JMJD3调控强直性脊柱炎Th17分化的表观遗传机制及清热利湿活血法干预作用
发布时间：2018-08-19 17:59
【摘要】：背景:强直性脊柱炎(Ankylosing Spondylitis,AS)属慢性炎症性的自身免疫性的疾病,可造成髋关节破坏和脊柱强直,严重影响患者的工作能力和生活自理能力,降低患者的生活质量。炎症是AS首要病理改变。辅助性T细胞(Thelper cell 17,Th17)是触发AS炎症的重要效应细胞,由初始CD4+T细胞(Naive CD4+T cell)分化而来。研究表明,表观遗传调控机制在CD4+T细胞向Th17分化中扮演着重要角色,组蛋白去甲基化酶JMJD3催化H3K27位点去甲基化,可能是Th17分化的关键调控因子。在前期临床研究中,我们发现清热利湿活血法缓解AS炎症的临床疗效满意。且经清热利湿活血方治疗后,AS患者IL-17表达水平显著下降,Th17数量及特征性转录因子RORc表达明显减少,JAK/STAT通路活化水平显著下降,表明清热利湿活血法可以通过干预Th17分化,发挥缓解AS炎症的作用。本研究基于此,进一步探究JMJD3调控AS Th17分化的表观遗传机制及清热利湿活血法的干预作用。目的:初步探究AS患者JMJD3表达情况及其去甲基化H3K27对Th17分化的干预作用;中药清热强脊汤治疗及中药单体雷公藤甲素体外干预PBMC对AS患者JMJD3的表达及Th17分化的调节作用。方法:研究一、研究二及研究三以活动期AS患者的血清及PBMC为研究对象,运用Western Blotting检测蛋白表达情况,Quantitative Real-time PCR等技术检测mRNA表达情况,ELISA检测血清炎性细胞因子分泌情况。分别检测疾病活动期、疾病相对稳定期、中药治疗3个月对AS患者JMJD3表达、H3K27me3的甲基化情况及Th17分化状况的影响作用。研究四以体外分离培养的活动期AS患者外周血PBMC为研究对象,运用Western Blotting检测蛋白表达情况,Quantitative Real-time PCR等技术检测mRNA表达情况,研究中药雷公藤有效单体雷公藤甲素体外干预对AS患者JMJD3表达、JMJD3催化的H3K27去甲基化情况及Th17分化状况的影响作用。结果:1.活动期AS患者JMJD3表达情况分析中,发现活动期AS患者血清中Th17特异性分泌的细胞因子IL-17表达水平较正常对照组显著增高,且差异具有统计学意义(p0.001);与患者炎症指标ESR、CRP以及疾病活动指数BASDAI做了相关性分析,发现IL-17、ESR、CRP互相高度相关(IL-17-ESR:p0.001;IL-17-CRP:p0.01)。活动期 AS 患者 PBMC 中,JMJD3 的 mRNA表达水平较正常对照显著增高,(p0.001);JMJD3与炎症指标ESR、CRP间均显著相关(ESR:r= 0.631,p=0.0030.01)(CRP:r= 0.567,p=0.0090.01)。JMJD3与炎性细胞因子IL-17间显著相关(IL-17:p0.01),而JMJD3、IL-17与BASDAI均无明显相关性关系。2.活动期AS患者JMJD3去甲基化H3K27及对Th17分化的干预作用研究中,检测AS患者(AS-Active)、稳定期AS患者(AS-Stable)、正常对照组(N)的JMJD3、H3K27me3、JAK/STAT信号通路及特征性转录因子RORc蛋白及mRNA表达水平。活动期AS患者的JMJD3蛋白表达水平显著高于正常对照组与非活动期AS患者(p0.001),而非活动期AS患者的JMJD3蛋白表达水平则与正常对照无明显差异(p0.05)。在基因水平上,活动期AS患者的JMJD3 mRNA表达水平较正常对照组及与非活动期AS患者均显著增高,非活动期AS患者较正常对照组则无明显差异(AS-Active:p0.001;AS-Stable:p0.05),活动期与非活动期AS患者间JMJD3的mRNA表达水平亦存在显著差异(p0.001)。活动期AS患者的H3K27me3甲基化水平均显著降低,较正常对照组差异有统计学意义(p0.01);活动期AS患者与非活动期AS患者的H3K27甲基化水平亦存在明显差异(p0.001),正常对照组与非活动期AS患者无明显差异(p0.05)。JAK/STAT信号通路中信号分子STAT3的磷酸化水平(pSTAT3/STAT3)较正常对照显著升高(AS-Active:p0.001;AS-Stable:p0.01)。与非活动期患者相比较,活动期AS患者JAK2的表达水平虽没有明显差异,但磷酸化的JAK2表达水平显著增高(p=0.0130.05);STAT3的蛋白表达水平及磷酸化水平均较非活动期AS患者明显增高(STAT3:p0.01;pSTAT3:p0.001)。在基因水平上,活动期AS患者及非活动期AS患者的JAK2及STAT3 mRNA表达水平均明显高于正常对照组(AS-Active:p0.001;AS-Stable:p0.01);而相较于非活动期AS患者,活动期AS患者上述信号分子的mRNA表达量亦存在明显差异(p0.001)。活动期AS患者与非活动期AS患者转录因子RORc表达水平较正常对照组显著增高(p0.001);活动期AS患者的RORc表达水平较非活动期无明显差异(p0.05)。在基因表达水平上,相较于正常对照组,活动期AS患者及非活动期AS患者RORc的mRNA均显著增高(p0.01);活动期AS患者与非活动期AS患者直接亦存在表达差异(p0.01)。3.在清热利湿活血法对活动期AS患者JMJD3表达及Th17分化的调节作用研究中,我们选用本科治疗活动期骨痹的临床有效方剂清热强脊汤辨证治疗湿热瘀阻证的AS患者,并在服药3个月后检测其Th17细胞的活性与功能。经清热强脊汤治疗3个月后,患者ESR、CRP、BASDAI均较治疗前明显下降,差异有统计学意义(p0.001)。治疗后患者血清炎性细胞因子IL-17的表达水平较治疗前也明显下降(p0.05);JMJD3的蛋白和mRNA表达情况和相对灰度值变化均较治疗前存在显著差异(p0.05);患者H3K27me3的甲基化水平均较治疗前也表现出了显著下降(p0.001);患者RORc的基因及蛋白表达水平均较治疗前显著下降(p0.001)。4.以雷公藤提取物雷公藤甲素干预活动期AS患者的PBMC,经雷公藤甲素干预后,AS患者的JMJD3蛋白表达水平较干预前显著降低(p0.001);基因水平的检测得到了相同的结果(p0.001)。经雷公藤甲素干预后,H3K27甲基化水平较治疗前显著提高,差异具有统计学意义(p0.001);雷公藤甲素干预后的H3K27me3水平与正常对照组则无明显统计学差异(p=0.080.05)。经雷公藤甲素干预后,患者JAK2/STAT3信号通路的活化被明显抑制,各信号分子的磷酸化水平显著下降(p0.001)。基因水平上,JAK2、STAT3的mRNA表达量明显下降(p0.001)。经雷公藤甲素干预后,RORc的蛋白和mRNA表达量显著下降(p0.001)。结论:1.JMJD3是Th17分化及功能的重要调控因子,参与了活动期AS的炎症发生。JMJD3的表达水平与Th17的分化及功能高度相关;JMJD3与AS炎症指标也密切相关,可能是控制AS炎症有意义的治疗靶点之一。2.AS患者存在着JMJD3的高度表达和总体H3K27me3甲基化水平的下降,且在疾病不同活动阶段的JMJD3表达水平和H3K27甲基化水平存在明显差异。同时不同疾病活动阶段的患者,其RORc表达、JAK/STAT信号通路活化及IL-17分泌均存在差异。JMJD3调控的H3K27me3去甲基化,可能是干预Th17的分化、活化及功能,从而影响AS炎症及疾病活动机制之一。3.清热利湿活血法对患者的炎症指标及疾病活动都有较好的控制作用,可干预JMJD3的表达水平,以及JMJD3催化的H3K27me3去甲基化活性,从而影响表观遗传调控的Th17分化,使RORc的表达水平和JAK/STAT信号通路的活化水平降低,从而干预了Th17的活化及IL-17的表达。我们推测,清热利湿活血法对AS炎症的缓解作用,可能是通过干预JMJD的活化与功能,从而抑制Th17的分化、活化以及功能而实现的。4.中药单体雷公藤甲素体外干预,可降低AS患者PBMC中JMJD3的表达水平,影响JMJD3调控的H3K27me3去甲基化过程,从而使Th17转录因子RORc、信号通路JAK/STAT及IL-17的转录抑制和蛋白表达被抑制,可能是调节Th17的分化偏移及功能,从而缓解AS炎症的有意义的治疗药物之一。
[Abstract]:BACKGROUND: Ankylosing Spondylitis (AS) is a chronic inflammatory autoimmune disease, which can cause hip joint destruction and spinal rigidity, seriously affect the working ability and self-care ability of patients, and reduce the quality of life of patients. Inflammation is the primary pathological change of AS. The helper T cell (Th17) is the trigger of A. The important effector cells of S inflammation are differentiated from the initial CD4 + T cells. Studies have shown that epigenetic regulation plays an important role in the differentiation of CD4 + T cells into Th17. Histone demethylase JMJD3 catalyzes the demethylation of H3K27 site and may be a key regulator of Th17 differentiation. They found that the method of clearing away heat and dampness and activating blood circulation has a satisfactory clinical effect on alleviating inflammation of AS. After treatment with the prescription of clearing away heat and removing dampness and activating blood circulation, the level of IL-17 expression, the number of Th17 and the expression of RORc, the activation level of JAK/STAT pathway were significantly decreased in AS patients, indicating that the method of clearing away heat and removing dampness and activating blood circulation could be exerted by interfering the differentiation of Th17. Objective: To investigate the expression of JMJD3 and the effect of demethylated H3K27 on the differentiation of Th17 in AS patients. Methods: Study 1, Study 2 and Study 3 were used to detect the expression of JMJD3 and the differentiation of Th17 in the serum and PBMC of AS patients in active phase. The expression of JMJD3 and Th17 mRNA were detected by Western Blotting, Quantitative Real-time PCR and serum inflammatory cytokines were detected by ELISA. Secretion of JMJD3, methylation of H3K27me3 and differentiation of Th17 in AS patients were detected at active stage, relatively stable stage, and three months after treatment with Chinese herbs. Objective:To study the effect of triptolide on the expression of JMJD3, the demethylation of H3K27 catalyzed by JMJD3 and the differentiation of Th17 in AS patients in vitro. Results:1. The expression of Th17 in AS patients in active phase was detected by the analysis of JMJD3 expression. The expression of cytokine IL-17 in heterosexual secretion was significantly higher than that in normal control group (p0.001), and the difference was statistically significant (p0.001); the correlation analysis with inflammatory markers ESR, CRP and disease activity index BASDAI showed that IL-17, ESR and CRP were highly correlated (IL-17-ESR: p0.001; IL-17-CRP: p0.01). The expression of JMJD3 mRNA was significantly higher than that of normal controls (p0.001); JMJD3 was significantly correlated with inflammatory markers ESR and CRP (ESR: r = 0.631, P = 0.0030.01) (CRP: r = 0.567, P = 0.0090.01). JMJD3 was significantly correlated with inflammatory cytokine IL-17 (IL-17: p0.01), but JMJD3, IL-17 were not significantly correlated with BASDAI.2. The expression of JMJD3, H3K27me3, JAK/STAT signaling pathway and characteristic transcription factor RORc protein and mRNA in AS patients (AS-Active), AS-Stable patients (AS-Stable), normal control group (N), and active AS patients were detected. The expression level of JMJD3 mRNA in active AS patients was significantly higher than that in non-active AS patients and normal AS patients (p 0.001), but not in active AS patients (p 0.05). There were significant differences in the expression of JMJD3 mRNA between active and inactive AS patients (p0.001). The methylation level of H3K27me3 in active AS patients was significantly lower than that in normal control group (p0.01). The methylation level of H3K27 in active AS patients and inactive AS patients was also significantly lower than that in normal control group (p0.01). The phosphorylation level of STAT3 in JAK / STAT signaling pathway (pSTAT3 / STAT3) was significantly higher than that in normal controls (AS-Active: p0.001; AS-Stable: p0.01). Compared with non-active patients, the expression level of JAK2 in active AS patients was not significantly different. However, the expression of phosphorylated JAK2 was significantly increased (p=0.0130.05), and the expression of STAT3 protein and phosphorylation were significantly higher than those of inactive AS patients (STAT3:p0.01; pSTAT3:p0.001). At the gene level, the expression of JAK2 and STAT3 mRNA in active AS patients and inactive AS patients were significantly higher than those of normal control group (AS-Active:p0.01). The expression level of RORc in active AS patients and inactive AS patients was significantly higher than that in normal control group (p0.001), while the expression level of RORc in active AS patients was significantly higher than that in inactive AS patients (p0.001). The expression of RORc mRNA was significantly higher in active AS patients and inactive AS patients than in normal control group (p0.01). The expression of JMJD3 and Th17 was also significantly different in active AS patients and inactive AS patients (p0.01). 3. The regulation of heat-clearing, dampness-activating and Blood-Activating Therapy on on JMJD3 expression and Th17 differentiation in active AS patients. In the study of action, we chose Qingre Qiangji Decoction, a clinical effective prescription for active bone arthralgia, to treat AS patients with dampness-heat-stasis syndrome, and detected the activity and function of Th17 cells 3 months after taking the medicine. After treatment, the levels of serum inflammatory cytokine IL-17 were also significantly lower than before treatment (p0.05); JMJD3 protein and mRNA expression and relative gray value changes were significantly different than before treatment (p0.05); H3K27me3 methylation levels in patients were also significantly lower than before treatment (p0.001); The expression of JMJD3 protein in active AS patients treated with triptolide was significantly lower than that before treatment (p0.001). The same result was obtained by gene level detection (p0.001). Dry triptolide was used to treat active AS patients with PBMC. Prognosis, H3K27 methylation level was significantly higher than before treatment, the difference was statistically significant (p0.001); Tripterygium wilfordii intervention H3K27me3 level and normal control group, there was no significant difference (p = 0.080.05). After triptolide intervention, JAK2 / STAT3 signal pathway activation was significantly inhibited, each signal molecule phosphorylated water. At the gene level, JAK2 and STAT3 mRNA expression decreased significantly (p0.001). After triptolide intervention, RORc protein and mRNA expression decreased significantly (p0.001). Conclusion: 1. JMJD3 is an important regulator of Th17 differentiation and function, and participates in the inflammation of active AS. JMJD3 is also closely related to the inflammation index of AS, and may be one of the therapeutic targets for controlling inflammation of AS. 2. There is a high expression of JMJD3 and a decrease of H3K27me3 methylation in AS patients. There are differences in RORc expression, JAK/STAT signaling pathway activation and IL-17 secretion in patients with active disease. H3K27me3 demethylation regulated by JMJD3 may interfere with the differentiation, activation and function of Th17, thus affecting the inflammation and disease activity of AS. 3. Clearing away heat, eliminating dampness and activating blood circulation method has a better effect on inflammatory indexes and disease activity of patients. Controlling effect can interfere with the expression of JMJD3 and the demethylation activity of H3K27me3 catalyzed by JMJD3, thus affecting the Th17 differentiation of epigenetic regulation, reducing the expression of RORc and the activation of JAK/STAT signaling pathway, thus interfering with the activation of Th17 and the expression of IL-17. Mitigation may be achieved by interfering with the activation and function of JMJD, thereby inhibiting the differentiation, activation and function of Th17. 4. Tripterygium Wilfordii in vitro can reduce the expression of JMJD3 in PBMC of AS patients, and affect the H3K27me3 demethylation process regulated by JMJD3, thus making Th17 transcription factor RORc, JAK/STAT signaling pathway. Inhibition of transcriptional and protein expression of IL-17 and IL-17 may be one of the significant therapeutic drugs to alleviate AS inflammation by regulating the differentiation and function of Th17.
【学位授予单位】：中国中医科学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R259
本文编号：2192400
[Abstract]:BACKGROUND: Ankylosing Spondylitis (AS) is a chronic inflammatory autoimmune disease, which can cause hip joint destruction and spinal rigidity, seriously affect the working ability and self-care ability of patients, and reduce the quality of life of patients. Inflammation is the primary pathological change of AS. The helper T cell (Th17) is the trigger of A. The important effector cells of S inflammation are differentiated from the initial CD4 + T cells. Studies have shown that epigenetic regulation plays an important role in the differentiation of CD4 + T cells into Th17. Histone demethylase JMJD3 catalyzes the demethylation of H3K27 site and may be a key regulator of Th17 differentiation. They found that the method of clearing away heat and dampness and activating blood circulation has a satisfactory clinical effect on alleviating inflammation of AS. After treatment with the prescription of clearing away heat and removing dampness and activating blood circulation, the level of IL-17 expression, the number of Th17 and the expression of RORc, the activation level of JAK/STAT pathway were significantly decreased in AS patients, indicating that the method of clearing away heat and removing dampness and activating blood circulation could be exerted by interfering the differentiation of Th17. Objective: To investigate the expression of JMJD3 and the effect of demethylated H3K27 on the differentiation of Th17 in AS patients. Methods: Study 1, Study 2 and Study 3 were used to detect the expression of JMJD3 and the differentiation of Th17 in the serum and PBMC of AS patients in active phase. The expression of JMJD3 and Th17 mRNA were detected by Western Blotting, Quantitative Real-time PCR and serum inflammatory cytokines were detected by ELISA. Secretion of JMJD3, methylation of H3K27me3 and differentiation of Th17 in AS patients were detected at active stage, relatively stable stage, and three months after treatment with Chinese herbs. Objective:To study the effect of triptolide on the expression of JMJD3, the demethylation of H3K27 catalyzed by JMJD3 and the differentiation of Th17 in AS patients in vitro. Results:1. The expression of Th17 in AS patients in active phase was detected by the analysis of JMJD3 expression. The expression of cytokine IL-17 in heterosexual secretion was significantly higher than that in normal control group (p0.001), and the difference was statistically significant (p0.001); the correlation analysis with inflammatory markers ESR, CRP and disease activity index BASDAI showed that IL-17, ESR and CRP were highly correlated (IL-17-ESR: p0.001; IL-17-CRP: p0.01). The expression of JMJD3 mRNA was significantly higher than that of normal controls (p0.001); JMJD3 was significantly correlated with inflammatory markers ESR and CRP (ESR: r = 0.631, P = 0.0030.01) (CRP: r = 0.567, P = 0.0090.01). JMJD3 was significantly correlated with inflammatory cytokine IL-17 (IL-17: p0.01), but JMJD3, IL-17 were not significantly correlated with BASDAI.2. The expression of JMJD3, H3K27me3, JAK/STAT signaling pathway and characteristic transcription factor RORc protein and mRNA in AS patients (AS-Active), AS-Stable patients (AS-Stable), normal control group (N), and active AS patients were detected. The expression level of JMJD3 mRNA in active AS patients was significantly higher than that in non-active AS patients and normal AS patients (p 0.001), but not in active AS patients (p 0.05). There were significant differences in the expression of JMJD3 mRNA between active and inactive AS patients (p0.001). The methylation level of H3K27me3 in active AS patients was significantly lower than that in normal control group (p0.01). The methylation level of H3K27 in active AS patients and inactive AS patients was also significantly lower than that in normal control group (p0.01). The phosphorylation level of STAT3 in JAK / STAT signaling pathway (pSTAT3 / STAT3) was significantly higher than that in normal controls (AS-Active: p0.001; AS-Stable: p0.01). Compared with non-active patients, the expression level of JAK2 in active AS patients was not significantly different. However, the expression of phosphorylated JAK2 was significantly increased (p=0.0130.05), and the expression of STAT3 protein and phosphorylation were significantly higher than those of inactive AS patients (STAT3:p0.01; pSTAT3:p0.001). At the gene level, the expression of JAK2 and STAT3 mRNA in active AS patients and inactive AS patients were significantly higher than those of normal control group (AS-Active:p0.01). The expression level of RORc in active AS patients and inactive AS patients was significantly higher than that in normal control group (p0.001), while the expression level of RORc in active AS patients was significantly higher than that in inactive AS patients (p0.001). The expression of RORc mRNA was significantly higher in active AS patients and inactive AS patients than in normal control group (p0.01). The expression of JMJD3 and Th17 was also significantly different in active AS patients and inactive AS patients (p0.01). 3. The regulation of heat-clearing, dampness-activating and Blood-Activating Therapy on on JMJD3 expression and Th17 differentiation in active AS patients. In the study of action, we chose Qingre Qiangji Decoction, a clinical effective prescription for active bone arthralgia, to treat AS patients with dampness-heat-stasis syndrome, and detected the activity and function of Th17 cells 3 months after taking the medicine. After treatment, the levels of serum inflammatory cytokine IL-17 were also significantly lower than before treatment (p0.05); JMJD3 protein and mRNA expression and relative gray value changes were significantly different than before treatment (p0.05); H3K27me3 methylation levels in patients were also significantly lower than before treatment (p0.001); The expression of JMJD3 protein in active AS patients treated with triptolide was significantly lower than that before treatment (p0.001). The same result was obtained by gene level detection (p0.001). Dry triptolide was used to treat active AS patients with PBMC. Prognosis, H3K27 methylation level was significantly higher than before treatment, the difference was statistically significant (p0.001); Tripterygium wilfordii intervention H3K27me3 level and normal control group, there was no significant difference (p = 0.080.05). After triptolide intervention, JAK2 / STAT3 signal pathway activation was significantly inhibited, each signal molecule phosphorylated water. At the gene level, JAK2 and STAT3 mRNA expression decreased significantly (p0.001). After triptolide intervention, RORc protein and mRNA expression decreased significantly (p0.001). Conclusion: 1. JMJD3 is an important regulator of Th17 differentiation and function, and participates in the inflammation of active AS. JMJD3 is also closely related to the inflammation index of AS, and may be one of the therapeutic targets for controlling inflammation of AS. 2. There is a high expression of JMJD3 and a decrease of H3K27me3 methylation in AS patients. There are differences in RORc expression, JAK/STAT signaling pathway activation and IL-17 secretion in patients with active disease. H3K27me3 demethylation regulated by JMJD3 may interfere with the differentiation, activation and function of Th17, thus affecting the inflammation and disease activity of AS. 3. Clearing away heat, eliminating dampness and activating blood circulation method has a better effect on inflammatory indexes and disease activity of patients. Controlling effect can interfere with the expression of JMJD3 and the demethylation activity of H3K27me3 catalyzed by JMJD3, thus affecting the Th17 differentiation of epigenetic regulation, reducing the expression of RORc and the activation of JAK/STAT signaling pathway, thus interfering with the activation of Th17 and the expression of IL-17. Mitigation may be achieved by interfering with the activation and function of JMJD, thereby inhibiting the differentiation, activation and function of Th17. 4. Tripterygium Wilfordii in vitro can reduce the expression of JMJD3 in PBMC of AS patients, and affect the H3K27me3 demethylation process regulated by JMJD3, thus making Th17 transcription factor RORc, JAK/STAT signaling pathway. Inhibition of transcriptional and protein expression of IL-17 and IL-17 may be one of the significant therapeutic drugs to alleviate AS inflammation by regulating the differentiation and function of Th17.
【学位授予单位】：中国中医科学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R259
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