中药清毒栓对HR-HPV感染宫颈上皮细胞MHC-Ⅰ抗原呈递通路及阴道免疫微环境的调节
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摘要
目的
1以阴道免疫微环境为切入点,研究宫颈上皮内瘤变(CIN)患者及正常人群阴道分泌物中细胞因子IFN-γ、IL-10的含量变化,探讨细胞因子变化与病变进展的相关性,寻找潜在的预后评价及疗效评价指标。
2研究中药清毒栓及干扰素α-2b对宫颈高危型HPV感染的疗效,及其对阴道局部免疫环境的调节作用,探讨中药清毒栓可能的免疫调节机制。
3以HPV18阳性的宫颈癌细胞系HeLa为研究对象,以MHC-Ⅰ抗原呈递通路为切入点,研究中药清毒栓及中药单体β-榄香烯抗病毒、抗肿瘤的分子机制。
方法
临床研究
1采用病例对照研究,以宫颈细胞病理学为良性反应性改变的女性为对照组,以宫颈组织病理学为CINⅠ、CINⅡ～Ⅲ的女性为试验组,于入组患者卵泡期收集阴道灌洗液,ELISA法检测阴道灌洗液中IFN-γ、IL-10的含量,采用非参数Kruskal-Wallis检验3组间细胞因子含量差异,并采用spearman分析细胞因子与病变程度及细胞因子与年龄的相关性。
2以对照组IFN-γ、IL-10含量均值95%可信区间的下限作为标准,将试验组IFN-γ、IL-10含量二分为含量上升、含量下降两组,作为自变量,以官颈上皮内瘤变作为因变量,采用单因素logistic回归分析,分析IFN-γ、IL-10含量变化与宫颈上皮内瘤变的相关性,对相关因素进行多因素logistic回归分析,建立回归模型,并对回归模型的预测能力进行评价。
3对符合宫颈高危型HPV感染病例入组标准患者进行治疗,按照患者治疗意愿,分为清毒栓治疗组、干扰素α-2b治疗组、随访组,治疗3个疗程,在完成治疗后的第1个月随访,于治疗前及随访时收集阴道灌洗液。ELISA法检测阴道灌洗液中IFN-γ、IL-10含量。分析药物治疗HR-HPV感染的临床疗效,探讨药物治疗、疗效及阴道免疫微环境改变3者的相关性。
实验研究
1以MTT法检测中药清毒栓水提醇沉液、中药单体β-榄香烯、干扰素α-2b对HeLa田胞生长抑制作用,选出合适的药物浓度及干预时间,进行下一步试验。
2以流式细胞术检测细胞表面HLA-Ⅰ蛋白表达,western blot检测细胞内HLA-Ⅰ蛋白表达,real-time PCR检测细胞中HLA-Ⅰ类分子HLA-A、B、C基因表达,评价药物干预对HLA-Ⅰ的调节作用。
3分别以western blot去及real-time PCR去检测MHC-I抗原呈递通路相关分子TAP1、TAP2、LMP2、LMP7及内质网分子伴侣CNX、CRT、BIP蛋白及基因表达,探讨中药对于MHC-Ⅰ抗原呈递通路的调节作用。
结果
1正常对照组、CINⅠ组、CINⅡ-Ⅲ组比较,阴道灌洗液中IFN-γ含量组间差异有统计学意义,与病变进展相关；IL-10含量组间差异有统计学意义,但与病变进展无明显相关性。
2阴道灌洗液中IFN-γ含量的降低(OR：6.003(95%CI 2.759～13.062)),IL-10含量的升高(OR：2.367(95%CI 1.201～4.667)),可作为CIN患病的危险因素。建立回归模型,该模型阳性预测值为84.9%,阴性预测值为51.7%,准确度为71.2%,尚无法应用于临床。
3清毒栓治疗组、干扰素α-2b治疗组及随访组,HPV转阴率分别为38.46%、30.00%、20.00%,疗效差异无统计学意义。
4清毒栓及干扰素α-2b凝胶治疗后,阴道灌洗液中IFN-γ水平升高(β<0.05),IL-10前后比较差异无统计学意义。
5中药清毒栓、中药单体β-榄香烯、干扰素α-2b均可促进HeLa细胞表面HLA-I蛋白表达,其中干扰素α-2b可上调HLA-A mRNA表达,β-榄香烯及清毒栓可上调HLA-A、BmRNA表达。
6中药清毒栓、中药单体β-榄香烯、干扰素α-2b均可增加HeLa细胞内抗原呈递通路相关分子TAP1、TAP2、LMP2、LMP7的蛋白表达,清毒栓可上调4种分子的基因表达,但β-榄香烯及干扰素α-2b对4种分子的基因表达无影响。
7中药清毒栓、中药单体β-榄香烯、干扰素α-2b均可上调内质网分子伴侣CRT、CNX的蛋白表达,干扰素及β-榄香烯可上调BIP的蛋白表达。3种药物均有上调CRT、CNX、BIP基因表达的趋势,但差异无统计学意义。
结论
1通过临床研究,我们认为阴道灌洗液中IFN-γ的含量变化可能是反映宫颈上皮内瘤变局部免疫反应的指标。阴道灌洗液中IFN-γ含量的降低、IL-10含量的升高是CIN患病的危险因素。中药清毒栓可能通过上调阴道免疫微环境IFN-γ水平起到抗病毒的作用。
2基于实验研究的结果,我们认为中药清毒栓、中药单体β-榄香烯及干扰素均可通过调节抗原呈递通路相关分子的蛋白及基因表达,起到促进抗原呈递的作用,可能是以上药物抗肿瘤、抗病毒的作用机制之一。
Objective
1 By focusing on vaginal immune microenvironment, the objective of this study was to explore the association between the possible shift of cytokine network and the disease progression and probe the potential indicator to predict further outcome and evaluate effect by measuring the levels of IFN-y as well as IL-10 in vaginal secretions in different stages of cervical disease.
2 The second aim of this project was to study the effects of Qingdu Suppository (QDS) and interferonα-2b suppository on high risk HPV infection and the regulation of these two agents in vaginal immune microenvironment and explored the potential immune regulation mechanism of Qingdu Suppository.
3 By focusing on MHC-I antigen presentation pathway, the aim of this research was also to investigate the molecular mechanism of Qingdu Suppository andβ-elemene in anti-virus and anti-tumor function based on cervical cancer cell lines HeLa (HPV 18 positive).
Methods
Clinical research
1 A case-control study was carried out in this research. We enrolled women with normal cytology for the control,women with CIN 1 or CIN2-3 as the study groups, and sampled all the patients'vaginal washing fluid in their follicular phases. By using enzyme-linked immunosorbent assay(ELISA),the levels of IFN-y,IL-10 in vaginal washing fluid were tested. Differences in the cytokine concentrations between the groups were analyzed by the nonparametric Kruskal-Wallis.The correlation between the cytokine and stages of cervical lesion as well as that between cytokine and age were determined by Spearman analysis.
2 In this study,the cutoff point for each cytokine was assigned by using the lower limit of 95% confidence interval for the mean of the control group. The study groups were classified into two groups,level-up group and level-down group. We used these two as independent variables and CIN as dependent variable. The association between level s of IFN-y and IL-10 and stages of cervical leslon was evaluated by single factor logistic regression. Related factors were analysed by multivariate logistic regression and a regression model was established. Finally,the predictive function of the regression model was evaluated.
3 According to the options of patients,we classified them into three groups: the QDS group, interferonα-2b group and follow-up group as the control group. The treatment lasted for 3 months. After that, all patients received a follow-up interview in 1 or 2 months later and the vaginal washing fluid was sampled. By using ELISA, the levels of IFN-γand IL-10 in the vaginal washing fluid were measured. The effects of these two drugs were analysed and the relationship between treatments,effects and the shifts of vaginal immune microenvironment were explored.
Experimental research
1 The appropriate inhibitory concentrations and time points of QDS,β-elemene and IFN-α-2b were detected by methyl thiazolyl tetrazolium (MTT)assay for next experiment.
2 To assess the regulation of these drugs on HLA-I,flow cytometry(FCM) and Western blot were performed to test the protein expression level of HLA-I on the surface and inside the cells respectively,and real-time PCR for the mRNA expression level of HLA-A,B,C.
3 To analyse the regulation of these drugs on MHC-I antigen presentation pathway,Western blot and real time-PCR were performed to test the protein and mRNA expression level of MHC-I antigen presentation pathway associated molecules TAP1,TAP2,LMP2 and LMP7 respectively.
Results
1 In the levels of IFN-γof the vaginal washing fluid, there were marked differences between these three groups,which were associated with disease progression. There were also significant cross-group differences in the levels of IL-10,but not associated with disease progression.
2 The down-regulation of IFN-y in the vaginal washing fluid (OR:6.003,95%CI 2.759～13.062) and up-regulat ion of IL-10 (OR:2.367,95%CI 1.201～4.667) could be considered as risk factors of CIN. The positive predictive value of the regression model was 84.9% while the negative predictive value was 51.7% and accuracy value was 71.2%.According to these results,the regression model still cannot be used in clinic.
3 The HPV clearance rates in the QDS group, IFNα-2b group and control group were respectively 38.46%,30.00% and 20.00%, with no significant difference.
4 After the treatments with QDS and IFNα-2b, the levels of IFN-y in the vaginal washing fluid increased markedly(p<0.05),whereas no difference was observed for IL-10.
5 Water-extraction and alcohol-precipitation of Qingdu Suppository (QDS),β-elemene and IFNα-2b up-regulated the protein expression of HLA-I at the cell surface significantly (p<0.05). In detail, IFNα-2b up-regulated constitutive molecule HLA-A mRNA expression, whileβ-elemene and Qingdu Suppository both up-regulated constitutive molecules HLA-A, B mRNA expression.
6 These three agents increased the protein expression of antigen presentation pathway associated molecules TAP1, TAP2, LMP2 and LMP7 in cell line HeLa. Qingdu Suppository up-regulated the mRNA expression of these four molecules, whereas no significant difference was observed after treatments withβ-elemene and IFNα-2b.
7 These three agents increased the protein expression of endoplasmic reticulum chaperones CNX and CRT, while IFNα-2b andβ-elemene both increased the protein expression of BIP. These three agents all up-regulated the mRNA expression of molecules above, but there was no significant difference.
Conclusions
1 We conclude by clinical research that the IFN-y in the vaginal washing fluid may be a useful indicator of local immune responses for the stage of the cervical lesions. The down-regulat ion of IFN-y and up-regulat ion of IL-10 in the vaginal washing fluid could be considered as the risk factors of cervical intraepi thel ial neoplasia. Qingdu Suppository can up-regulate the level of IFN-γin vaginal immune microenvironment,which is a potential anti-viral mechanism for it.
2 On the basis of the experimental research, the following conclusion can be drawn that Qingdu Suppository,β-elemene and IFNα-2b can promote antigen presentation through up-regulating the gene and protein expression of antigen presentation associated molecules,which is a potential mechanism of anti-virus and anti-tumor function for these agents.
1以阴道免疫微环境为切入点,研究宫颈上皮内瘤变(CIN)患者及正常人群阴道分泌物中细胞因子IFN-γ、IL-10的含量变化,探讨细胞因子变化与病变进展的相关性,寻找潜在的预后评价及疗效评价指标。
2研究中药清毒栓及干扰素α-2b对宫颈高危型HPV感染的疗效,及其对阴道局部免疫环境的调节作用,探讨中药清毒栓可能的免疫调节机制。
3以HPV18阳性的宫颈癌细胞系HeLa为研究对象,以MHC-Ⅰ抗原呈递通路为切入点,研究中药清毒栓及中药单体β-榄香烯抗病毒、抗肿瘤的分子机制。
方法
临床研究
1采用病例对照研究,以宫颈细胞病理学为良性反应性改变的女性为对照组,以宫颈组织病理学为CINⅠ、CINⅡ～Ⅲ的女性为试验组,于入组患者卵泡期收集阴道灌洗液,ELISA法检测阴道灌洗液中IFN-γ、IL-10的含量,采用非参数Kruskal-Wallis检验3组间细胞因子含量差异,并采用spearman分析细胞因子与病变程度及细胞因子与年龄的相关性。
2以对照组IFN-γ、IL-10含量均值95%可信区间的下限作为标准,将试验组IFN-γ、IL-10含量二分为含量上升、含量下降两组,作为自变量,以官颈上皮内瘤变作为因变量,采用单因素logistic回归分析,分析IFN-γ、IL-10含量变化与宫颈上皮内瘤变的相关性,对相关因素进行多因素logistic回归分析,建立回归模型,并对回归模型的预测能力进行评价。
3对符合宫颈高危型HPV感染病例入组标准患者进行治疗,按照患者治疗意愿,分为清毒栓治疗组、干扰素α-2b治疗组、随访组,治疗3个疗程,在完成治疗后的第1个月随访,于治疗前及随访时收集阴道灌洗液。ELISA法检测阴道灌洗液中IFN-γ、IL-10含量。分析药物治疗HR-HPV感染的临床疗效,探讨药物治疗、疗效及阴道免疫微环境改变3者的相关性。
实验研究
1以MTT法检测中药清毒栓水提醇沉液、中药单体β-榄香烯、干扰素α-2b对HeLa田胞生长抑制作用,选出合适的药物浓度及干预时间,进行下一步试验。
2以流式细胞术检测细胞表面HLA-Ⅰ蛋白表达,western blot检测细胞内HLA-Ⅰ蛋白表达,real-time PCR检测细胞中HLA-Ⅰ类分子HLA-A、B、C基因表达,评价药物干预对HLA-Ⅰ的调节作用。
3分别以western blot去及real-time PCR去检测MHC-I抗原呈递通路相关分子TAP1、TAP2、LMP2、LMP7及内质网分子伴侣CNX、CRT、BIP蛋白及基因表达,探讨中药对于MHC-Ⅰ抗原呈递通路的调节作用。
结果
1正常对照组、CINⅠ组、CINⅡ-Ⅲ组比较,阴道灌洗液中IFN-γ含量组间差异有统计学意义,与病变进展相关；IL-10含量组间差异有统计学意义,但与病变进展无明显相关性。
2阴道灌洗液中IFN-γ含量的降低(OR：6.003(95%CI 2.759～13.062)),IL-10含量的升高(OR：2.367(95%CI 1.201～4.667)),可作为CIN患病的危险因素。建立回归模型,该模型阳性预测值为84.9%,阴性预测值为51.7%,准确度为71.2%,尚无法应用于临床。
3清毒栓治疗组、干扰素α-2b治疗组及随访组,HPV转阴率分别为38.46%、30.00%、20.00%,疗效差异无统计学意义。
4清毒栓及干扰素α-2b凝胶治疗后,阴道灌洗液中IFN-γ水平升高(β<0.05),IL-10前后比较差异无统计学意义。
5中药清毒栓、中药单体β-榄香烯、干扰素α-2b均可促进HeLa细胞表面HLA-I蛋白表达,其中干扰素α-2b可上调HLA-A mRNA表达,β-榄香烯及清毒栓可上调HLA-A、BmRNA表达。
6中药清毒栓、中药单体β-榄香烯、干扰素α-2b均可增加HeLa细胞内抗原呈递通路相关分子TAP1、TAP2、LMP2、LMP7的蛋白表达,清毒栓可上调4种分子的基因表达,但β-榄香烯及干扰素α-2b对4种分子的基因表达无影响。
7中药清毒栓、中药单体β-榄香烯、干扰素α-2b均可上调内质网分子伴侣CRT、CNX的蛋白表达,干扰素及β-榄香烯可上调BIP的蛋白表达。3种药物均有上调CRT、CNX、BIP基因表达的趋势,但差异无统计学意义。
结论
1通过临床研究,我们认为阴道灌洗液中IFN-γ的含量变化可能是反映宫颈上皮内瘤变局部免疫反应的指标。阴道灌洗液中IFN-γ含量的降低、IL-10含量的升高是CIN患病的危险因素。中药清毒栓可能通过上调阴道免疫微环境IFN-γ水平起到抗病毒的作用。
2基于实验研究的结果,我们认为中药清毒栓、中药单体β-榄香烯及干扰素均可通过调节抗原呈递通路相关分子的蛋白及基因表达,起到促进抗原呈递的作用,可能是以上药物抗肿瘤、抗病毒的作用机制之一。
Objective
1 By focusing on vaginal immune microenvironment, the objective of this study was to explore the association between the possible shift of cytokine network and the disease progression and probe the potential indicator to predict further outcome and evaluate effect by measuring the levels of IFN-y as well as IL-10 in vaginal secretions in different stages of cervical disease.
2 The second aim of this project was to study the effects of Qingdu Suppository (QDS) and interferonα-2b suppository on high risk HPV infection and the regulation of these two agents in vaginal immune microenvironment and explored the potential immune regulation mechanism of Qingdu Suppository.
3 By focusing on MHC-I antigen presentation pathway, the aim of this research was also to investigate the molecular mechanism of Qingdu Suppository andβ-elemene in anti-virus and anti-tumor function based on cervical cancer cell lines HeLa (HPV 18 positive).
Methods
Clinical research
1 A case-control study was carried out in this research. We enrolled women with normal cytology for the control,women with CIN 1 or CIN2-3 as the study groups, and sampled all the patients'vaginal washing fluid in their follicular phases. By using enzyme-linked immunosorbent assay(ELISA),the levels of IFN-y,IL-10 in vaginal washing fluid were tested. Differences in the cytokine concentrations between the groups were analyzed by the nonparametric Kruskal-Wallis.The correlation between the cytokine and stages of cervical lesion as well as that between cytokine and age were determined by Spearman analysis.
2 In this study,the cutoff point for each cytokine was assigned by using the lower limit of 95% confidence interval for the mean of the control group. The study groups were classified into two groups,level-up group and level-down group. We used these two as independent variables and CIN as dependent variable. The association between level s of IFN-y and IL-10 and stages of cervical leslon was evaluated by single factor logistic regression. Related factors were analysed by multivariate logistic regression and a regression model was established. Finally,the predictive function of the regression model was evaluated.
3 According to the options of patients,we classified them into three groups: the QDS group, interferonα-2b group and follow-up group as the control group. The treatment lasted for 3 months. After that, all patients received a follow-up interview in 1 or 2 months later and the vaginal washing fluid was sampled. By using ELISA, the levels of IFN-γand IL-10 in the vaginal washing fluid were measured. The effects of these two drugs were analysed and the relationship between treatments,effects and the shifts of vaginal immune microenvironment were explored.
Experimental research
1 The appropriate inhibitory concentrations and time points of QDS,β-elemene and IFN-α-2b were detected by methyl thiazolyl tetrazolium (MTT)assay for next experiment.
2 To assess the regulation of these drugs on HLA-I,flow cytometry(FCM) and Western blot were performed to test the protein expression level of HLA-I on the surface and inside the cells respectively,and real-time PCR for the mRNA expression level of HLA-A,B,C.
3 To analyse the regulation of these drugs on MHC-I antigen presentation pathway,Western blot and real time-PCR were performed to test the protein and mRNA expression level of MHC-I antigen presentation pathway associated molecules TAP1,TAP2,LMP2 and LMP7 respectively.
Results
1 In the levels of IFN-γof the vaginal washing fluid, there were marked differences between these three groups,which were associated with disease progression. There were also significant cross-group differences in the levels of IL-10,but not associated with disease progression.
2 The down-regulation of IFN-y in the vaginal washing fluid (OR:6.003,95%CI 2.759～13.062) and up-regulat ion of IL-10 (OR:2.367,95%CI 1.201～4.667) could be considered as risk factors of CIN. The positive predictive value of the regression model was 84.9% while the negative predictive value was 51.7% and accuracy value was 71.2%.According to these results,the regression model still cannot be used in clinic.
3 The HPV clearance rates in the QDS group, IFNα-2b group and control group were respectively 38.46%,30.00% and 20.00%, with no significant difference.
4 After the treatments with QDS and IFNα-2b, the levels of IFN-y in the vaginal washing fluid increased markedly(p<0.05),whereas no difference was observed for IL-10.
5 Water-extraction and alcohol-precipitation of Qingdu Suppository (QDS),β-elemene and IFNα-2b up-regulated the protein expression of HLA-I at the cell surface significantly (p<0.05). In detail, IFNα-2b up-regulated constitutive molecule HLA-A mRNA expression, whileβ-elemene and Qingdu Suppository both up-regulated constitutive molecules HLA-A, B mRNA expression.
6 These three agents increased the protein expression of antigen presentation pathway associated molecules TAP1, TAP2, LMP2 and LMP7 in cell line HeLa. Qingdu Suppository up-regulated the mRNA expression of these four molecules, whereas no significant difference was observed after treatments withβ-elemene and IFNα-2b.
7 These three agents increased the protein expression of endoplasmic reticulum chaperones CNX and CRT, while IFNα-2b andβ-elemene both increased the protein expression of BIP. These three agents all up-regulated the mRNA expression of molecules above, but there was no significant difference.
Conclusions
1 We conclude by clinical research that the IFN-y in the vaginal washing fluid may be a useful indicator of local immune responses for the stage of the cervical lesions. The down-regulat ion of IFN-y and up-regulat ion of IL-10 in the vaginal washing fluid could be considered as the risk factors of cervical intraepi thel ial neoplasia. Qingdu Suppository can up-regulate the level of IFN-γin vaginal immune microenvironment,which is a potential anti-viral mechanism for it.
2 On the basis of the experimental research, the following conclusion can be drawn that Qingdu Suppository,β-elemene and IFNα-2b can promote antigen presentation through up-regulating the gene and protein expression of antigen presentation associated molecules,which is a potential mechanism of anti-virus and anti-tumor function for these agents.
引文
[1]Ahmedin Jemal, Freddie Bray, Melissa M. Center, et al. Global cancer statistics [J]. CA Cancer J Clin,2011,61 (2):69-90.
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