青蒿琥酯、氧化苦参碱对L929肿瘤细胞免疫抑制作用影响及相关分子机制研究
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摘要
目的:肿瘤是当今严重威害人类生命健康的重大疾病,发病率和死亡率都很高。用药物治疗肿瘤,是肿瘤治疗的重要措施。中药是我国宝贵的医药资源,研究抗瘤中药是研究抗瘤药物的重要领域。研究不同中药制剂的不同抗瘤作用及其相关分子机制,是临床正确选择和使用这些抗瘤中药制剂的重要依据。肿瘤细胞来源于机体正常细胞的突变。机体免疫功能,特别是NK细胞和T细胞功能,在对肿瘤的免疫监视,防止肿瘤的发生发展中具有重要作用。肿瘤细胞分泌免疫抑制物质抑制机体免疫功能,即肿瘤细胞免疫抑制作用,特别是对NK细胞和T细胞功能的抑制,是肿瘤细胞逃避机体免疫监视的重要机制,在促进肿瘤的发生发展中具有重要作用。因此,肿瘤的发生发展,不仅与机体的免疫功能,同时也与肿瘤细胞的免疫抑制作用密切相关。迄今已知可为肿瘤细胞分泌的免疫抑制分子约有20余种,其中报道较多且免疫抑制作用较强的有转化生长因子-β1(TGF-β1)、前列腺素E2(PGE2)、血管内皮生长因子(VEGF)和白细胞介素-10(IL-10)等。由于肿瘤细胞分泌的免疫抑制分子可在肿瘤局部形成深度免疫抑制“黑洞”区,不但身在其中的免疫细胞严重受抑,即使功能正常甚至活化的免疫细胞一旦进入,也将成为功能受抑的“沉默”细胞,结果使免疫细胞无能对其攻击清除,应是肿瘤逃避免疫监视得以发生发展的重要机制。显然,研究抗瘤中药制剂对肿瘤细胞免疫抑制作用影响及其相关分子机制具有重要意义。
本室前期研究发现,L929肿瘤细胞(小鼠成纤维母细胞瘤)培养上清有免疫抑制作用,提示其有免疫抑制分子分泌。青蒿琥酯和氧化苦参碱,是两个有一定抗瘤作用的市售中药制剂,但目前国内外尚无青蒿琥酯和氧化苦参碱对L929肿瘤细胞免疫抑制作用影响及相关分子机制的研究报道。为此,本研究拟在前期工作基础上,研究青蒿琥酯和氧化苦参碱对L929肿瘤细胞免疫抑制作用影响及相关分子机制,为进一步深入揭示这两种中药制剂的抗瘤机理,指导临床正确选择和合理使用,提供实验和理论依据。
方法:分别以含选定浓度青蒿琥酯(ART)或氧化苦参碱(MOX)的培液培养L929肿瘤细胞24h后,洗涤去除中药制剂,细胞再用不含中药制剂的培液连续作两次24h的再培养,分别留取第一次和第二次再培养的细胞和培养上清。其中,经ART作用后第一次再培养的细胞称为A-C1,第二次再培养的细胞称为A-C2,相应的上清分别称为A-S1和A-S2;经MOX作用后再培养的细胞分别称为O-C1和O-C2,上清分别称为O-S1和O-S2。以不含中药制剂培液作同步对照培养的细胞分别称为C-C1和C-C2,上清分别称为C-S1和C-S2。实验研究这些上清对小鼠脾细胞MTT法测定的NK杀伤和ConA诱导转化,以及直接免疫荧光FCM法分析的CD4+、CD8+、IL-2Rα、CD3ε+ζ+和CD3ε-ζ+表达共7项免疫功能指标的影响;定量ELISA法测定这些上清中TGF-β1、PGE2、VEGF和IL-10共4种免疫抑制分子的含量;以β-actin作内参照,RT-PCR法检测细胞中受影响最大的免疫抑制分子或其胞内合成限速酶的mRNA表达,表达强度以相对表达系数RC表示。将这些上清免疫抑制作用变化与相应上清中免疫抑制分子含量变化列表进行专业比对分析,以最大相似性推测两者的关系,然后作单因素相关统计分析,确定中药制剂影响L929肿瘤细胞对不同免疫功能指标免疫抑制作用的相关免疫抑制分子;将受影响最大的免疫抑制分子的上清中含量与其相应细胞内mRNA或其胞内合成限速酶mRNA表达强度进行单因素相关统计分析,明确中药制剂下调该分子分泌是发生在基因转录水平还是基因转录后水平。
结果:
1 L929单纯肿瘤细胞培养上清对小鼠脾细胞免疫功能指标的影响
在以培液代替L929单纯肿瘤细胞培养上清的正常对照(C-nS)组,小鼠脾细胞NK杀伤率、ConA诱导转化的A值和CD4+、CD8+、IL-2Rα、CD3ε+ζ+、CD3ε-ζ+表达细胞百分率分别为65.39±0.87%、0.925±0.026、48.24±2.10%、19.23±0.60%、26.50±0.85%、21.67±1.29%和16.33%±0.18%。与C-nS组相比,在以不含中药制剂培液作同步对照培养的L929单纯肿瘤细胞培养上清(C-S1、C-S2)组,均可使所检测的这7项免疫功能指标明显受抑:C-S1组分别为60.97±3.86%(P<0.01)、0.440±0.038(P<0.01)、22.72±2.61%(P<0.01)、11.42±1.25%(P<0.01)、10.39±0.49%(P<0.001)、7.89±0.78%(P<0.001)和10.93%±0.16%(P<0.001),抑制率分别为8.34±4.55%、47.88%±1.89%、53.00±3.37%、40.71±4.65%、59.91%±0.77%、63.33±5.77%和33.05%±1.52% ; C-S2组分别为59.59±3.13%(P<0.01)、0.441±0.047(P<0.001)、21.89±2.18%(P<0.01)、12.15±0.65%(P<0.01)、9.76±0. 94%(P<0.001)、7.45±0.54%(P<0.001)和10.75%±0.59%(P<0.001);抑制率分别为9.79±3.95%、48.00%±2.16%、54.69±2.55%、36.85±1.41%、61.49±0.85%、65.63±0.87%和33.32%±0.25%;而C-S1组与C-S2组无统计学差异(均P>0.05)。
2青蒿琥酯或氧化苦参碱作用后L929再培养上清对小鼠脾细胞免疫功能指标的影响
经青蒿琥酯作用后的L929肿瘤细胞:⑴其第一次再培养上清(A-S1)与相应对照上清(C-S1)相比,除对CD8+表达的抑制作用无明显改变(P>0.05)外,对其余6项免疫功能指标的抑制作用均明显降低(分别为P<0.001,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01);⑵其第二次再培养上清(A-S2)与A-S1相比:①对CD8+表达的抑制作用明显上升(P<0.05);②对CD3ε+ζ+表达的抑制作用明显回升(P<0.01),但未至相应对照C-S2水平(P<0.01);③对NK杀伤、ConA诱导转化和CD4+、IL-2Rα和CD3ε-ζ+表达的抑制均无显著变化(均P>0.05)。经氧化苦参碱作用后的L929肿瘤细胞:①其第一次再培养上清(O-S1)与相应对照上清(C-S1)相比,除对CD8+表达的免疫抑制作用无明显变化(P>0.05)外,对其余6项免疫功能指标的免疫抑制作用均明显降低(分别为P<0.05,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01);②其第二次再培养上清(O-S2)与O-S1相比,除对CD3ε+ζ+表达的抑制作用明显回升外(P<0.05;但未至相应对照上清C-S2水平,P<0.01),对其余6项免疫功能指标(NK杀伤、ConA诱导转化和CD4+、CD8+、IL-2Rα和CD3ε-ζ+表达)的抑制作用均无显著变化(均P>0.05)。
3青蒿琥酯或氧化苦参碱对L929肿瘤细胞4种免疫抑制分子分泌的影响
未经中药制剂作用的L929肿瘤细胞可稳定分泌所测的4种免疫抑制分子(C-S1与C-S2相比,P>0.05),以TGF-β1及PGE2含量最高,分别为(198.15±3.23)pg/ml和(133.76±5.16)pg/ml,VEGF和IL-10含量较低,分别为(33.38±0.59)pg/ml和(27.31±0.37)pg/ml。
经青蒿琥酯作用后的L929肿瘤细胞:①其第一次再培养上清(A-S1)与相应对照上清(C-S1)相比:4种免疫抑制分子的浓度均明显降低,分别为(99.05±8.02)pg/ml(P<0.001,降低50.01%)、(66.57±4.71)pg/ml(P<0.001,降低50.23%)、(21.03±0.87)pg/ml(P<0.01,降低36.99%)和(22.89±0.57)pg/ml(P<0.01,降低16.18%);②其第二次再培养上清(A-S2)与A-S1相比,除IL-10含量明显上升(P<0.05)外,其余3种分子含量无显著变化(均P>0.05)。
经氧化苦参碱作用后的L929肿瘤细胞:①其第一次再培养上清(O-S1)与对照上清(C-S1)相比:4种免疫抑制分子的含量均明显降低(均P<0.01),分别为TGF-β1(91.35±9.62)pg/m(l降低53.89%),PGE2,(69.43±2.32)pg/ml(降低48.23%),VEGF(21.36±0.75)pg/ml (降低36.01%)和IL-10(22.84±0.33)pg/ml(降低16.37%)。②其第二次再培养上清(O-S2)与O-S1相比,4种免疫抑制分子含量均无显著变化(均P>0.05)。
4青蒿琥酯和氧化苦参碱影响L929肿瘤细胞免疫抑制作用的相关分子分析
专业和统计分析表明:①青蒿琥酯和氧化苦参碱下调L929肿瘤细胞对小鼠脾细胞ConA诱导转化及CD4+、IL-2Rα和CD3ε-ζ+表达的免疫抑制作用的相关分子是TGF-β1和PGE2 ;②青蒿琥酯下调L929肿瘤细胞对小鼠脾细胞NK杀伤的免疫抑制作用的相关分子是TGF-β1和PGE2;③氧化苦参碱下调L929肿瘤细胞对小鼠脾细胞NK杀伤的免疫抑制作用的相关分子是TGF-β1。
5青蒿琥酯和氧化苦参碱对L929肿瘤细胞TGF-β1 mRNA和COX-2mRNA表达的影响
在所测的L929肿瘤细胞分泌的4种免疫抑制分子中,受青蒿琥酯和氧化苦参碱影响最大的是TGF-β1和PGE2,而COX-2是PGE2的胞内合成限速酶,故测定TGF-β1 mRNA和COX-2 mRNA表达,可以揭示这两种中药制剂下调这两种免疫抑制分子分泌是发生在基因转录水平还是基因转录后水平。结果显示,未受中药制剂作用的L929肿瘤细胞可稳定高表达TGF-β1 mRNA和COX-2 mRNA(C-C1与C-C2相比,均P>0.05);中药制剂作用后再培养的L929肿瘤细胞(A-C1和A-C2、O-C1和O-C2)的TGF-β1 mRNA和COX-2 mRNA表达水平均显著降低(分别为:TGF-β1mRNA,P<0.001;COX-2 mRNA,P<0.005),其mRNA表达水平与上清中相应免疫抑制分子TGF-β1和PGE2含量之间呈显著正相关关系(分别为ART:r =1.000, P=0.000; r =0.992, P=0.008; MOX:r =0.997, P=0.003; r =0.995, P=0.005),表明两种中药制剂下调L929肿瘤细胞TGF-β1和PGE2的分泌是发生在基因转录水平。
结论:
1不经ART或MOX作用的L929肿瘤细胞,其培养上清可显著抑制所测小鼠脾细胞7项免疫功能指标(ConA诱导转化、NK杀伤及CD4+、CD8+、IL-2Rα、CD3ε+ζ+和CD3ε-ζ+表达);经ART或MOX作用后再培养的L929肿瘤细胞,其培养上清对这7项免疫功能指标的抑制作用显著降低。
2不经ART或MOX作用的L929肿瘤细胞能稳定分泌所测4种免疫抑制分子(TGF-β1、PGE2、VEGF和IL-10);ART或MOX均能显著下调L929肿瘤细胞这4种免疫抑制分子分泌。
3 ART下调L929肿瘤细胞对小鼠脾细胞ConA诱导转化、NK杀伤和IL-2Rα、CD4+及CD3ε-ζ+表达的免疫抑制作用的相关分子是TGF-β1和PGE2。
4 MOX下调L929肿瘤细胞对小鼠脾细胞ConA诱导转化和IL-2Rα、CD4+及CD3ε-ζ+表达的免疫抑制作用的相关分子是TGF-β1和PGE2;下调L929肿瘤细胞对小鼠脾细胞NK杀伤的免疫抑制作用的相关分子是TGF-β1。
5 ART和MOX下调L929肿瘤细胞TGF-β1和PGE2分泌与降低L929肿瘤细胞TGF-β1 mRNA和COX-2 mRNA表达相关。
Objective: Tumor is a kind of severe disease threatening the health and lives of human at present. The morbidity and mortality of patients with tumor are higher. Administrating drugs is an important measure in the process of treating tumors. The traditional Chinese drug (TCD) is a precious medicine resource in China. Investigating anti-tumor TCD is an important territory of investigating anti-tumor drugs. Studying the different anti-tumor effect and the related molecular mechanism of different traditional Chinese drug preparations (TCDP) is the important evidence of correctly selecting and using these TCDP clinically. Tumor cell is derived from mutation of normal cell in organism. The immune function of organism, especially the functions of natural killer cell (NK cell) and T cell, play an important role in immunologic surveillance against tumor and preventing the generation and development of tumor. That the tumor cells secrete immunosuppressive substances to inhibit immunofuctions, i.e the tumor-induced immunosuppression, especially to inhibit the immuofunctions of NK cells and T cells, was the important mechanism of making tumor escaping organism immunosurveillance and had important effect on promoting the generation and development of tumor. Thus, the generation and development of tumor is related not only to the immune function of organism, but also to immunosuppressive action induced by tumor cells closely. Up to now, it has been known that there are about twenty kinds of immunosuppressive molecules which could be secreted by tumor cells. Among these, those reported more frequently and having more intensive immunosuppression are transforming growth factorβ1 (TGF-β1), prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10). Tumor cells secrete these immunosuppressive molecules to form an extensive immunosuppressive“block hole”region in location of tumor, not only making that the immunocytes there are inhibited severely, but also that once the normal even activated immunocytes enter into there they would become function-inhibited“the silent cell”, resulting in that the immunocytes could not attack and eliminate the tumor cells, which should be an important mechanism that the tumor could escape immunosurveillance to generate and to develop. Obviously, it is of vital significance to study the effect of anti-tumor TCDP on the tumor-induced immunosuppression and the related molecular mechanism.
Previous studies in our laboratory showed that supernatant from cultured L929 tumor cells had immunosuppression, suggesting there was secretion of immunosuppressive molecules from L929 tumor cells. Artesunate and Oxymatrine are the two kinds of TCDP with some anti-tumor effect. But, so far, there has been no report about the effect of Artesunate and Oxymatrine on the immunosuppression induced by L929 tumor cells and the related molecular mechanism. Therefore, on the basis of previous studies, we study the effect of Artesunate and Oxymatrine on immunosuppression induced by L929 tumor cells and the related molecular mechanism in order to further find out their antitumor mechanism, to guide effectively selecting and rationally using them in clinical and provide the evidences of experiment and theory.
Methods: After cultured in complete medium(CM)containing the selected concentration of ART or MOX for 24h and washing off ART or MOX, the L929 tumor cells were re-cultured in CM without ART or MOX for sequential two times of 24h re-culture. The cells and supernatants from the two times of re-cutured L929 tumor cells were harvested respectively. Of them, for the L929 tumor cells treated with ART the cells and supernatant of the first re-culture called A-C1 and A-S1, and the cells and supernatant from the second re-culture called A-C2 and A-S2 respectively; for the L929 tumor cells treated with MOX the cells and supernatant from the first re-culture called O-C1 and O-S1, and the cells and supernatant from the second re-culture called O-C2 and O-S2 respectively. The cells and supernatants harvested from the synchronistically cultured L929 tumor cells in CM without ART or MOX as corresponding control called C-C1, C-S1, C-C2 and C-S2 respectively. Then the effect of different supernatants on seven immunofunctions of murine splenocytes, including NK killing and ConA-induced transformation detected by MTT, and expression levels of CD4+, CD8+, IL-2Rα, CD3ε+ζ+ and CD3ε-ζ+ detected by FCM of direct immunofluorescence were determined. The concentrations of four immunosuppressive molecules, including TGF-β1, PGE2, VEGF and IL-10 in different supernatants were measured by quantitative ELISA. The mRNA expression of the immunosuppressive molecule or its cell-intrinic synthesis rate-limiting enzyme of the immunosuppressive molecule that among the detected four kinds of immunosuppressive molecules secreted by L929 tumor cells its secretion was affected more highly by ART or MOX was detected by RT-PCR usingβ-actin as intrinsic reference. The mRNA expression level was shown by the relative coefficient (RC). The correlations between the congcentrations of immunosuppressive molecules in supernatants and the immunosuppressions of corresponding supernatants were analysed based on professional and statistical analysis to determine the relative molecules that ART and MOX down-regulated the immunosuppression induced by L929 tumor cells. For the immunosuppressive molecule that the inhibitory effect of ART or MOX on its secretion from L929 tumor cells was more higher, using the single-analysis of correlativity the relative correlation between its supernatant' concentration and its mRNA expression or its synthysis rate-limiting enzyme mRNA expression was determined to estimate that the ART or MOX down-regulated the molecule' secretion happened at either gene transcription or post-transcription.
Results:
1 The effect of supernatants from cultured L929 tumor cells on the immunofunctions of murine splenocytes
In the normal control group replacing supernatant from cultured L929 tumor cells with CM, i.e C-nS group, the detected values of the seven kinds of murine splenocytes' immunofunctions were 65.39±0.87% (NK killing rate), 0.925±0.026 ( A value of ConA-induced transformation),48.24±2.10%(CD4+cells),19.23±0.60% (CD8+ cells),26.50±0.85%(IL-2Rα+cells),21.67±1.29% (CD3ε+ζ+ cells) and 16.33%±0.18% (CD3ε-ζ+ cells). Compared with the C-nS group, the supernatants(C-S1 and C-S2) from synchronistically cultured L929 tumor cells treated without ART or MOX as corresponding control inhibited all of the seven immunofunctions apparently:①in C-S1 group the detected values of the seven kinds of murine splenocytes' immunofunctions respectively were (60.97±3.86)% (NK killing rate ,P<0.01), 0.440±0.038 (A value of ConA-induced transformation, P<0.01), (22.72±2.61)% (CD4+cells, P<0.01), (11.42±1.25)% (CD8+ cells,P<0.01), (10.39±0.49)% (IL-2Rα+cells,P<0.001), (7.89±0.78)% (CD3ε+ζ+cells,P<0.001) and (10.93%±0.16)% (CD3ε-ζ+ cells,P<0.001),and the corresponding inhibitory rate respectively were (8.34±4.55)%, (47.88%±1.89)%, (53.00±3.37)%, (40.71±4.65)%, (59.91%±0.77)%, (63.33±5.77)% and (33.05%±1.52)%;②in C-S2 group the detected values of the seven kinds of murine splenocytes' immunofunctions respectively were (59.59±3.13)% (P<0.01), 0.441±0.047 (P<0.001), (21.89±2.18)%(P<0.01),(12.15±0.65)%(P<0.01),(9.76±0. 94)%(P<0.001), (7.45±0.54)%(P<0.001) and( 10.75%±0.59 ) % ( P<0.001), and the corresponding inhibitory rate respectively were (9.79±3.95)%,(48.00%±2.16)%,(54.69±2.55)%,(36.85±1.41)%,(61.49±0.85)%,(65.63±0.87)%, (33.32%±0.25)%; while the C-S1 group compared with C-S2 groups these values had no changes (P>0.05).
2 The effect of supernatant from L929 treated with ART or MOX on the immunofunctions of murine splenocytes
For L929 tumor cells after treated with ART:⑴The first re-culture' supernatant (A-S1) compared with C-S1, the inhibitory effect of A-S1 on the others six immunofunctions except for CD8+ (P>0.05) decreased greatly (P<0.001,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01, respectively);⑵The second re-culture' supernatant (A-S2) compared with A-S1:①The inhibition of CD8+ expression increased greatly(P<0.05);②The inhibitory effect on CD3ε+ζ+ expression increased significantly(P<0.01),but had not reached the level of C-S2 (P<0.01);③The inhibitory effect on the NK killing rate , A of ConA-induced transformation and expression of CD4+,IL-2Rαas well as CD3ε-ζ+ had no changes (All P>0.05).
For L929 tumor cells after treated with MOX:①The first re-culture' supernatant (O-S1) compared with C-S1, the inhibitory effect on the others six immunofunctions except for CD8+ (P>0.05) decreased greatly (P<0.05,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01, respectively);②The inhibitory effect on CD3ε+ζ+expression increased markedly(P<0.05),but had not reached the level of C-S2 (P<0.01);③The inhibitory effect on the NK killing rate , A of ConA-induced transformation and the expression of CD4+ ,CD8+,IL-2Rαas well as CD3ε-ζ+ had no changes (All P>0.05).
3 The effect of ART and MOX on secretion of four kinds of immunosuppressive molecules from L929 tumor cells
The L929 tumor cells treated without any TCDP secrete the four kinds of immunosuppressive molecules steadily (C-S1 VS C-S2, all P>0.05), the concentrations of TGF-β1 and PGE2 were more higher(:198.15±3.23)pg/ml and(133.76±5.16)pg/ml respectively, and the concentrations of VEGF and IL-10 were relatively lower: (33.38±0.59)pg/ml and(27.31±0.37)pg/ml respectively. For L929 tumor cells after treated with ART:①The first re-culture' supernatant (A-S1) compared with corresponding C-S1: the concentrations of TGF-β1, PGE2, VEGF and IL-10 in A-S1 decreased greatly:(99.05±8.02)pg/ml( P <0.001, decreased 50.01%), PGE2(66.57±4.71)pg/ml(P <0.001, decreased 50.23%), VEGF(21.03±0.87)pg/ml(P <0.01, decreased 36.99%)and IL-10(22.89±0.57)pg/ml(P <0.01, decreased 16.18%)respectively;②The second re-culture' supernatant (A-S2) compared with A-S1, the concentration of IL-10 increased highly(P<0.05), and the others had no changes(All P>0.05).
For L929 tumor cells after treated with MOX:①The first re-culture' supernatant (O-S1) compared with corresponding C-S1: the concentrations of TGF-β1, PGE2,VEGF and IL-10 in O-S1 decreased greatly: TGF-β1(91.35±9.62)pg/ml(decreased 53.89%), PGE2(69.43±2.32)pg/ml(decreased 48.23%), VEGF(21.36±0.75)pg/ml (decreased 36.01%)and IL-10(22.84±0.33)pg/ml(decreased 16.37%)(all P<0.01)respectively;②The second re-culture' supernatant (O-S2) compared with O-S1, the concentrations of the four kinds of immunosuppressive molecules had no changes(all P>0.05).
4 The analysis of related molecules to the effect of ART and MOX on the immunosuppression induced by L929 tumor cells
The professional and statistical analysis demonstrated:①The related molecules to that ART and MOX down-regulated immunosuppression induced by L929 tumor cells on the ConA-induced transformation and the expression of CD4+,IL-2Rαand CD3ε-ζ+of murine splenocytes were TGF-β1 and PGE2.②The related molecules to that ART and MOX down-regulated immunosuppression induced by L929 tumor cells on the NK killing were TGF-β1and PGE2.③The related molecules to that MOX down-regulated immunosuppression induced by L929 tumor cells on the NK killing was TGF-β1.
5 The effect of ART and MOX on the expression of TGF-β1 mRNA and COX-2mRNA in L929 tumor cells
In all the detected four kinds of molecules secreted by L929 tumor cells the secretions of TGF-β1 and PGE2 were affected more higher by ART and MOX. The COX-2 was cell-intrinic synthesis rate-limiting enzyme of PGE2. Detecting the expression of TGF-β1 mRNA and COX-2 mRNA could reveal that the two kinds of TCDP down-regulated the secretions of TGF-β1 and PGE2 happened at either gene transcription or post-transcreption. The results demonstrated①In the L929 tumor cells treated without any TCDP, TGF-β1 mRNA and COX-2 mRNA were expressed highly and steadily (C-C1 VS C-C2 , all P>0.05);②In the L929 tumor cells treated with ART and MOX , the expression of TGF-β1 mRNA and COX-2 mRNA were decreased significantly(A-C1 vs C-C1,O-C1 vs C-C1,A-C2 vs C-C2 and O-C2 vs C-C2: TGF-β1 mRNA,P<0.001; COX-2 mRNA,P<0.005). That ART and MOX down-regulated the secretion of TGF-β1 and PGE2 from L929 tumor cells was positively related to down-regulating the transcription of TGF-β1 mRNA and COX-2 mRNA significantly(after treated with ART : r =1.000, P=0.000; r =0.992, P=0.008; after treated with MOX : r =0.997, P=0.003; r =0.995, P=0.005). Demonstrating that the two kinds of TCDP down-regulated the secretion of TGF-β1 and PGE2 from L929 tumor cells happened at gene transcription.
Conclusion:
1 The supernatants from cutured L929 tumor cells treated without ART or MOX could inhibit all of the detected seven immunofunctions (ConA-induced transformation, NK killing, and expression of CD4+,CD8+, IL-2Rα, CD3ε+ζ+andCD3ε-ζ+) of mouse splenocytes significantly. The immunosuppressive effect of supernatants from cutured L929 tumor cells treated with ART or MOX on all of the detected seven immunofunctions was reduced markedly.
2 The L929 tumor cells treated without ART or MOX could secrete all of the detected four immunosuppressive molecules(TGF-β1,PGE2,VEGF and IL-10)steadily. The secretion of the detected four kinds of immunosuppressive molecules from L929 tumor cells treated with ART or MOX was down-regulated greatly.
3 The related immunosuppressive molecules that ART down-regulated the immunosuppressive effect of L929 tumor cells on the ConA-induced transformation, NK killing and expression of CD4+, IL-2Rαand CD3ε-ζ+ of murine splenocytes were TGF-β1and PGE2.
4 The related molecules that MOX down-regulated the immunosuppressive effect of L929 tumor cells on expression of CD4+, IL-2Rαand CD3ε-ζ+ of murine splenocytes were TGF-β1 and PGE2. The related molecule that MOX down-regulated the immunosuppressive effect of L929 tumor cells on murine splenocytes’NK killing was TGF-β1.
5 That ART and MOX down-regulated the secretion of TGF-β1 and PGE2 from L929 tumor cells was positively related to down-regulating the expression of TGF-β1 mRNA and COX-2 mRNA significantly.
本室前期研究发现,L929肿瘤细胞(小鼠成纤维母细胞瘤)培养上清有免疫抑制作用,提示其有免疫抑制分子分泌。青蒿琥酯和氧化苦参碱,是两个有一定抗瘤作用的市售中药制剂,但目前国内外尚无青蒿琥酯和氧化苦参碱对L929肿瘤细胞免疫抑制作用影响及相关分子机制的研究报道。为此,本研究拟在前期工作基础上,研究青蒿琥酯和氧化苦参碱对L929肿瘤细胞免疫抑制作用影响及相关分子机制,为进一步深入揭示这两种中药制剂的抗瘤机理,指导临床正确选择和合理使用,提供实验和理论依据。
方法:分别以含选定浓度青蒿琥酯(ART)或氧化苦参碱(MOX)的培液培养L929肿瘤细胞24h后,洗涤去除中药制剂,细胞再用不含中药制剂的培液连续作两次24h的再培养,分别留取第一次和第二次再培养的细胞和培养上清。其中,经ART作用后第一次再培养的细胞称为A-C1,第二次再培养的细胞称为A-C2,相应的上清分别称为A-S1和A-S2;经MOX作用后再培养的细胞分别称为O-C1和O-C2,上清分别称为O-S1和O-S2。以不含中药制剂培液作同步对照培养的细胞分别称为C-C1和C-C2,上清分别称为C-S1和C-S2。实验研究这些上清对小鼠脾细胞MTT法测定的NK杀伤和ConA诱导转化,以及直接免疫荧光FCM法分析的CD4+、CD8+、IL-2Rα、CD3ε+ζ+和CD3ε-ζ+表达共7项免疫功能指标的影响;定量ELISA法测定这些上清中TGF-β1、PGE2、VEGF和IL-10共4种免疫抑制分子的含量;以β-actin作内参照,RT-PCR法检测细胞中受影响最大的免疫抑制分子或其胞内合成限速酶的mRNA表达,表达强度以相对表达系数RC表示。将这些上清免疫抑制作用变化与相应上清中免疫抑制分子含量变化列表进行专业比对分析,以最大相似性推测两者的关系,然后作单因素相关统计分析,确定中药制剂影响L929肿瘤细胞对不同免疫功能指标免疫抑制作用的相关免疫抑制分子;将受影响最大的免疫抑制分子的上清中含量与其相应细胞内mRNA或其胞内合成限速酶mRNA表达强度进行单因素相关统计分析,明确中药制剂下调该分子分泌是发生在基因转录水平还是基因转录后水平。
结果:
1 L929单纯肿瘤细胞培养上清对小鼠脾细胞免疫功能指标的影响
在以培液代替L929单纯肿瘤细胞培养上清的正常对照(C-nS)组,小鼠脾细胞NK杀伤率、ConA诱导转化的A值和CD4+、CD8+、IL-2Rα、CD3ε+ζ+、CD3ε-ζ+表达细胞百分率分别为65.39±0.87%、0.925±0.026、48.24±2.10%、19.23±0.60%、26.50±0.85%、21.67±1.29%和16.33%±0.18%。与C-nS组相比,在以不含中药制剂培液作同步对照培养的L929单纯肿瘤细胞培养上清(C-S1、C-S2)组,均可使所检测的这7项免疫功能指标明显受抑:C-S1组分别为60.97±3.86%(P<0.01)、0.440±0.038(P<0.01)、22.72±2.61%(P<0.01)、11.42±1.25%(P<0.01)、10.39±0.49%(P<0.001)、7.89±0.78%(P<0.001)和10.93%±0.16%(P<0.001),抑制率分别为8.34±4.55%、47.88%±1.89%、53.00±3.37%、40.71±4.65%、59.91%±0.77%、63.33±5.77%和33.05%±1.52% ; C-S2组分别为59.59±3.13%(P<0.01)、0.441±0.047(P<0.001)、21.89±2.18%(P<0.01)、12.15±0.65%(P<0.01)、9.76±0. 94%(P<0.001)、7.45±0.54%(P<0.001)和10.75%±0.59%(P<0.001);抑制率分别为9.79±3.95%、48.00%±2.16%、54.69±2.55%、36.85±1.41%、61.49±0.85%、65.63±0.87%和33.32%±0.25%;而C-S1组与C-S2组无统计学差异(均P>0.05)。
2青蒿琥酯或氧化苦参碱作用后L929再培养上清对小鼠脾细胞免疫功能指标的影响
经青蒿琥酯作用后的L929肿瘤细胞:⑴其第一次再培养上清(A-S1)与相应对照上清(C-S1)相比,除对CD8+表达的抑制作用无明显改变(P>0.05)外,对其余6项免疫功能指标的抑制作用均明显降低(分别为P<0.001,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01);⑵其第二次再培养上清(A-S2)与A-S1相比:①对CD8+表达的抑制作用明显上升(P<0.05);②对CD3ε+ζ+表达的抑制作用明显回升(P<0.01),但未至相应对照C-S2水平(P<0.01);③对NK杀伤、ConA诱导转化和CD4+、IL-2Rα和CD3ε-ζ+表达的抑制均无显著变化(均P>0.05)。经氧化苦参碱作用后的L929肿瘤细胞:①其第一次再培养上清(O-S1)与相应对照上清(C-S1)相比,除对CD8+表达的免疫抑制作用无明显变化(P>0.05)外,对其余6项免疫功能指标的免疫抑制作用均明显降低(分别为P<0.05,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01);②其第二次再培养上清(O-S2)与O-S1相比,除对CD3ε+ζ+表达的抑制作用明显回升外(P<0.05;但未至相应对照上清C-S2水平,P<0.01),对其余6项免疫功能指标(NK杀伤、ConA诱导转化和CD4+、CD8+、IL-2Rα和CD3ε-ζ+表达)的抑制作用均无显著变化(均P>0.05)。
3青蒿琥酯或氧化苦参碱对L929肿瘤细胞4种免疫抑制分子分泌的影响
未经中药制剂作用的L929肿瘤细胞可稳定分泌所测的4种免疫抑制分子(C-S1与C-S2相比,P>0.05),以TGF-β1及PGE2含量最高,分别为(198.15±3.23)pg/ml和(133.76±5.16)pg/ml,VEGF和IL-10含量较低,分别为(33.38±0.59)pg/ml和(27.31±0.37)pg/ml。
经青蒿琥酯作用后的L929肿瘤细胞:①其第一次再培养上清(A-S1)与相应对照上清(C-S1)相比:4种免疫抑制分子的浓度均明显降低,分别为(99.05±8.02)pg/ml(P<0.001,降低50.01%)、(66.57±4.71)pg/ml(P<0.001,降低50.23%)、(21.03±0.87)pg/ml(P<0.01,降低36.99%)和(22.89±0.57)pg/ml(P<0.01,降低16.18%);②其第二次再培养上清(A-S2)与A-S1相比,除IL-10含量明显上升(P<0.05)外,其余3种分子含量无显著变化(均P>0.05)。
经氧化苦参碱作用后的L929肿瘤细胞:①其第一次再培养上清(O-S1)与对照上清(C-S1)相比:4种免疫抑制分子的含量均明显降低(均P<0.01),分别为TGF-β1(91.35±9.62)pg/m(l降低53.89%),PGE2,(69.43±2.32)pg/ml(降低48.23%),VEGF(21.36±0.75)pg/ml (降低36.01%)和IL-10(22.84±0.33)pg/ml(降低16.37%)。②其第二次再培养上清(O-S2)与O-S1相比,4种免疫抑制分子含量均无显著变化(均P>0.05)。
4青蒿琥酯和氧化苦参碱影响L929肿瘤细胞免疫抑制作用的相关分子分析
专业和统计分析表明:①青蒿琥酯和氧化苦参碱下调L929肿瘤细胞对小鼠脾细胞ConA诱导转化及CD4+、IL-2Rα和CD3ε-ζ+表达的免疫抑制作用的相关分子是TGF-β1和PGE2 ;②青蒿琥酯下调L929肿瘤细胞对小鼠脾细胞NK杀伤的免疫抑制作用的相关分子是TGF-β1和PGE2;③氧化苦参碱下调L929肿瘤细胞对小鼠脾细胞NK杀伤的免疫抑制作用的相关分子是TGF-β1。
5青蒿琥酯和氧化苦参碱对L929肿瘤细胞TGF-β1 mRNA和COX-2mRNA表达的影响
在所测的L929肿瘤细胞分泌的4种免疫抑制分子中,受青蒿琥酯和氧化苦参碱影响最大的是TGF-β1和PGE2,而COX-2是PGE2的胞内合成限速酶,故测定TGF-β1 mRNA和COX-2 mRNA表达,可以揭示这两种中药制剂下调这两种免疫抑制分子分泌是发生在基因转录水平还是基因转录后水平。结果显示,未受中药制剂作用的L929肿瘤细胞可稳定高表达TGF-β1 mRNA和COX-2 mRNA(C-C1与C-C2相比,均P>0.05);中药制剂作用后再培养的L929肿瘤细胞(A-C1和A-C2、O-C1和O-C2)的TGF-β1 mRNA和COX-2 mRNA表达水平均显著降低(分别为:TGF-β1mRNA,P<0.001;COX-2 mRNA,P<0.005),其mRNA表达水平与上清中相应免疫抑制分子TGF-β1和PGE2含量之间呈显著正相关关系(分别为ART:r =1.000, P=0.000; r =0.992, P=0.008; MOX:r =0.997, P=0.003; r =0.995, P=0.005),表明两种中药制剂下调L929肿瘤细胞TGF-β1和PGE2的分泌是发生在基因转录水平。
结论:
1不经ART或MOX作用的L929肿瘤细胞,其培养上清可显著抑制所测小鼠脾细胞7项免疫功能指标(ConA诱导转化、NK杀伤及CD4+、CD8+、IL-2Rα、CD3ε+ζ+和CD3ε-ζ+表达);经ART或MOX作用后再培养的L929肿瘤细胞,其培养上清对这7项免疫功能指标的抑制作用显著降低。
2不经ART或MOX作用的L929肿瘤细胞能稳定分泌所测4种免疫抑制分子(TGF-β1、PGE2、VEGF和IL-10);ART或MOX均能显著下调L929肿瘤细胞这4种免疫抑制分子分泌。
3 ART下调L929肿瘤细胞对小鼠脾细胞ConA诱导转化、NK杀伤和IL-2Rα、CD4+及CD3ε-ζ+表达的免疫抑制作用的相关分子是TGF-β1和PGE2。
4 MOX下调L929肿瘤细胞对小鼠脾细胞ConA诱导转化和IL-2Rα、CD4+及CD3ε-ζ+表达的免疫抑制作用的相关分子是TGF-β1和PGE2;下调L929肿瘤细胞对小鼠脾细胞NK杀伤的免疫抑制作用的相关分子是TGF-β1。
5 ART和MOX下调L929肿瘤细胞TGF-β1和PGE2分泌与降低L929肿瘤细胞TGF-β1 mRNA和COX-2 mRNA表达相关。
Objective: Tumor is a kind of severe disease threatening the health and lives of human at present. The morbidity and mortality of patients with tumor are higher. Administrating drugs is an important measure in the process of treating tumors. The traditional Chinese drug (TCD) is a precious medicine resource in China. Investigating anti-tumor TCD is an important territory of investigating anti-tumor drugs. Studying the different anti-tumor effect and the related molecular mechanism of different traditional Chinese drug preparations (TCDP) is the important evidence of correctly selecting and using these TCDP clinically. Tumor cell is derived from mutation of normal cell in organism. The immune function of organism, especially the functions of natural killer cell (NK cell) and T cell, play an important role in immunologic surveillance against tumor and preventing the generation and development of tumor. That the tumor cells secrete immunosuppressive substances to inhibit immunofuctions, i.e the tumor-induced immunosuppression, especially to inhibit the immuofunctions of NK cells and T cells, was the important mechanism of making tumor escaping organism immunosurveillance and had important effect on promoting the generation and development of tumor. Thus, the generation and development of tumor is related not only to the immune function of organism, but also to immunosuppressive action induced by tumor cells closely. Up to now, it has been known that there are about twenty kinds of immunosuppressive molecules which could be secreted by tumor cells. Among these, those reported more frequently and having more intensive immunosuppression are transforming growth factorβ1 (TGF-β1), prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10). Tumor cells secrete these immunosuppressive molecules to form an extensive immunosuppressive“block hole”region in location of tumor, not only making that the immunocytes there are inhibited severely, but also that once the normal even activated immunocytes enter into there they would become function-inhibited“the silent cell”, resulting in that the immunocytes could not attack and eliminate the tumor cells, which should be an important mechanism that the tumor could escape immunosurveillance to generate and to develop. Obviously, it is of vital significance to study the effect of anti-tumor TCDP on the tumor-induced immunosuppression and the related molecular mechanism.
Previous studies in our laboratory showed that supernatant from cultured L929 tumor cells had immunosuppression, suggesting there was secretion of immunosuppressive molecules from L929 tumor cells. Artesunate and Oxymatrine are the two kinds of TCDP with some anti-tumor effect. But, so far, there has been no report about the effect of Artesunate and Oxymatrine on the immunosuppression induced by L929 tumor cells and the related molecular mechanism. Therefore, on the basis of previous studies, we study the effect of Artesunate and Oxymatrine on immunosuppression induced by L929 tumor cells and the related molecular mechanism in order to further find out their antitumor mechanism, to guide effectively selecting and rationally using them in clinical and provide the evidences of experiment and theory.
Methods: After cultured in complete medium(CM)containing the selected concentration of ART or MOX for 24h and washing off ART or MOX, the L929 tumor cells were re-cultured in CM without ART or MOX for sequential two times of 24h re-culture. The cells and supernatants from the two times of re-cutured L929 tumor cells were harvested respectively. Of them, for the L929 tumor cells treated with ART the cells and supernatant of the first re-culture called A-C1 and A-S1, and the cells and supernatant from the second re-culture called A-C2 and A-S2 respectively; for the L929 tumor cells treated with MOX the cells and supernatant from the first re-culture called O-C1 and O-S1, and the cells and supernatant from the second re-culture called O-C2 and O-S2 respectively. The cells and supernatants harvested from the synchronistically cultured L929 tumor cells in CM without ART or MOX as corresponding control called C-C1, C-S1, C-C2 and C-S2 respectively. Then the effect of different supernatants on seven immunofunctions of murine splenocytes, including NK killing and ConA-induced transformation detected by MTT, and expression levels of CD4+, CD8+, IL-2Rα, CD3ε+ζ+ and CD3ε-ζ+ detected by FCM of direct immunofluorescence were determined. The concentrations of four immunosuppressive molecules, including TGF-β1, PGE2, VEGF and IL-10 in different supernatants were measured by quantitative ELISA. The mRNA expression of the immunosuppressive molecule or its cell-intrinic synthesis rate-limiting enzyme of the immunosuppressive molecule that among the detected four kinds of immunosuppressive molecules secreted by L929 tumor cells its secretion was affected more highly by ART or MOX was detected by RT-PCR usingβ-actin as intrinsic reference. The mRNA expression level was shown by the relative coefficient (RC). The correlations between the congcentrations of immunosuppressive molecules in supernatants and the immunosuppressions of corresponding supernatants were analysed based on professional and statistical analysis to determine the relative molecules that ART and MOX down-regulated the immunosuppression induced by L929 tumor cells. For the immunosuppressive molecule that the inhibitory effect of ART or MOX on its secretion from L929 tumor cells was more higher, using the single-analysis of correlativity the relative correlation between its supernatant' concentration and its mRNA expression or its synthysis rate-limiting enzyme mRNA expression was determined to estimate that the ART or MOX down-regulated the molecule' secretion happened at either gene transcription or post-transcription.
Results:
1 The effect of supernatants from cultured L929 tumor cells on the immunofunctions of murine splenocytes
In the normal control group replacing supernatant from cultured L929 tumor cells with CM, i.e C-nS group, the detected values of the seven kinds of murine splenocytes' immunofunctions were 65.39±0.87% (NK killing rate), 0.925±0.026 ( A value of ConA-induced transformation),48.24±2.10%(CD4+cells),19.23±0.60% (CD8+ cells),26.50±0.85%(IL-2Rα+cells),21.67±1.29% (CD3ε+ζ+ cells) and 16.33%±0.18% (CD3ε-ζ+ cells). Compared with the C-nS group, the supernatants(C-S1 and C-S2) from synchronistically cultured L929 tumor cells treated without ART or MOX as corresponding control inhibited all of the seven immunofunctions apparently:①in C-S1 group the detected values of the seven kinds of murine splenocytes' immunofunctions respectively were (60.97±3.86)% (NK killing rate ,P<0.01), 0.440±0.038 (A value of ConA-induced transformation, P<0.01), (22.72±2.61)% (CD4+cells, P<0.01), (11.42±1.25)% (CD8+ cells,P<0.01), (10.39±0.49)% (IL-2Rα+cells,P<0.001), (7.89±0.78)% (CD3ε+ζ+cells,P<0.001) and (10.93%±0.16)% (CD3ε-ζ+ cells,P<0.001),and the corresponding inhibitory rate respectively were (8.34±4.55)%, (47.88%±1.89)%, (53.00±3.37)%, (40.71±4.65)%, (59.91%±0.77)%, (63.33±5.77)% and (33.05%±1.52)%;②in C-S2 group the detected values of the seven kinds of murine splenocytes' immunofunctions respectively were (59.59±3.13)% (P<0.01), 0.441±0.047 (P<0.001), (21.89±2.18)%(P<0.01),(12.15±0.65)%(P<0.01),(9.76±0. 94)%(P<0.001), (7.45±0.54)%(P<0.001) and( 10.75%±0.59 ) % ( P<0.001), and the corresponding inhibitory rate respectively were (9.79±3.95)%,(48.00%±2.16)%,(54.69±2.55)%,(36.85±1.41)%,(61.49±0.85)%,(65.63±0.87)%, (33.32%±0.25)%; while the C-S1 group compared with C-S2 groups these values had no changes (P>0.05).
2 The effect of supernatant from L929 treated with ART or MOX on the immunofunctions of murine splenocytes
For L929 tumor cells after treated with ART:⑴The first re-culture' supernatant (A-S1) compared with C-S1, the inhibitory effect of A-S1 on the others six immunofunctions except for CD8+ (P>0.05) decreased greatly (P<0.001,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01, respectively);⑵The second re-culture' supernatant (A-S2) compared with A-S1:①The inhibition of CD8+ expression increased greatly(P<0.05);②The inhibitory effect on CD3ε+ζ+ expression increased significantly(P<0.01),but had not reached the level of C-S2 (P<0.01);③The inhibitory effect on the NK killing rate , A of ConA-induced transformation and expression of CD4+,IL-2Rαas well as CD3ε-ζ+ had no changes (All P>0.05).
For L929 tumor cells after treated with MOX:①The first re-culture' supernatant (O-S1) compared with C-S1, the inhibitory effect on the others six immunofunctions except for CD8+ (P>0.05) decreased greatly (P<0.05,P<0.01,P<0.05,P<0.05,P<0.001,P<0.01, respectively);②The inhibitory effect on CD3ε+ζ+expression increased markedly(P<0.05),but had not reached the level of C-S2 (P<0.01);③The inhibitory effect on the NK killing rate , A of ConA-induced transformation and the expression of CD4+ ,CD8+,IL-2Rαas well as CD3ε-ζ+ had no changes (All P>0.05).
3 The effect of ART and MOX on secretion of four kinds of immunosuppressive molecules from L929 tumor cells
The L929 tumor cells treated without any TCDP secrete the four kinds of immunosuppressive molecules steadily (C-S1 VS C-S2, all P>0.05), the concentrations of TGF-β1 and PGE2 were more higher(:198.15±3.23)pg/ml and(133.76±5.16)pg/ml respectively, and the concentrations of VEGF and IL-10 were relatively lower: (33.38±0.59)pg/ml and(27.31±0.37)pg/ml respectively. For L929 tumor cells after treated with ART:①The first re-culture' supernatant (A-S1) compared with corresponding C-S1: the concentrations of TGF-β1, PGE2, VEGF and IL-10 in A-S1 decreased greatly:(99.05±8.02)pg/ml( P <0.001, decreased 50.01%), PGE2(66.57±4.71)pg/ml(P <0.001, decreased 50.23%), VEGF(21.03±0.87)pg/ml(P <0.01, decreased 36.99%)and IL-10(22.89±0.57)pg/ml(P <0.01, decreased 16.18%)respectively;②The second re-culture' supernatant (A-S2) compared with A-S1, the concentration of IL-10 increased highly(P<0.05), and the others had no changes(All P>0.05).
For L929 tumor cells after treated with MOX:①The first re-culture' supernatant (O-S1) compared with corresponding C-S1: the concentrations of TGF-β1, PGE2,VEGF and IL-10 in O-S1 decreased greatly: TGF-β1(91.35±9.62)pg/ml(decreased 53.89%), PGE2(69.43±2.32)pg/ml(decreased 48.23%), VEGF(21.36±0.75)pg/ml (decreased 36.01%)and IL-10(22.84±0.33)pg/ml(decreased 16.37%)(all P<0.01)respectively;②The second re-culture' supernatant (O-S2) compared with O-S1, the concentrations of the four kinds of immunosuppressive molecules had no changes(all P>0.05).
4 The analysis of related molecules to the effect of ART and MOX on the immunosuppression induced by L929 tumor cells
The professional and statistical analysis demonstrated:①The related molecules to that ART and MOX down-regulated immunosuppression induced by L929 tumor cells on the ConA-induced transformation and the expression of CD4+,IL-2Rαand CD3ε-ζ+of murine splenocytes were TGF-β1 and PGE2.②The related molecules to that ART and MOX down-regulated immunosuppression induced by L929 tumor cells on the NK killing were TGF-β1and PGE2.③The related molecules to that MOX down-regulated immunosuppression induced by L929 tumor cells on the NK killing was TGF-β1.
5 The effect of ART and MOX on the expression of TGF-β1 mRNA and COX-2mRNA in L929 tumor cells
In all the detected four kinds of molecules secreted by L929 tumor cells the secretions of TGF-β1 and PGE2 were affected more higher by ART and MOX. The COX-2 was cell-intrinic synthesis rate-limiting enzyme of PGE2. Detecting the expression of TGF-β1 mRNA and COX-2 mRNA could reveal that the two kinds of TCDP down-regulated the secretions of TGF-β1 and PGE2 happened at either gene transcription or post-transcreption. The results demonstrated①In the L929 tumor cells treated without any TCDP, TGF-β1 mRNA and COX-2 mRNA were expressed highly and steadily (C-C1 VS C-C2 , all P>0.05);②In the L929 tumor cells treated with ART and MOX , the expression of TGF-β1 mRNA and COX-2 mRNA were decreased significantly(A-C1 vs C-C1,O-C1 vs C-C1,A-C2 vs C-C2 and O-C2 vs C-C2: TGF-β1 mRNA,P<0.001; COX-2 mRNA,P<0.005). That ART and MOX down-regulated the secretion of TGF-β1 and PGE2 from L929 tumor cells was positively related to down-regulating the transcription of TGF-β1 mRNA and COX-2 mRNA significantly(after treated with ART : r =1.000, P=0.000; r =0.992, P=0.008; after treated with MOX : r =0.997, P=0.003; r =0.995, P=0.005). Demonstrating that the two kinds of TCDP down-regulated the secretion of TGF-β1 and PGE2 from L929 tumor cells happened at gene transcription.
Conclusion:
1 The supernatants from cutured L929 tumor cells treated without ART or MOX could inhibit all of the detected seven immunofunctions (ConA-induced transformation, NK killing, and expression of CD4+,CD8+, IL-2Rα, CD3ε+ζ+andCD3ε-ζ+) of mouse splenocytes significantly. The immunosuppressive effect of supernatants from cutured L929 tumor cells treated with ART or MOX on all of the detected seven immunofunctions was reduced markedly.
2 The L929 tumor cells treated without ART or MOX could secrete all of the detected four immunosuppressive molecules(TGF-β1,PGE2,VEGF and IL-10)steadily. The secretion of the detected four kinds of immunosuppressive molecules from L929 tumor cells treated with ART or MOX was down-regulated greatly.
3 The related immunosuppressive molecules that ART down-regulated the immunosuppressive effect of L929 tumor cells on the ConA-induced transformation, NK killing and expression of CD4+, IL-2Rαand CD3ε-ζ+ of murine splenocytes were TGF-β1and PGE2.
4 The related molecules that MOX down-regulated the immunosuppressive effect of L929 tumor cells on expression of CD4+, IL-2Rαand CD3ε-ζ+ of murine splenocytes were TGF-β1 and PGE2. The related molecule that MOX down-regulated the immunosuppressive effect of L929 tumor cells on murine splenocytes’NK killing was TGF-β1.
5 That ART and MOX down-regulated the secretion of TGF-β1 and PGE2 from L929 tumor cells was positively related to down-regulating the expression of TGF-β1 mRNA and COX-2 mRNA significantly.
引文
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