)量,結(jié)果顯示,在siRNA沉默STAT3的細(xì)胞組中,p-STAT3的表達(dá)量的下降,隨著p-STAT3的表達(dá)量的下降,IL-10、TGF-β的表達(dá)水平也較非沉默組巨噬細(xì)胞中IL-10、TGF-β的表達(dá)水平相應(yīng)降低。3、實(shí)驗(yàn)將M2樣巨噬細(xì)胞的培養(yǎng)上清分別與兩種胃癌細(xì)胞系(AGS、SGC-7901)共培養(yǎng)。Transwell細(xì)胞遷移結(jié)果顯示:在兩種細(xì)胞系中,M2樣巨噬細(xì)胞上清液培養(yǎng)組穿過基底膜的腫瘤細(xì)胞數(shù)(AGS 257.6±6.26,SGC 218.6±4.62)都比相應(yīng)的對(duì)照組中穿過基底膜的腫瘤細(xì)胞數(shù)(AGS187.8±6.09,SGC 152±7.91)顯著增多。同樣,CCK8增殖實(shí)驗(yàn)結(jié)果顯示,與M2樣巨噬細(xì)胞上清共培養(yǎng)組的胃癌細(xì)胞在72 h時(shí)間點(diǎn)的OD450值(AGS 1.25±0.12;SGC 1.33±0.14)顯著高于RPMI-1640對(duì)照組的OD450值(AGS0.90±0.02;SGC 0.98±0.07)。最后,在M2巨噬細(xì)胞的上清液中加入IL-10或TGF-β阻斷抗體后,該M2樣巨噬細(xì)胞上清液的促腫瘤細(xì)胞遷移和增殖作用均減弱。結(jié)論:1、IL-6誘導(dǎo)巨噬細(xì)胞高表達(dá)IL-10和TGF-β,而低表達(dá)IL-12p35,其誘導(dǎo)的巨噬細(xì)胞表型呈M2樣表型(IL-10high TGF-βhigh IL-12p35 low),同時(shí),IL-10,TGF-β的表達(dá)量隨IL-6的刺激濃度升高而升高,誘導(dǎo)效應(yīng)存在IL-6濃度依賴性。2、IL-6誘導(dǎo)巨噬細(xì)胞M2樣分化的過程中,JAK/STAT3信號(hào)通路被大量激活,活化的p-STAT3進(jìn)入細(xì)胞核,從而促進(jìn)IL-10和TGF-β的表達(dá),抑制IL-12p35的表達(dá),參與調(diào)控IL-6誘導(dǎo)的巨噬細(xì)胞M2樣極化。3、IL-6誘導(dǎo)的M2樣巨噬細(xì)胞能促進(jìn)胃癌細(xì)胞的增殖和遷移,進(jìn)而促進(jìn)腫瘤的進(jìn)展。
[Abstract]:BACKGROUND Macrophages are a group of cells with various characteristics in the human immune system, which play an important role in the body's defense against bacterial, viral and parasitic infections. It is a tumor-associated macrophage (TAMs). TAM is the aggregation and differentiation of peripheral circulating monocytes stimulated by local CCL2, macrophage colony-stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF). Macrophages have two main phenotypes, M1 and M2. M1 macrophages can be induced by LPS or IFN-gamma. M1 macrophages are powerful effector cells that kill microorganisms, produce inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and IL-12, and play an important role in eliminating bacterial, viral and fungal infections. Instead, M2 macrophages produce IL-10 and transform growth factors. M2 macrophages also play an important role in tissue remodeling, parasitic infection, angiogenesis and tumor progression. Interleukin-6 is multipotent and can affect many functions of the body, such as vascular disease, lipid metabolism, insulin resistance and neuropsychological behavior. IL-6 is a STAT3 signaling pathway. A powerful activator, activated P-STAT3 signaling protein, translocates rapidly into the nucleus and binds to the recognition sequence of target genes such as cyclin D1, c-myc, and the promoter of VEGF, thereby increasing the transcription and expression of these target genes. In previous studies, we found that the expression of IL-6 in cancer tissues was higher than that in non-tumor tissues. At the same time, the infiltration of M2 macrophages was also increased in cancer tissues. By detecting the phenotypic characteristics of macrophages induced by IL-6 stimulation, we found that IL-6 could induce normal macrophages to differentiate into M2-like macrophages. The expression of IL-10 and TGF-beta increased, while the expression of IL-12p35 decreased. Objective: 1. To establish a cell model of macrophage differentiation induced by IL-6 in vitro and explore the effect of IL-6 on macrophage differentiation and the specific signal mechanism of inducing differentiation. CD14+ monocytes from peripheral blood (PBMC) of healthy adults were selected by sorting method. The purity of CD14+ monocytes was detected by flow cytometry. After 5 days of induction and differentiation by recombinant human macrophage colony-stimulating factor (M-CSF), macrophages were induced to differentiate into macrophages. After stimulation by IL-6, macrophages were further differentiated into M2 phenotypes. Real-time fluorescence quantitative PCR was used to detect the molecular marker (IL-10, TGF-beta). IL-6 could activate JAK-STAT3 signaling pathway. Activated STAT3 (p-stat3) could enter the nucleus, act on its downstream target genes and participate in transcriptional regulation. In this study, Western blot and immunofluorescence were used to confirm that IL-6 could activate STAT3-p-STAT3 signaling pathway. At the same time, small interfering RNA (si RNA) was used to interfere with STAT3 target gene. STAT3 expression in macrophages was silenced in advance. The expression of IL-10 and TGF-beta was detected by real-time fluorescence quantitative PCR. The regulatory role of STAT3 in the process of IL-6 induced macrophage differentiation was further explored. Invasion and cell proliferation assay (CCK8) was used to study the biological function of induced macrophages. Gastric cancer cells (AGS, SGC-7901) were co-cultured with IL-6-induced M2-like macrophage supernatant to study the effects of induced macrophages on the invasion and proliferation of gastric cancer cells. After nuclear cells differentiated into macrophages, the expression of IL-10, TGF-beta and IL-12p35 were increased and decreased by IL-6 stimulation. Moreover, with the increase of IL-6 stimulation concentration, the expression of IL-10 and TGF-beta in macrophages increased, while the expression of IL-12p35 decreased with the increase of IL-6 concentration. The expression of STAT3 and p-STAT3 in macrophages stimulated by IL-6 did not increase, but the expression of activated phosphorylated STAT3, p-STAT3, increased significantly in macrophages stimulated by IL-6. Immunofluorescence assay showed that a large number of activated p-STAT3 fluorescent signals were observed in the macrophages stimulated by IL-6, and the activated p-STAT3 was distributed in the nucleus of the cells. In the cell group, the expression of p-STAT 3 decreased. With the decrease of p-STAT 3 expression, the expression levels of IL-10 and TGF-beta were also lower than those in the non-silent group. 3. The supernatants of M2-like macrophages were co-cultured with two gastric cancer cell lines (AGS, SGC-7901). The results showed that the number of tumor cells passing through basement membrane (AGS 257.6 (+ 6.26) and SGC 218.6 (+ 4.62) in M2-like macrophage supernatant culture group was significantly higher than that in the corresponding control group (AGS 187.8 (+ 6.09) and SGC 152 (+ 7.91). Similarly, CCK8 proliferation test showed that the number of tumor cells passing through basement membrane in M2-like macrophage supernatant culture group was significantly higher than that in the corresponding control group. The OD450 value of gastric cancer cells in co-culture group at 72 h (AGS 1.25+0.12; SGC 1.33+0.14) was significantly higher than that of RPMI-1640 control group (AGS 0.90+0.02; SGC 0.98+0.07). Conclusion: 1. IL-6 induces macrophages to overexpress IL-10 and TGF-beta, whereas IL-12p35 is underexpressed. The induced macrophage phenotype is M2-like (IL-10 high TGF-beta high IL-12p35 low). At the same time, the expression of IL-10 and TGF-beta increases with the increase of IL-6 stimulation concentration, and the induction effect is IL-6 concentration-dependent.2, IL-6 induces macrophage fineness. During M2-like differentiation, JAK/STAT3 signaling pathway is activated, and activated p-STAT3 enters the nucleus, which promotes the expression of IL-10 and TGF-beta, inhibits the expression of IL-12p35, and participates in the regulation of IL-6-induced M2-like polarization of macrophages.3, IL-6-induced M2-like macrophages can promote the proliferation and migration of gastric cancer cells, and thus promote tumor. Progress.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R392

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