白细胞介素-17（IL-17）正向调节星形胶质细胞IL-6正反馈表达及其调控机理的研究
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摘要
星形胶质细胞在神经系统的发育、突触传递、神经组织修复与再生、神经免疫等方面都起着十分重要的作用。星形胶质细胞是脑内特化的免疫细胞,具有多种免疫功能：(1)分泌众多产生许多趋化因子和细胞因子如IL-6、IL-1、IL-3、TNF-a和单核细胞趋化活化因子等等,从而参与神经疾病的免疫防御。(2)星形胶质细胞可增加巨噬细胞和小胶质细胞吞噬髓磷脂,诱导小胶质细胞分化。(3)星形胶质细胞表面的MHC-II和B7分子,提呈抗原给CD4+、CD8+ T细胞,促进T细胞增殖。活化的星形胶质细胞表达具有向特异的T细胞亚群递呈脂质抗原的能力,从而提示星形胶质细胞可能参与T细胞非肽抗原的递呈过程。目前认为,星形胶质细胞在免疫系统和神经系统之间起到了重要的桥梁作用。IL-17细胞因子家族包括6个家族成员——IL-17A(即一般意义上的IL-17、IL-17B、IL-17C、IL-17D (IL-27)和IL-17E (IL-25)。Th17细胞通过高表达IL-17,介导炎性反应,防御胞外病原菌的感染；Th17细胞被证实能通过分泌炎症介质IL-17诱导严重的自身免疫反应,参与自身免疫性疾病和移植排斥等的发生和发展；Th17还参与由于肿瘤、外伤和血管性疾病所导致的组织炎症发应,在疾病的不同阶段起到重要作用。Th17的分化受细胞因子水平和转录水平的多种因素的调控,其中TGF-β、IL-6、IL-23和IL-1 p在促进IL-17的分化过程中起到了重要作用。目前已经证实在成纤维细胞中,IL-6不仅可以促进Th17的分化,而且IL-17可以诱导靶细胞表达IL-6。IL-17通过跨胞膜的IL-17受体A(IL-17RA)和IL-17RC组成的异聚体进行信号传递,目前已经发现了多种类型细胞可以表达这两种IL-17受体。许多证据表明IL-17RA和IL-17RC异聚体可以激活NF-κB和MAPK信号传导通路。但是目前关于IL-17在中枢神经系统细胞通路中的研究还很少见。细胞因子信号转导抑制因子(suppressor of cytokine signaling，SOCS)3是SOCS家族成员之一,其中SOCS3是研究最为广泛的一种,是JAK/STAT3信号传导通路的负向调节因子。我们最近发现TGF-β可以抑制IL-6和IL-21诱导的SOCS3的表达,延长CD4+CD25-T细胞内STAT3通路的活化,从而促进Th17的分化,这说明了SOCS3很可能也参与了Th17细胞的分化调节和IL-17的功能。
目前研究的关键在于IL-17在中枢神经系统疾病发生发展过程中的作用及其调控机理,确定IL-17在中枢神经系统的主要靶细胞,将加深我们对IL-17所介导的炎症发应在神经肿瘤、颅脑外伤、脑血管病及自身免疫性疾病作用的认识。本课题主要涉及IL-17对星形胶质细胞的作用及其调控机理,分以下三部分：一、IL-17协同IL-6／R上调星形胶质细胞IL-6表达的研究；二、IL-17正向调节星形胶质细胞IL-6正反馈表达通路作用机理的研究；三、SOCS3负向调控星形胶质细胞IL-17和IL-6的协同作用及其机理的研究。
一、IL-17协同IL-6／R上调星形胶质细胞IL-6表达的研究
目的
验证星形胶质细胞IL-17受体的表达,并明确IL-17协同IL-6／R上调IL-6的表达情况
方法
1、RT-PCR检测星形胶质细胞IL-17RA和IL-17RC的基因表达情况。
2、RT-PCR和TaqMan Realtime-PCR检测不同时间点、不同IL-17浓度、不同IL-6R的浓度和IL-17、IL-6及IL-6R不同组合对IL-6基因表达的影响,并进行统计学分析
3、Elisa检测不同时间点IL-17加IL-6／R对星形胶质细胞IL-6蛋白表达的影响,并进行统计学分析。
结果
1、星形胶质细胞存在有IL-17RA和IL-17RC的基因表达。
2、基因和蛋白水平均证实IL-6可以单独诱导星形胶质细胞IL-6的表达,IL-17单独刺激星形胶质细胞不诱导IL-6,但是IL-6／R和IL-17共同刺激星形胶质细胞可以显著上调IL-6的表达。
结论
1、星形胶质细胞可以表达IL-17RA和IL-17RC,为IL-17潜在的靶细胞。2、IL-6／R诱导星形胶质细胞的IL-6表达,验证了星形胶质细胞内存在IL-6正反馈表达通路。
3、IL-17协同IL-6／R可以诱导星形胶质细胞显著上调IL-6的表达。
二、IL-17正向调节星形胶质细胞IL-6正反馈表达通路调控机理的研究；
目的
研究IL-17对于星形胶质细胞IL-6正反馈表达相关的信号传导通路活性的影响,及信号传导蛋白质与DNA在染色质环境下的相互作用,以阐明其上调IL-6表达的作用机理
方法
1、应用TaqMan Realtime-PCR测定IL-17对IL-6 RNA稳定性的影响。
2、应用Western Blot测定IL-17对IL-6基因表达相关信号传导通路活性的影响。
3、应用NF-κB、ERK MAPK、JNK MAPK和p38 MAPK信号传导通路的抑制剂检测各信号传导通路对IL-6表达的影响。
4、应用染色质免疫共沉淀(Chromatin Immunoprecipitation, ChIP)检测信号传导通路中的磷酸化蛋白与IL-6启动序列的结合情况。
结果
1、与IL-6单独刺激相比,IL-17加IL-6／R能够上调星形胶质细胞NF-κB、ERK MAPK、JNK MAPK和p38 MAPK的活性。
2、与IL-6单独刺激相比,IL-17加IL-6／R对星形胶质细胞IL-6 mRNA稳定性的影响没有显著性差别。
3、NF-κB传导通路抑制剂BAY-11、JNK传导通路抑制剂JNKiⅡ和p38传导通路抑制剂SB203580可以抑制IL-17加IL-6／R对IL-6基因表达的协同作用。
4、IL-17增加IL-6诱导的星形胶质细胞IL-6启动序列对NF-κB p65、c-Fos、c-Jun、CBP、p300和乙酰化的组蛋白H3和H4的募集。
结论
1、IL-17可以协同IL-6诱导星形胶质细胞内NF-κB、ERK MAPK、JNK MAPK和p38 MAPK的激活。
2、IL-17不影响星形胶质细胞IL-6 mRNA的稳定性。
3、IL-17协同IL-6／R上调IL-6的基因表达依赖NF-κB、JNK MAPK和p38MAPK信号传导通路的激活。
3、IL-17和IL-6／R能诱导上调NF-κB p65、c-Fos和c-Jun特异性结合到IL-6启动序列的NF-κB和AP-1绑定位点,且增加IL-6启动序列对NF-κB p65、c-Fos、c-Jun、CBP、p300和乙酰化的组蛋白H3和H4的募集。
三、SOCS3负向调控星形胶质细胞IL-17和IL-6的协同作用及其机理的研究
目的
条件性基因敲除SOCS3和应用siRNA技术沉默SOCS3,并检测基因敲出和基因抑制的效果；检测SOCS3对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用,并明确其作用机制。
方法
1、RT-PCR和TaqMan Realtime-PCR检测不同时间点IL-17加IL-6／R对星形胶质细胞SOCS3基因表达的影响。
2、应用siRNA干扰SOCS3的基因表达,并用RT-PCR和TaqMan Realtime-PCR验证基因干扰效果。
3、RT-PCR、TaqMan Realtime-PCR和Elisa检测siRNA沉默SOCS3对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用。
4、应用SOCS3 flox系统体外敲除星形胶质细胞SOCS基因,提取基因组DNA,验证基因敲除效果。
5、RT-PCR、TaqMan Realtime-PCR和Elisa检测SOCS3基因敲除对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用。
6、应用Western Blot测定SOCS3基因敲除对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用。
结果
1、IL-17协同IL-6／R可以诱导星形胶质细胞显著上调SOCS3的表达。
2、siRNA沉默星形胶质细胞SOCS3基因表达49%。
3、基因水平和蛋白水平证实siRNA沉默SOCS3可以上调IL-17和IL-6／R对IL-6表达的协同作用。
4、SOCS3 flox系统体外敲除SOCS基因效果可达90%以上。
5、基因水平和蛋白水平验证了SOCS3基因敲除上调IL-17和IL-6／R对IL-6表达的协同作用。
6、SOCS3敲除能够上调IL-17和IL-6／R诱导的星形胶质细胞NF-κB、JNK MAPK和p38 MAPK的激活。
结论
1、SOCS3参与IL-17协同IL-6／R上调IL-6的表达过程,并起到负向调控IL-6信号通路的作用,这表明SOCS3作为一个负向调节因子参与IL-17在中枢神经系统的功能调控。
2、SOCS3可以抑制星形胶质细胞NF-κB、JNK MAPK和p38 MAPK的活性,基于前面的研究结果,可以得出SOCS3抑制IL-17协同IL-6／R上调IL-6的表达,是通过抑制NF-κB、JNK MAPK和p38 MAPK的活性来实现的。
总之,目前研究的关键在于IL-17在中枢神经系统疾病发生发展过程中的作用及其调控机理,确定IL-17在中枢神经系统的主要靶细胞,将加深我们对IL-17所介导的炎症发应在神经肿瘤、颅脑外伤、脑血管病及自身免疫性疾病作用的认识。在本课题中,我们验证了星形胶质细胞是IL-17的靶细胞,IL-17可以正向调节IL-6/sIL-6R所诱导信号传导通路的激活及IL-6正反馈表达通路,这种正反馈效应在中枢神经系统免疫中起到了重要的潜在的促炎症作用。SOCS3参与IL-17协同IL-6／R上调IL-6的表达,并起到负向调控IL-6信号通路的作用,这表明SOCS3作为一个负向调节因子参与IL-17在中枢神经系统的功能调控。
Background
Astrocytes are the major glial cell type within the CNS and are critical for CNS homeostasis. Astrocytes regulate neuronal function by releasing neurotrophic factors, guiding neuronal development, contributing to neurotransmitter metabolism, and participating in the formation of the blood-brain-barrier. Astrocytes can serve as a bridge between the CNS and the immune system. In particular, astrocytes produce a wide array of chemokines and cytokines that act as immune mediators in cooperation with those produced by microglia. Aberrant expression of chemokines and cytokines accompanies CNS disorders such as Multiple Sclerosis (MS), Alzheimer's Disease, HIV-1-Associated Dementia, and brain injury/trauma. However, the mechanisms by which astrocytes contribute to these disorders remains unclear.
IL-6 is a regulator of inflammatory and immunological responses and acts on target cells through a receptor complex composed of an IL-6-binding subunit, the IL-6 receptor (IL-6R), and the signal transducing receptor gp130. Initiation of IL-6 signaling occurs when IL-6 binds to the IL-6R, leading to an association with gp130. This leads to activation of gp130-associated Janus Kinases (JAKs), and various signaling pathways such as JAK/STAT, MAPK, and NF-κB. The IL-6R is found in both membrane-bound and soluble (sIL-6R) forms. Astrocytes are the major source of IL-6 in CNS injury and neuroinflammation. We previously determined that the IL-6/sIL-6R complex plays an important role in regulation of IL-6 expression by astrocytes, particularly in conjunction with the proinflammatory cytokines TNF-a and IL-1p.
Th17 cells produce IL-17A (IL-17), IL-17F, IL-21 and IL-22, and are required for the induction of several autoimmune diseases, including collagen-induced arthritis, experimental autoimmune encephalomyelitis (EAE), and inflammatory bowel disease. Th17 cells are generated as a discrete lineage following priming in the presence of TGF-βand IL-6, and expansion in the presence of IL-23 and IL-1β. IL-6 not only functions upstream of IL-17 but also acts as a critical downstream target of IL-17, and IL-17 together with IL-6 triggers a positive-feedback loop of IL-6 expression through the activation of NF-κB and STAT-3 in fibroblasts. IL-17 signals through a heteromeric receptor complex consisting of IL-17 receptor A (IL-17RA) and IL-17RC, which are single-pass transmembrane proteins expressed by a variety of cells. Evidence indicates that NF-κB and MAPK pathways are involved in IL-17RA and IL-17RC signaling, however, little is known about its signaling in cells of the CNS.
Suppressor Of Cytokine Signaling (SOCS) proteins function in a negative feedback loop to terminate signal transduction through the JAK/STAT pathway. One member, SOCS3, is expressed by immune cells and cells of CNS, and regulates inflammatory cytokine and chemokine production, activation of microglia, macrophages and astrocytes, immune cell infiltration and autoimmunity. The predominant function of SOCS3 is inhibition of signaling by the IL-6 family of cytokines. However, SOCS3 exerts a much broader effect on immune responses by inhibiting signaling of additional mediators such as LPS, type I and type II IFNs, IL-2 and IL-12. Furthermore, SOCS3 inhibits the NF-κB pathway, antagonizes cAMP-mediated signaling and enhances signaling through the Ras pathway. We recently found that TGF-βinhibits IL-6-and IL-21-induced SOCS3 expression, thus enhancing as well as prolonging STAT-3 activation in naive CD4+CD25- T cells and promoting Th17 cell development. These results suggest that SOCS3 may participate in the regulation of Th17 cell differentiation and IL-17 functions.
An important question is how IL-17 contributes to autoimmune diseases and/or inflammation in the CNS. Thus, identification of the downstream targets of IL-17 in the CNS should advance our understanding of the mechanisms underlying IL-17-mediated autoimmune diseases. In this study, we demonstrate that astrocytes are a target of IL-17. IL-17 enhances the IL-6/sIL-6R (IL-6/R) signaling cascade and positive-feedback loop of IL-6 expression in astrocytes. SOCS3 participates in the regulation of IL-6/R plus IL-17 enhanced IL-6 expression in astrocytes, and plays an important role in down-regulating the IL-6 signaling cascade, indicating that SOCS3 participates in IL-17 functions in the CNS as a negative feedback regulator.
PartⅠIL-17 Enhances IL-6-induced IL-6 Expression in Primary Astrocytes.
Objective
To investigate whether IL-17RA and IL-17RC genes are expressed in astrocytes, we prepared primary astrocytes and cultured RAW264.7 cells as positive control. To detect the effect of IL-17 on IL-6/sIL-6R-mediated IL-6 expression in primary astrocytes.
Methods
1. IL-17RA and IL-17RC mRNA expression was determined by RT-PCR in RAW264.7 cells (positive control), and primary astrocytes, in duplicate.
2. Primary astrocytes were treated with medium (UN), IL-6, sIL-6R or IL-17 in various combinations for 4 h, and levels of IL-6 mRNA expression were determined by QRT-PCR.
3. Primary astrocytes were treated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 for 2-48 h, and supernatants were analyzed for IL-6 protein using ELISA.
Results
1. IL-17RA and IL-17RC mRNA was expressed in both astrocytes and RAW264.7 cells.
2. IL-17 enhances IL-6/R-induced IL-6 expression at the mRNA levels in astrocytes.
3. Added with IL-6/R, the expression of IL-6 protein was significantly enhanced at all time points
Conclusion
1. Astrocytes are a target of Th17 cells and IL-17 in the CNS
2. IL-17 enhances IL-6-induced IL-6 expression in primary astrocytes.
Part II Investigation of the Mechanism on IL-17 Enhancement of IL-6-induced IL-6 Expression in Primary Astrocytes.
Objective
To study the transfection efficiency of SIM2-s siRNA in T98G and U251 cell lines. To detect the silencing potency of SIM2-s siRNA in T98G and U251 cell lines. To detect the effect of silencing SIM2-s expression in GBM cell proliferation and invasion.
Methods
1. Astrocytes were incubated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 for 15 and 30 min, and then cell lysates were immunoblotted with antibodies.
2. Astrocytes were cultured in absence or presence of IL-17 followed by IL-6/R treatment for 4 h. Actinomycin D (5 ng/ml) was then added, and cells harvested at 0, 30,60,120, and 240 min after addition. The abundance of IL-6 mRNA was determined by QRT-PCR.
3. BAY 11 (5μM), U0126 (10μM), SB203580 (10μM) or JNKi II (10μM) were added to cultures 1 h before cytokine addition, and then astrocytes were incubated with medium, IL-6/R, IL-17 or IL-6/R plus IL-17 for 4 h. Levels of IL-6 mRNA expression were determined by QRT-PCR.
4. Primary astrocytes were treated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 and then cells were cross-linked with formaldehyde. Soluble chromatin was subjected to immunoprecipitation with Abs against p65, P-p65, c-Fos, c-Jun, histone acetylation (Ac-H3 and Ac-H4), p300, CBP, RNA Pol II or normal rabbit IgG
Results
1. IL-17 effect is not mediated by stabilization of IL-6 mRNA.
2. IL-17 alone induces activation of the NF-κB, ERK1/2 and p38 pathways, and synergizes with IL-6/R for enhancement of NF-κB, ERK1/2, p38 and JNK signaling.
3. The NF-κB pathway inhibitor BAY11, JNK MAPK inhibitor II, and p38 MAPK inhibitor SB203580 suppressed the synergistic effect of IL-6 and IL-17 on IL-6 mRNA induction.
4. IL-6/R plus IL-17 enhance phospho-p65, c-Jun, c-Fos, RNA Pol II, and the coactivators CBP and p300 to the IL-6 promoter and modification of H3 and H4 acetylation recruitment to initiate transcription of the IL-6 gene.
Conclusion
1. The synergetic effect of IL-17 and IL-6 on IL-6 gene expression involved numerous signaling pathways including NF-κB, JNK MAPK and p38 MAPK.
2. IL-17 synergizes with IL-6 to enhance the recruitment of activated NF-κB p65, c-Fos, c-Jun, and the histone acetyltransferases CBP, p300 and RNA Pol II to the IL-6 promoter to induce transcription of IL-6 in astrocytes. This was accompanied by enhanced acetylation of Histones H3 and H4 on the IL-6 promoter.
PartⅢSOCS3 is a Negative Regulator of the Synergistic Effect of IL-6/R and IL-17.
Objective
To detect the effect of SOCS3 in the regulation of synergistic effect of IL-6/R and IL-17 and valuate NF-κB and MAPK activation in the absence or presence of SOCS3 to investigate the mechanism of the regulation.
Methods
1. Astrocytes were transfected with SOCS3 siRNA (100 nM) or siRNA control (100 nM) for 48 h. Transfected cells were then treated with medium (UN) or IL-6/R plus IL-17 for 4 h. Levels of SOCS3 and IL-6 mRNA expression was determined by QRT-PCR and supernatants analyzed for IL-6 protein by ELISA
2. SOCS3 floxed astrocytes were infected with GFP as control or GFP-Cre for deletion. After 48 h in culture, the cells were treated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 for 4 h, and levels of IL-6 mRNA expression determined by QRT-PCR and supernatants analyzed for IL-6 protein by ELISA
3. SOCS3 floxed astrocytes were infected with GFP as control or GFP-Cre for deletion. After 48 h in culture, cells were treated with medium (UN) or IL-6/R plus IL-17, and then cell lysates were immunoblotted with antibodies against phospho-p65 Ser 536, p65, phospho-p38, p38, phospho-JNK, JNK or GAPDH.
Results
1. SOCS3 mRNA induced by IL-6/R plus IL-17 was inhibited approximately 49% by siSOCS3. SOCS3 mRNA expression indicated more than 90% removal of SOCS3 in GFP-Cre infected SOCS3 floxed astrocytes compared with GFP infected SOCS3 floxed astrocytes at each treatment conditions
1. In the GFP-Cre infected SOCS3 flox astrocytes, we observed a highly increase of IL-6 expression in all conditions including treatment of medium (UN), IL-6/R, IL-17 or IL-6/R and IL-17, and the enhanced of IL-6 expression still existed in sIL-6R plus IL-17 treatment compared to sIL-6R or IL-17 alone
2. The expression of IL-6 protein was dramatically increased in SOCS3 knockout astrocytes compared to the GFP infected cells in the treatment of medium (UN), IL-6 with SIL-6R, IL-17 or IL-6 with sIL-6R and IL-17.
3. Activation of the NF-κB, p38 and JNK MAPK pathways pathway following exposure to IL-6/R plus IL-17 is enhanced in GFP-Cre infected SOCS3 flox astrocytes.
Conclusion
SOCS3 siRNA knockdown and SOCS3 deletion in astrocytes enhances the synergistic effect of IL-6 and IL-17 on IL-6 gene expression, which is due to an enhancement of activation of the NF-κB and MAPK pathways.
目前研究的关键在于IL-17在中枢神经系统疾病发生发展过程中的作用及其调控机理,确定IL-17在中枢神经系统的主要靶细胞,将加深我们对IL-17所介导的炎症发应在神经肿瘤、颅脑外伤、脑血管病及自身免疫性疾病作用的认识。本课题主要涉及IL-17对星形胶质细胞的作用及其调控机理,分以下三部分：一、IL-17协同IL-6／R上调星形胶质细胞IL-6表达的研究；二、IL-17正向调节星形胶质细胞IL-6正反馈表达通路作用机理的研究；三、SOCS3负向调控星形胶质细胞IL-17和IL-6的协同作用及其机理的研究。
一、IL-17协同IL-6／R上调星形胶质细胞IL-6表达的研究
目的
验证星形胶质细胞IL-17受体的表达,并明确IL-17协同IL-6／R上调IL-6的表达情况
方法
1、RT-PCR检测星形胶质细胞IL-17RA和IL-17RC的基因表达情况。
2、RT-PCR和TaqMan Realtime-PCR检测不同时间点、不同IL-17浓度、不同IL-6R的浓度和IL-17、IL-6及IL-6R不同组合对IL-6基因表达的影响,并进行统计学分析
3、Elisa检测不同时间点IL-17加IL-6／R对星形胶质细胞IL-6蛋白表达的影响,并进行统计学分析。
结果
1、星形胶质细胞存在有IL-17RA和IL-17RC的基因表达。
2、基因和蛋白水平均证实IL-6可以单独诱导星形胶质细胞IL-6的表达,IL-17单独刺激星形胶质细胞不诱导IL-6,但是IL-6／R和IL-17共同刺激星形胶质细胞可以显著上调IL-6的表达。
结论
1、星形胶质细胞可以表达IL-17RA和IL-17RC,为IL-17潜在的靶细胞。2、IL-6／R诱导星形胶质细胞的IL-6表达,验证了星形胶质细胞内存在IL-6正反馈表达通路。
3、IL-17协同IL-6／R可以诱导星形胶质细胞显著上调IL-6的表达。
二、IL-17正向调节星形胶质细胞IL-6正反馈表达通路调控机理的研究；
目的
研究IL-17对于星形胶质细胞IL-6正反馈表达相关的信号传导通路活性的影响,及信号传导蛋白质与DNA在染色质环境下的相互作用,以阐明其上调IL-6表达的作用机理
方法
1、应用TaqMan Realtime-PCR测定IL-17对IL-6 RNA稳定性的影响。
2、应用Western Blot测定IL-17对IL-6基因表达相关信号传导通路活性的影响。
3、应用NF-κB、ERK MAPK、JNK MAPK和p38 MAPK信号传导通路的抑制剂检测各信号传导通路对IL-6表达的影响。
4、应用染色质免疫共沉淀(Chromatin Immunoprecipitation, ChIP)检测信号传导通路中的磷酸化蛋白与IL-6启动序列的结合情况。
结果
1、与IL-6单独刺激相比,IL-17加IL-6／R能够上调星形胶质细胞NF-κB、ERK MAPK、JNK MAPK和p38 MAPK的活性。
2、与IL-6单独刺激相比,IL-17加IL-6／R对星形胶质细胞IL-6 mRNA稳定性的影响没有显著性差别。
3、NF-κB传导通路抑制剂BAY-11、JNK传导通路抑制剂JNKiⅡ和p38传导通路抑制剂SB203580可以抑制IL-17加IL-6／R对IL-6基因表达的协同作用。
4、IL-17增加IL-6诱导的星形胶质细胞IL-6启动序列对NF-κB p65、c-Fos、c-Jun、CBP、p300和乙酰化的组蛋白H3和H4的募集。
结论
1、IL-17可以协同IL-6诱导星形胶质细胞内NF-κB、ERK MAPK、JNK MAPK和p38 MAPK的激活。
2、IL-17不影响星形胶质细胞IL-6 mRNA的稳定性。
3、IL-17协同IL-6／R上调IL-6的基因表达依赖NF-κB、JNK MAPK和p38MAPK信号传导通路的激活。
3、IL-17和IL-6／R能诱导上调NF-κB p65、c-Fos和c-Jun特异性结合到IL-6启动序列的NF-κB和AP-1绑定位点,且增加IL-6启动序列对NF-κB p65、c-Fos、c-Jun、CBP、p300和乙酰化的组蛋白H3和H4的募集。
三、SOCS3负向调控星形胶质细胞IL-17和IL-6的协同作用及其机理的研究
目的
条件性基因敲除SOCS3和应用siRNA技术沉默SOCS3,并检测基因敲出和基因抑制的效果；检测SOCS3对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用,并明确其作用机制。
方法
1、RT-PCR和TaqMan Realtime-PCR检测不同时间点IL-17加IL-6／R对星形胶质细胞SOCS3基因表达的影响。
2、应用siRNA干扰SOCS3的基因表达,并用RT-PCR和TaqMan Realtime-PCR验证基因干扰效果。
3、RT-PCR、TaqMan Realtime-PCR和Elisa检测siRNA沉默SOCS3对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用。
4、应用SOCS3 flox系统体外敲除星形胶质细胞SOCS基因,提取基因组DNA,验证基因敲除效果。
5、RT-PCR、TaqMan Realtime-PCR和Elisa检测SOCS3基因敲除对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用。
6、应用Western Blot测定SOCS3基因敲除对IL-17和IL-6／R协同诱导IL-6基因表达的调控作用。
结果
1、IL-17协同IL-6／R可以诱导星形胶质细胞显著上调SOCS3的表达。
2、siRNA沉默星形胶质细胞SOCS3基因表达49%。
3、基因水平和蛋白水平证实siRNA沉默SOCS3可以上调IL-17和IL-6／R对IL-6表达的协同作用。
4、SOCS3 flox系统体外敲除SOCS基因效果可达90%以上。
5、基因水平和蛋白水平验证了SOCS3基因敲除上调IL-17和IL-6／R对IL-6表达的协同作用。
6、SOCS3敲除能够上调IL-17和IL-6／R诱导的星形胶质细胞NF-κB、JNK MAPK和p38 MAPK的激活。
结论
1、SOCS3参与IL-17协同IL-6／R上调IL-6的表达过程,并起到负向调控IL-6信号通路的作用,这表明SOCS3作为一个负向调节因子参与IL-17在中枢神经系统的功能调控。
2、SOCS3可以抑制星形胶质细胞NF-κB、JNK MAPK和p38 MAPK的活性,基于前面的研究结果,可以得出SOCS3抑制IL-17协同IL-6／R上调IL-6的表达,是通过抑制NF-κB、JNK MAPK和p38 MAPK的活性来实现的。
总之,目前研究的关键在于IL-17在中枢神经系统疾病发生发展过程中的作用及其调控机理,确定IL-17在中枢神经系统的主要靶细胞,将加深我们对IL-17所介导的炎症发应在神经肿瘤、颅脑外伤、脑血管病及自身免疫性疾病作用的认识。在本课题中,我们验证了星形胶质细胞是IL-17的靶细胞,IL-17可以正向调节IL-6/sIL-6R所诱导信号传导通路的激活及IL-6正反馈表达通路,这种正反馈效应在中枢神经系统免疫中起到了重要的潜在的促炎症作用。SOCS3参与IL-17协同IL-6／R上调IL-6的表达,并起到负向调控IL-6信号通路的作用,这表明SOCS3作为一个负向调节因子参与IL-17在中枢神经系统的功能调控。
Background
Astrocytes are the major glial cell type within the CNS and are critical for CNS homeostasis. Astrocytes regulate neuronal function by releasing neurotrophic factors, guiding neuronal development, contributing to neurotransmitter metabolism, and participating in the formation of the blood-brain-barrier. Astrocytes can serve as a bridge between the CNS and the immune system. In particular, astrocytes produce a wide array of chemokines and cytokines that act as immune mediators in cooperation with those produced by microglia. Aberrant expression of chemokines and cytokines accompanies CNS disorders such as Multiple Sclerosis (MS), Alzheimer's Disease, HIV-1-Associated Dementia, and brain injury/trauma. However, the mechanisms by which astrocytes contribute to these disorders remains unclear.
IL-6 is a regulator of inflammatory and immunological responses and acts on target cells through a receptor complex composed of an IL-6-binding subunit, the IL-6 receptor (IL-6R), and the signal transducing receptor gp130. Initiation of IL-6 signaling occurs when IL-6 binds to the IL-6R, leading to an association with gp130. This leads to activation of gp130-associated Janus Kinases (JAKs), and various signaling pathways such as JAK/STAT, MAPK, and NF-κB. The IL-6R is found in both membrane-bound and soluble (sIL-6R) forms. Astrocytes are the major source of IL-6 in CNS injury and neuroinflammation. We previously determined that the IL-6/sIL-6R complex plays an important role in regulation of IL-6 expression by astrocytes, particularly in conjunction with the proinflammatory cytokines TNF-a and IL-1p.
Th17 cells produce IL-17A (IL-17), IL-17F, IL-21 and IL-22, and are required for the induction of several autoimmune diseases, including collagen-induced arthritis, experimental autoimmune encephalomyelitis (EAE), and inflammatory bowel disease. Th17 cells are generated as a discrete lineage following priming in the presence of TGF-βand IL-6, and expansion in the presence of IL-23 and IL-1β. IL-6 not only functions upstream of IL-17 but also acts as a critical downstream target of IL-17, and IL-17 together with IL-6 triggers a positive-feedback loop of IL-6 expression through the activation of NF-κB and STAT-3 in fibroblasts. IL-17 signals through a heteromeric receptor complex consisting of IL-17 receptor A (IL-17RA) and IL-17RC, which are single-pass transmembrane proteins expressed by a variety of cells. Evidence indicates that NF-κB and MAPK pathways are involved in IL-17RA and IL-17RC signaling, however, little is known about its signaling in cells of the CNS.
Suppressor Of Cytokine Signaling (SOCS) proteins function in a negative feedback loop to terminate signal transduction through the JAK/STAT pathway. One member, SOCS3, is expressed by immune cells and cells of CNS, and regulates inflammatory cytokine and chemokine production, activation of microglia, macrophages and astrocytes, immune cell infiltration and autoimmunity. The predominant function of SOCS3 is inhibition of signaling by the IL-6 family of cytokines. However, SOCS3 exerts a much broader effect on immune responses by inhibiting signaling of additional mediators such as LPS, type I and type II IFNs, IL-2 and IL-12. Furthermore, SOCS3 inhibits the NF-κB pathway, antagonizes cAMP-mediated signaling and enhances signaling through the Ras pathway. We recently found that TGF-βinhibits IL-6-and IL-21-induced SOCS3 expression, thus enhancing as well as prolonging STAT-3 activation in naive CD4+CD25- T cells and promoting Th17 cell development. These results suggest that SOCS3 may participate in the regulation of Th17 cell differentiation and IL-17 functions.
An important question is how IL-17 contributes to autoimmune diseases and/or inflammation in the CNS. Thus, identification of the downstream targets of IL-17 in the CNS should advance our understanding of the mechanisms underlying IL-17-mediated autoimmune diseases. In this study, we demonstrate that astrocytes are a target of IL-17. IL-17 enhances the IL-6/sIL-6R (IL-6/R) signaling cascade and positive-feedback loop of IL-6 expression in astrocytes. SOCS3 participates in the regulation of IL-6/R plus IL-17 enhanced IL-6 expression in astrocytes, and plays an important role in down-regulating the IL-6 signaling cascade, indicating that SOCS3 participates in IL-17 functions in the CNS as a negative feedback regulator.
PartⅠIL-17 Enhances IL-6-induced IL-6 Expression in Primary Astrocytes.
Objective
To investigate whether IL-17RA and IL-17RC genes are expressed in astrocytes, we prepared primary astrocytes and cultured RAW264.7 cells as positive control. To detect the effect of IL-17 on IL-6/sIL-6R-mediated IL-6 expression in primary astrocytes.
Methods
1. IL-17RA and IL-17RC mRNA expression was determined by RT-PCR in RAW264.7 cells (positive control), and primary astrocytes, in duplicate.
2. Primary astrocytes were treated with medium (UN), IL-6, sIL-6R or IL-17 in various combinations for 4 h, and levels of IL-6 mRNA expression were determined by QRT-PCR.
3. Primary astrocytes were treated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 for 2-48 h, and supernatants were analyzed for IL-6 protein using ELISA.
Results
1. IL-17RA and IL-17RC mRNA was expressed in both astrocytes and RAW264.7 cells.
2. IL-17 enhances IL-6/R-induced IL-6 expression at the mRNA levels in astrocytes.
3. Added with IL-6/R, the expression of IL-6 protein was significantly enhanced at all time points
Conclusion
1. Astrocytes are a target of Th17 cells and IL-17 in the CNS
2. IL-17 enhances IL-6-induced IL-6 expression in primary astrocytes.
Part II Investigation of the Mechanism on IL-17 Enhancement of IL-6-induced IL-6 Expression in Primary Astrocytes.
Objective
To study the transfection efficiency of SIM2-s siRNA in T98G and U251 cell lines. To detect the silencing potency of SIM2-s siRNA in T98G and U251 cell lines. To detect the effect of silencing SIM2-s expression in GBM cell proliferation and invasion.
Methods
1. Astrocytes were incubated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 for 15 and 30 min, and then cell lysates were immunoblotted with antibodies.
2. Astrocytes were cultured in absence or presence of IL-17 followed by IL-6/R treatment for 4 h. Actinomycin D (5 ng/ml) was then added, and cells harvested at 0, 30,60,120, and 240 min after addition. The abundance of IL-6 mRNA was determined by QRT-PCR.
3. BAY 11 (5μM), U0126 (10μM), SB203580 (10μM) or JNKi II (10μM) were added to cultures 1 h before cytokine addition, and then astrocytes were incubated with medium, IL-6/R, IL-17 or IL-6/R plus IL-17 for 4 h. Levels of IL-6 mRNA expression were determined by QRT-PCR.
4. Primary astrocytes were treated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 and then cells were cross-linked with formaldehyde. Soluble chromatin was subjected to immunoprecipitation with Abs against p65, P-p65, c-Fos, c-Jun, histone acetylation (Ac-H3 and Ac-H4), p300, CBP, RNA Pol II or normal rabbit IgG
Results
1. IL-17 effect is not mediated by stabilization of IL-6 mRNA.
2. IL-17 alone induces activation of the NF-κB, ERK1/2 and p38 pathways, and synergizes with IL-6/R for enhancement of NF-κB, ERK1/2, p38 and JNK signaling.
3. The NF-κB pathway inhibitor BAY11, JNK MAPK inhibitor II, and p38 MAPK inhibitor SB203580 suppressed the synergistic effect of IL-6 and IL-17 on IL-6 mRNA induction.
4. IL-6/R plus IL-17 enhance phospho-p65, c-Jun, c-Fos, RNA Pol II, and the coactivators CBP and p300 to the IL-6 promoter and modification of H3 and H4 acetylation recruitment to initiate transcription of the IL-6 gene.
Conclusion
1. The synergetic effect of IL-17 and IL-6 on IL-6 gene expression involved numerous signaling pathways including NF-κB, JNK MAPK and p38 MAPK.
2. IL-17 synergizes with IL-6 to enhance the recruitment of activated NF-κB p65, c-Fos, c-Jun, and the histone acetyltransferases CBP, p300 and RNA Pol II to the IL-6 promoter to induce transcription of IL-6 in astrocytes. This was accompanied by enhanced acetylation of Histones H3 and H4 on the IL-6 promoter.
PartⅢSOCS3 is a Negative Regulator of the Synergistic Effect of IL-6/R and IL-17.
Objective
To detect the effect of SOCS3 in the regulation of synergistic effect of IL-6/R and IL-17 and valuate NF-κB and MAPK activation in the absence or presence of SOCS3 to investigate the mechanism of the regulation.
Methods
1. Astrocytes were transfected with SOCS3 siRNA (100 nM) or siRNA control (100 nM) for 48 h. Transfected cells were then treated with medium (UN) or IL-6/R plus IL-17 for 4 h. Levels of SOCS3 and IL-6 mRNA expression was determined by QRT-PCR and supernatants analyzed for IL-6 protein by ELISA
2. SOCS3 floxed astrocytes were infected with GFP as control or GFP-Cre for deletion. After 48 h in culture, the cells were treated with medium (UN), IL-6/R, IL-17 or IL-6/R plus IL-17 for 4 h, and levels of IL-6 mRNA expression determined by QRT-PCR and supernatants analyzed for IL-6 protein by ELISA
3. SOCS3 floxed astrocytes were infected with GFP as control or GFP-Cre for deletion. After 48 h in culture, cells were treated with medium (UN) or IL-6/R plus IL-17, and then cell lysates were immunoblotted with antibodies against phospho-p65 Ser 536, p65, phospho-p38, p38, phospho-JNK, JNK or GAPDH.
Results
1. SOCS3 mRNA induced by IL-6/R plus IL-17 was inhibited approximately 49% by siSOCS3. SOCS3 mRNA expression indicated more than 90% removal of SOCS3 in GFP-Cre infected SOCS3 floxed astrocytes compared with GFP infected SOCS3 floxed astrocytes at each treatment conditions
1. In the GFP-Cre infected SOCS3 flox astrocytes, we observed a highly increase of IL-6 expression in all conditions including treatment of medium (UN), IL-6/R, IL-17 or IL-6/R and IL-17, and the enhanced of IL-6 expression still existed in sIL-6R plus IL-17 treatment compared to sIL-6R or IL-17 alone
2. The expression of IL-6 protein was dramatically increased in SOCS3 knockout astrocytes compared to the GFP infected cells in the treatment of medium (UN), IL-6 with SIL-6R, IL-17 or IL-6 with sIL-6R and IL-17.
3. Activation of the NF-κB, p38 and JNK MAPK pathways pathway following exposure to IL-6/R plus IL-17 is enhanced in GFP-Cre infected SOCS3 flox astrocytes.
Conclusion
SOCS3 siRNA knockdown and SOCS3 deletion in astrocytes enhances the synergistic effect of IL-6 and IL-17 on IL-6 gene expression, which is due to an enhancement of activation of the NF-κB and MAPK pathways.
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