25D3和1,25D3介导胸腺基质淋巴细胞生成素在人支气管上皮细胞中的表达
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摘要
前言
支气管哮喘是一种气道慢性炎症性疾病,它和气道的炎性细胞和结构细胞以及细胞因子等有关。1990年,我国儿科哮喘协作组对27个省市0-14岁儿童进行调查,显示我国儿童哮喘的患病率为0.09%-2.60%,平均0.91%。2000年再次调查结果为0.12%～3.34%,平均1.54%,较10年前平均上升了64.84%。哮喘使很多患者日常生活受到不同程度的影响,据WHO估计,全球由于哮喘导致的调整伤残生命年数量估计达到1500万,约占全球总医疗负担的1%。由哮喘所带来的经济负担无论从住院和药品使用等直接医疗费用还是误工及非正常死亡等造成的间接非医疗费用都相当大。尽管多种新的治疗措施和方法已经在临床证实了确切的疗效,但是还有很多的问题需要解决。一方面很多的治疗并没有触及哮喘的根本,不能起到逆转治疗的效果。另一方面一些治疗手段还有不同的副作用,有的还需要不断地进行药物监测,给患者造成了极大的不便。因此,不断探索研究出更新的更有效的治疗手段是当前迫切的方向,其中从支气管哮喘病因这个源头去发现和探讨疾病的治疗方法或许是一个不错的选择。
新的证据显示,维生素D不足可以引起包括哮喘在内的多种肺部疾病,这有可能是与肺功能受损而导致了感染和炎症的发生率增加有关。这种现象的内部机制尚不清楚,但是维生素D会影响炎症和结构细胞的功能,包括淋巴细胞、树突状细胞、单核细胞和上皮细胞。羟化酶负责终止和限制25羟基维生素D3(25-hydroxyvitamin D3,25D3)以循环和储存的形式活化合成1,25二羟基维生素D3(l,25-hydroxyvitamin D3,1,25D3)。2008年,Hansdottir等报道了呼吸道上皮细胞表达1α-羟化酶,后者可以将维生素D活化,而维生素D本身会影响其驱使基因的表达水平,并在机体内发挥着重要的防御作用。1a-羟化酶在呼吸道上皮细胞中的表达表明维生素D在呼吸系统疾病中起着很普遍的影响。
呼吸道上皮细胞不仅是物理屏障,也可以分泌细胞因子,例如发挥免疫应答作用的胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin, TSLP)。TSLP是一种白介素-7(interleukin-7,IL-7)类似的新型细胞因子,TSLP作为肺内的一种多效性的细胞因子,在变应性炎症和哮喘中起着重要的作用。最近的研究已经着眼于TSLP产生机制,这有助于我们阐明TSLP如何支气管哮喘发生和发展中起作用的。现已证实,哮喘中存在TSLP基因在呼吸道上皮细胞中的过表达,TSLP在过敏反应免疫应答的发生和发展中起着重要的作用。在SCC25(human oral squamous carcinoma cell, SCC25,人上皮肿瘤细胞,由鳞状细胞癌衍生而来)中,TSLP的表达是由1,25D3诱导的。另有证据显示,局部应用1,25D3可以诱导小鼠表皮角质形成细胞中TSLP的表达使其增加。然而,维生素D是否会影响TSLP在人支气管上皮细胞(human bronchial epithelial, HBE)这一特定的细胞中表达尚不清楚。
维生素D3上调蛋白(vitamin D3upregulated protein1,VDUP1)是硫氧还原蛋白的内源性抑制剂,它和维生素D发挥作用密切相关。VDUP1最初被认为是经由1,25D。处理过的白血病细胞(human promyelocytic leukemia cells, HL-60cells)的差异表达基因。该蛋白定位于胞质,在多种细胞反应中发挥着多种作用。最近的研究证实,VDUP1可以介导血管内皮生长因子(VEGF)和白细胞介素1β信号转导通路。然而,VDUP1在支气管上皮细胞中的表达及其在这个细胞中的活化参与也鲜有人知。
本研究旨在利用16-HBE细胞证实维生素D是否增强了TSLP在该细胞中的表达,以及在此过程中是否有VDUP1的参与,为探明支气管哮喘发生机制和治疗提供参考。
材料和方法
细胞培养和处理、转染
16-HBE支气管上皮细胞在MEM培养基中培养,辅以10%胎牛血清,5%C02,37℃恒温潮湿培养箱培养。细胞培养至少两天(70%-80%融合),在刺激前分别用与不用25D3和1,25D3预处理6h后,给予1000nM伊曲康唑刺激2h。
VDUP1靶向小干扰RNA (SiRNA)序列如下SiRNA1:上游5'-GUCAGAGGCAAUCAUAUUATT-3',下游5'-UAAUAUGAUUGCCUCUGACT G-3'; SiRNA2:上游5'-CUGUGAAGGUGA UGAUAUUTT-31,下游5'-AAU CUCAUCACCUUCACAGTT-3';SiRNA3:上游5'-GAAACAAAUAUGAGUACAATT-3’,下游5'-UUGUACUCAUAUUUGUUU CCA-3'; Negative control (NO:上游5'-UUCUCCGAACGUGUCACGUTT-3',下游5'-ACGUGACACGUUCGGAGA ATT-3'=16-HBE细胞置于12孔培养板中培养两天,调整细胞浓度至每孔1.2×105个。待细胞融合40%-60%时,用5nM VDUP1特异性SiRNA和HiPerFect转染试剂对照SiRNA进行转染。以MTT法测定细胞活力。经转染的细胞另培养48h,用500nM的25D3和50nM的1,25D3分别刺激6h。
使用1,25D3的酶联免疫测定试剂盒进行1,25D3定量
RNA的分离提纯和RT-PCR以RT-PCR技术分析基因的表达和Mx3005p实时定量PCR (qPCR)系统进行分析。提取总RNA后,用RNA iso PLUS试剂盒。用Prime ScriptTM的RT试剂盒将RNA合成为500ng cDNA。该定量RT-PCR反映混合物中含有1*SYBR与ExTaq预混物、200nM正向和反向引物,并在25μL终体积中加入2μL的cDNA。使用的引物分别为：人TSLP(上游：5'-GCCCAGGCTATTCGGA AAC-3',下游：5'-GAAGCGACG CCACAATCC-3'), VDUP1(上游：5'-ACTCGTGTCAAAGCCGTTAGGA-3',下游5'-AGCTCAAAGCCGAACT TGTACTCA-31),β-actin(上游：5'-GTGGACATCCGCAAAGAC-3',下游：5'-GAAAGGGTGTAACGC AACT-3')。通过CT(循环阈值：每个反应管内的荧光信号达到所设定的阈值时,所经历的反应循环数)值来计算mRNA的相对表达水平。以β-actin为内参来进行RNA定量。
Western Blot分析细胞用PBS洗涤三次,在O℃裂解液中裂解。用Bradford蛋白测定法测蛋白质浓度。以10%SDS聚丙酰胺凝胶(每泳道40mg蛋白)电泳,转膜至PVDF膜。以5%脱脂奶的TBST液室温封闭1h,兔抗人VDUP1多克隆抗体4℃孵育过夜。TBST洗膜(3×15min),1:5000辣根过氧化物酶孵育,室温抗兔IgG二抗孵育1h。Super ECL系统经由X线检测蛋白质信号。
TSLP的酶联免疫吸附试验(ELISA)上清液中通过ELISA法检测(Bradford总蛋白标准化定量)测定TSLP。最低检测检测水平为31.25pg/mL
统计方法数据采用(平均值±标准差)表示。组间差异用单因素方差分析法；以Bonferroni法进行多重比较。用单侧或双侧t检验单独比较两组间差异。P<0.05示有统计学差异。
结果
1、25D3诱导16-HBE细胞TSLP的表达
不同浓度的25D3(50-1000nM)处理后,16-HBE细胞的细胞活力没有受到任何影响。根据剂量-效应曲线,TSLP的mRNA水平在25D3的100nM浓度时显著增加。并且随着25D3的浓度增力P,TSLP的nRNA水平不断增加,在500nM处达到峰值。因此,500nM浓度被选做后续实验。时间-反应结果表明(刺激条件：500nM25D3,持续2-24h)TSLP的mRNA表达和蛋白质的水平显著上调。
2、25D3诱导16-HBE细胞VDUP1的表达
25D3刺激0.5-24h后,细胞内VDUP1的mRNA和蛋白质的表达水平。结果表明,与对照组相比,500nM25D3刺激2-24h后,细胞内VDUP1的mRNA表达和蛋白质表达水平显著上调。
3、下调VDUP1的蛋白表达
针对VDUP1合成了三种siRNA (siRNA1和siRNA2, siRNA3)(详见材料与方法)。从转染的siRNA2或siRNA3的细胞裂解液中发现VDUP1水平降低。这种现象在siRNA3中更加明显,与对照组相比,VDUP1的表达减少了35%,VDUP1siRNA3被选做后续实验。
4、VDUP1的沉默降低了在16-HBE细胞中25D3介导的TSLP的合成
采用VDUP1siRNA来抑制16-HBE细胞中VDUP1的表达。用siRNA转染的细胞存活率大于90%。在同样浓度D3(500nM)刺激下,经siRNA处理后的VDUP1沉默的细胞,其TSLP的mRNA和蛋白表达水平都有显著降低。
5、la-羟化酶抑制后限制了16-HBE细胞中25D3活化为1,25D3,并且减弱了TSLP的表达
25D3存在时,16-HBE细胞可以不经任何刺激的情况下,将25D3活化为1,25D3。经1000nM伊曲康唑预处理的16-HBE细胞,25D3活化为1,25D3的能力显著降低。在1000nM伊曲康唑预处理后,由25D3介导的TSLP的mRNA和蛋白水平显著降低。
6、VDUP1的沉默降低了16-HBE细胞中1,25D3介导的TSLP的表达水平
不同浓度的1,25D3(0.1-100nM)中,16-HBE细胞活力没有变化。根据剂量-效应曲线,1,25D3在0.1nM处,TSLP的nRNA和蛋白水平显著增加,并在50nM处达到峰值。而当同样在50nM浓度的1,25D3时,TSLP的mRNA和蛋白质的表达水平在2h时显著增加,并在12h处达到峰值。50nM浓度的1,25D3刺激6h后,测得、/DUP1的mRNA的表达水平。结果表明,在16-HBE细胞中,与对照组相比,在50nM终浓度的1,25D3刺激6h后,VDUP1的mRNA的表达显著上调。与对照组siRNA处理过的细胞相比,经由50nM浓度的1,25D3处理后的细胞,当VDUP1基因沉默表达时,其TSLP的mRNA和蛋白水平显著降低。以上结果显示,在16-HBE细胞中,1,25D3是经由VDUP1通路介导TSLP的表达。
7、1a-羟化酶的抑制对在16-HBE细胞中1,25D3诱导的TSLP表达水平没有明显的影响
1000nM的伊曲康唑预处理16-HBE细胞,仍然会有1,25D3介导生成TSLP。这进一步支持了16-HBE细胞在维生素D活化并介导TSLP表达通路中,1α-羟化酶并未发挥作用。
结论
1、非活化的25D3和活化的1,25D3都可以介导16-HBE细胞中TSLP的表达；
2、1α-羟化酶经伊曲康唑抑制后,部分抑制了25D3(而不是1,25D3)的TSLP在16-HBE细胞中的表达；
3、与25D3相比,极低浓度的1,25D3更能显著增加TSLP在气道上皮细胞中的表达；
4、维生素D对TSLP基因表达的影响是间接的。
Introduction
Bronchial asthma is a chronic inflammatory disease in airways, which are related to airway inflammatory cells, cell structure and cytokines. In1990, the collaborative group of pediatric asthma investigated children aged0to14from27provinces, showing a prevalence of asthma in children of0.09%-2.60%, with an average0.91percent. In2000, the prevalence was surveyed again and found it was increased to0.12%-3.34%, with an average of1.54%, comparing with the result10years ago, the average increase rate was64.84%. Many patients are suffered from asthma in different ways in their daily life. According to WHO, in the world the number of disability years is estimated to reach15million due to the asthma, which accounting for about1%of the total global health burden. Economic burden brought about by the asthma hospitalization and drug use in terms of direct medical costs, such as lost income and non-normal or death caused by indirect non-medical costs are quite large. Although the number of new treatments and methods have been confirmed in clinical treatments, but there are many problems need to be solved. On the one hand, a lot of treatment did not manage the root of asthma, some showed various reversal effects. On the other hand there are a number of different side effects of treatment, and some also need to continue to monitor the drug concentration of patients, which caused great inconvenience. Therefore, explore more effective means to treat is still urgent, discover and explore the way asthma occurred may be a nice choice.
Emerging evidence indicates that vitamin D insufficiency is associated with several lung diseases, including asthma and chronic obstructive pulmonary disease (COPD), which may be associated with impaired pulmonary function, and the increased incidence of inflammation and infection. The exact underlying mechanisms are unknown; however, vitamin D appears to affect the function of inflammatory and structural cells, including lymphocytes, dendritic cells, monocytes and epithelial cells, la-hydroxylase is responsible for the final and rate-limiting step in the synthesis of active1,25-dihydroxyvitamin D3(1,25D3) from the circulating or storage form,25-hydroxyvitamin D3(25D3).In2008, Hansdottir et al reported that airway epithelial cells express la-hydroxylase and are able to convert vitamin D from an inactive form into an active one, and that vitamin D affects the expression of vitamin D-driven genes that play a major role in host defense. The expression of la-hydroxylase in airway epithelial cells suggests a broader role of vitamin D in respiratory diseases.
Airway epithelial cells are not only physical barriers to invaders, but also produce cytokines, such as thymic stromal lymphopoietin (TSLP) in response to allergens. Thymic stromal lymphopoietin (TSLP) is a novel interleukin-7(IL-7) similar cytokines, which plays important roles in allergic inflammation and asthma as a pleiotropic cytokine in lungs. Recent research has focused on TSLP production mechanism, which helps us to clarify how TSLP bronchial asthma and development works. The overexpression of the TSLP gene in airway epithelial cells has been shown to lead to asthma and TSLP has been suggested to play an important role in the initiation and maintenance of the allergic immune response. TSLP expression has been shown tobe induced by1,25D3in SCC25human epithelial tumor cells (derived from a tongue squamous cell carcinoma). It has also been demonstrated that the topical application of1,25D3leads to the induction of TSLP expression in mouse epidermal keratinocytes. However, whether vitamin D affects the expression of TSLP in human bronchial epithelial (HBE) cells remains unresolved.
Vitamin D3upregulated protein1(VDUP1) is an endogenous inhibitor of thioredoxin. VDUP1was originally identifi ed as a differentially expressed gene in1,25D3-treated HL-60leukemia cells. It is cytoplasmically located and has been shown to play a multifunctional role in a variety of cellular responses. Recently, VDUP1has been shown to play a role in vascular endothelial growth factor (VEGF)-and interleukin-1β-mediated signal transduction pathways. However, little is known about the expression of VDUP1in bronchial epithelial cells and its involvement in the activation of these cells.
In this study, to determine whether vitamin D enhances the expression of TSLP in airway epithelial cells and whether VDUP1is involved in this process,16-HBE cells were used. This SV40large T antigen-transformed bronchial epithelial cell line is widely used for the investigation of the functional properties of bronchial epithelial cells. The results from this study demonstrate that TSLP expression can be manipulated by both inactive and active vitamin D via the VDUP1pathway, therefore suggesting a novel mechanism by which vitamin D regulates immune function in the lungs.
Materials and methods
Cell culture, treatment and transfection.16-HBE bronchial epithelial cells were cultured in MEM growth medium supplemented with10%fetal calf serum and maintained at37℃in a humidifi ed incubator in the presence of5%CO2. Cells were cultured for at least2days prior to stimulation with25D3and1,25D3for6h with or without pre-treatment with1,000nM itraconazole for2h.
The sequence of the VDUP1-targeting small interfering RNA (siRNA) was as follows:siRNA1sense,5'-GUCAGAGG CAAUCAUAUUATT-3'and antisense,5'-UAAUAUGAUUG CCUCUGACTG-31; siRNA2sense,5'-CUGUGAAGGUGA UGAUAUUTT-3'and antisense,5'-AAUCUCAUCACCUUC ACAGTT-3'; siRNA3sense,5'-GAAACAAAUAUGAGUACAATT-3'andantisense,5'-UUGUACUCAUAUUUGUUU CCA-3';and negative control (NO)sense, 5'-UUCUCCGAAC GUGUCACGUTT-3'and antisense,5'-ACGUGACACGUU CGGAGAATT-3'. The16-HBE cells were seeded at a density of1.2x105cells/well in12-well culture plates and cultured for2days. Cells that were40-60%confluent, were transfected with5nM VDUP1-specific siRNA or control siRNA using the HiPerFect transfection reagent. The viability of the cells was determined by MTT assay. The transfected cells were cultured for an additional48h and then stimulated with500nM25D3and50nM1,25D3for6h.
Quantitative determination of1,25D3.1,25D3was quantifi ed using an enzyme immunoassay kit for1,25D3.
RNA isolation and real-time polymerase chain reaction (PCR). Gene expression was analyzed by real-time RT-PCR using SYBR(?) Premix Ex TaqTM and the Mx3005p real-time qPCR system. Total RNA was extracted with RNAisoPLUS following the manufacturer's instructions and cDNA was synthesized from500ng of RNA using the PrimeScriptTM RT kit. The qRT-PCR reaction mixture contained1X SYBR Premix Ex Taq,200nM forward and reverse primers and2μl cDNA in a fi nal volume of25μ1. The primers used were:human TSLP (forward,5'-GCCC AGGCTATTCGGAAAC-31and reverse,5'-GAAGCGACG CCACAATCC-31) VDUP1(forward,5'-ACTCGTGTCAAAG CCGTTAGGA-3'and reverse,5'-AGCTCAAAGCCGAACTT GTACTCA-31) and β-actin (forward,5'-GTGGACATCCGC AAAGAC-3'and reverse,5'-GAAAGGGTGTAACGC AACT-3'). The cycle threshold (Ct) values were used to calculate the relative expression levels of the messenger RNA (mRNA). The expression levels of all genes were normalized to the expression of a reference gene (β-actin)
Western blot analysis. The cells were washed3times with phosphate-buffered saline (PBS) and disrupted in ice-cold lysis buffer (20mM Tris,20mM P-glycerophosphate,150mM NaCl,3mM EDTA,3mM EGTA,1mM Na3VO4,0.5%Nonidet P-40and1mM dithiothreitol). The protein concentration of the lysates was determined using the Bradford protein assay was separated on a10%SDS-polyacrylamide gel and transferred onto a PVDF membrane. The membrane was blocked with5%skim milk in Tris-buffered saline with Tween-20(TBST)(50mM Tris-HCl, pH7.5,150mM NaCl and0.05%Tween-20) for1h at room temperature and then incubated overnight with rabbit anti-human VDUP1polyclonal antibody1:600at4℃. The membrane was washed with TBST (3x15-min washes) and incubated in anti-rabbit IgG secondary antibody conjugated with horseradish peroxidase1:5,000for1h at room temperature. Protein signal was detected using the SuperECL system and detected by radiography. The immunoreactive bands were visualized using a Kodak2000M camera. An anti-GAPDH goat polyclonal antibody was used to confirm equal loading.
TSLP enzyme-linked immunosorbent assay (ELISA). TSLP in culture supernatants were detected by ELISA and the data were normalized to the total protein amounts in the samples, as determined by Bradford assay. The minimal detectable level of TSLP was31.25pg/ml.
Statistical analysis. Data are presented as the means±SEM. Differences among multiple groups were assessed for statistical signifi cance by one-way analysis of variance; Bonferroni's method was used for multiple comparisons. When2groups were being compared we used a one-or two-tailed Student's t-test depending on the hypothesis in question. A P-value<0.05was considered to indicate a statistically significant difference.
Results
1.25D3induces TSLP expression in16-HBE cells.
To determine whether inactive25D3affects TSLP expression in airway epithelial cells, we first investigated the effects of25D3on the viability of16-HBE cells. We found no loss in cell viability when the16-HBE cells were stimulated with various concentrations of25D3(50-1,000nM). Based on our concentration-response curve, TSLP mRNA levels significantly increased at concentrations of100nM and peaked at concentrations500nM25D3. Therefore, we used the concentration of500nM in the subsequent experiments. The time-response results revealed that TSLP mRNA and protein levels were significantly upregulated in the cells stimulated with500nM25D3for2to24h.
2.25D3induces VDUP1expression in16-HBE cells. The mRNA and protein expression of VDUP1following treatment with25D3from0.5to24h were determined. The results indicated that VDUP1mRNA and protein expression was significantly upregulated in the16-HBE cells treated with500nM25D3for2to24h when compared with the untreated cells.
3.VDUP1silencing by RNAi.
To determine the biological function of VDUP1, its expression was silenced by RNA interference. Three RNA duplexes (siRNA1, siRNA2and siRNA3) directed against VDUP1were synthesized (see Materials and methods). Extracts prepared from the cells transfected with either the siRNA2or siRNA3duplex showed reduced VDUP1levels. This effect was more pronounced with the use of siRNA3, wherein VDUP1expression was<35%of the control. siRNAl and siRNA2reduced VDUP1expression to40-80%of the control. Therefore, we selected VDUP1siRNA3in the subsequent experiments.
4. Silencing of VDUP1decreases25D3-induced TSLP production in16-HBE cells.
To elucidate the mechanism behind the25D3-induced TSLP production, we investigated whether VDUP1is involved in this process. We used VDUP1siRNA3to suppress VDUP1expression in the16-HBE cells. The viability of the cells was>90%in the siRNA-transfected cells. We observed a significantly lower level of TSLP mRNA and protein expression in the VDUP1-silenced cells when compared with the control siRNA-treated cells following treatment with500nM25D3.
5. Inhibition of la-hydroxylase blocks the conversion of25D3to1,25D3andattenuates the upregulation of TSLP expression in16-HBE cells.
To determine the effect of1,25D3, the16-HBE cells were first treated with increasing concentrations of25D3, and the levels of1,25D3in the supernatants were measured after24h. Consistent with a previous study, our results indicated that the16-HBE cells converted25D3to1,25D3when exposed to25D3without other stimuli. To further link the enzymatic machinery expressed by16-HBE cells to the1, 25D3generation and induction of TSLP expression, we used a chemical inhibitor of la-hydroxylase, itraconazole. Pre-treatment of the16-HBE cells with itraconazole (1,000nM) significantly reduced their ability to convert25D3to1,25D3. We then examined the effects of itraconazole on the induction of TSLP by25D3. The results revealed that in the presence of itraconazole (1,000nM), there was a signifi cantly lower production of TSLP mRNA and protein by25D3. These results indicate that in the presence of itraconazole, less25D3is being converted to1,25D3, resulting in a reduced production of TSLP.
6. VDUP1silencing decreases1,25D3-induced TSLP expression in16-HBE cells.
To further investigate the effect of active vitamin D on TSLP expression in airway epithelial cells, we directly used1,25D3as the stimulator. We found no loss in cellviability when the16-HBE cells were stimulated with various concentrations of1,25D3(0.1to100nM). Based on the concentration-response curve, TSLP mRNA and protein levels significantly increased at0.1nM, and peaked at concentrations of50nM1,25D3. The levels of TSLP mRNA and protein expression significantly increased at2h and peaked at12h in the cells exposed to50nM1,25D3. To determine the role of VDUP1in this process, we examined the mRNA expression level of VDUP1at the same time following treatment with50nM1,25D3for6h and VDUP1was also manipulated via the siRNA-mediated silencing of VDUP1. The results revealed that VDUP1mRNA expression was significantly upregulated in the16-HBE cells treated with50nM1,25D3for6h when compared with the untreated cells. In comparison with the control siRNA-treated cells, following treatment with50nM1,25D3, we observed a significantly lower level of TSLP mRNA and protein in the cells in which VDUP1was silenced. These results suggest that the VDUP1pathway is involved in the1,25D3-induced TSLP expression in16-HBE cells.
7. Inhibition of1α-hydroxylase exerts no effects on1,25D3-induced TSLP expression in16-HBE cells.
To confirm the specificity of the TSLP production induced by1,25D3, we treated the cells with itraconazole, as well as1,25D3. We found that in the presence of itraconazole (1,000nM), a similar induction of TSLP by1,25D3was obsevered. This further supports our primary hypothesis that1αhydroxylase converts inactive vitamin D to active vitamin D and induces TSLP expression in16-HBE cells.
Conclusion
1. Both inactive25D3and active1,25D3induce TSLP expression in16-HBE cells;
2. The inhibition of1α-hydroxylase by itraconazole partially suppresses the25D3-but not the1,25D3-induced TSLP expression in16-HBE cells.
3.0.1nM1,25D3significantly increased the expression of TSLP in airway epithelial cells, not25D3;
4. The effect of vitamin D on TSLP gene expression may be an indirect effect.
支气管哮喘是一种气道慢性炎症性疾病,它和气道的炎性细胞和结构细胞以及细胞因子等有关。1990年,我国儿科哮喘协作组对27个省市0-14岁儿童进行调查,显示我国儿童哮喘的患病率为0.09%-2.60%,平均0.91%。2000年再次调查结果为0.12%～3.34%,平均1.54%,较10年前平均上升了64.84%。哮喘使很多患者日常生活受到不同程度的影响,据WHO估计,全球由于哮喘导致的调整伤残生命年数量估计达到1500万,约占全球总医疗负担的1%。由哮喘所带来的经济负担无论从住院和药品使用等直接医疗费用还是误工及非正常死亡等造成的间接非医疗费用都相当大。尽管多种新的治疗措施和方法已经在临床证实了确切的疗效,但是还有很多的问题需要解决。一方面很多的治疗并没有触及哮喘的根本,不能起到逆转治疗的效果。另一方面一些治疗手段还有不同的副作用,有的还需要不断地进行药物监测,给患者造成了极大的不便。因此,不断探索研究出更新的更有效的治疗手段是当前迫切的方向,其中从支气管哮喘病因这个源头去发现和探讨疾病的治疗方法或许是一个不错的选择。
新的证据显示,维生素D不足可以引起包括哮喘在内的多种肺部疾病,这有可能是与肺功能受损而导致了感染和炎症的发生率增加有关。这种现象的内部机制尚不清楚,但是维生素D会影响炎症和结构细胞的功能,包括淋巴细胞、树突状细胞、单核细胞和上皮细胞。羟化酶负责终止和限制25羟基维生素D3(25-hydroxyvitamin D3,25D3)以循环和储存的形式活化合成1,25二羟基维生素D3(l,25-hydroxyvitamin D3,1,25D3)。2008年,Hansdottir等报道了呼吸道上皮细胞表达1α-羟化酶,后者可以将维生素D活化,而维生素D本身会影响其驱使基因的表达水平,并在机体内发挥着重要的防御作用。1a-羟化酶在呼吸道上皮细胞中的表达表明维生素D在呼吸系统疾病中起着很普遍的影响。
呼吸道上皮细胞不仅是物理屏障,也可以分泌细胞因子,例如发挥免疫应答作用的胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin, TSLP)。TSLP是一种白介素-7(interleukin-7,IL-7)类似的新型细胞因子,TSLP作为肺内的一种多效性的细胞因子,在变应性炎症和哮喘中起着重要的作用。最近的研究已经着眼于TSLP产生机制,这有助于我们阐明TSLP如何支气管哮喘发生和发展中起作用的。现已证实,哮喘中存在TSLP基因在呼吸道上皮细胞中的过表达,TSLP在过敏反应免疫应答的发生和发展中起着重要的作用。在SCC25(human oral squamous carcinoma cell, SCC25,人上皮肿瘤细胞,由鳞状细胞癌衍生而来)中,TSLP的表达是由1,25D3诱导的。另有证据显示,局部应用1,25D3可以诱导小鼠表皮角质形成细胞中TSLP的表达使其增加。然而,维生素D是否会影响TSLP在人支气管上皮细胞(human bronchial epithelial, HBE)这一特定的细胞中表达尚不清楚。
维生素D3上调蛋白(vitamin D3upregulated protein1,VDUP1)是硫氧还原蛋白的内源性抑制剂,它和维生素D发挥作用密切相关。VDUP1最初被认为是经由1,25D。处理过的白血病细胞(human promyelocytic leukemia cells, HL-60cells)的差异表达基因。该蛋白定位于胞质,在多种细胞反应中发挥着多种作用。最近的研究证实,VDUP1可以介导血管内皮生长因子(VEGF)和白细胞介素1β信号转导通路。然而,VDUP1在支气管上皮细胞中的表达及其在这个细胞中的活化参与也鲜有人知。
本研究旨在利用16-HBE细胞证实维生素D是否增强了TSLP在该细胞中的表达,以及在此过程中是否有VDUP1的参与,为探明支气管哮喘发生机制和治疗提供参考。
材料和方法
细胞培养和处理、转染
16-HBE支气管上皮细胞在MEM培养基中培养,辅以10%胎牛血清,5%C02,37℃恒温潮湿培养箱培养。细胞培养至少两天(70%-80%融合),在刺激前分别用与不用25D3和1,25D3预处理6h后,给予1000nM伊曲康唑刺激2h。
VDUP1靶向小干扰RNA (SiRNA)序列如下SiRNA1:上游5'-GUCAGAGGCAAUCAUAUUATT-3',下游5'-UAAUAUGAUUGCCUCUGACT G-3'; SiRNA2:上游5'-CUGUGAAGGUGA UGAUAUUTT-31,下游5'-AAU CUCAUCACCUUCACAGTT-3';SiRNA3:上游5'-GAAACAAAUAUGAGUACAATT-3’,下游5'-UUGUACUCAUAUUUGUUU CCA-3'; Negative control (NO:上游5'-UUCUCCGAACGUGUCACGUTT-3',下游5'-ACGUGACACGUUCGGAGA ATT-3'=16-HBE细胞置于12孔培养板中培养两天,调整细胞浓度至每孔1.2×105个。待细胞融合40%-60%时,用5nM VDUP1特异性SiRNA和HiPerFect转染试剂对照SiRNA进行转染。以MTT法测定细胞活力。经转染的细胞另培养48h,用500nM的25D3和50nM的1,25D3分别刺激6h。
使用1,25D3的酶联免疫测定试剂盒进行1,25D3定量
RNA的分离提纯和RT-PCR以RT-PCR技术分析基因的表达和Mx3005p实时定量PCR (qPCR)系统进行分析。提取总RNA后,用RNA iso PLUS试剂盒。用Prime ScriptTM的RT试剂盒将RNA合成为500ng cDNA。该定量RT-PCR反映混合物中含有1*SYBR与ExTaq预混物、200nM正向和反向引物,并在25μL终体积中加入2μL的cDNA。使用的引物分别为：人TSLP(上游：5'-GCCCAGGCTATTCGGA AAC-3',下游：5'-GAAGCGACG CCACAATCC-3'), VDUP1(上游：5'-ACTCGTGTCAAAGCCGTTAGGA-3',下游5'-AGCTCAAAGCCGAACT TGTACTCA-31),β-actin(上游：5'-GTGGACATCCGCAAAGAC-3',下游：5'-GAAAGGGTGTAACGC AACT-3')。通过CT(循环阈值：每个反应管内的荧光信号达到所设定的阈值时,所经历的反应循环数)值来计算mRNA的相对表达水平。以β-actin为内参来进行RNA定量。
Western Blot分析细胞用PBS洗涤三次,在O℃裂解液中裂解。用Bradford蛋白测定法测蛋白质浓度。以10%SDS聚丙酰胺凝胶(每泳道40mg蛋白)电泳,转膜至PVDF膜。以5%脱脂奶的TBST液室温封闭1h,兔抗人VDUP1多克隆抗体4℃孵育过夜。TBST洗膜(3×15min),1:5000辣根过氧化物酶孵育,室温抗兔IgG二抗孵育1h。Super ECL系统经由X线检测蛋白质信号。
TSLP的酶联免疫吸附试验(ELISA)上清液中通过ELISA法检测(Bradford总蛋白标准化定量)测定TSLP。最低检测检测水平为31.25pg/mL
统计方法数据采用(平均值±标准差)表示。组间差异用单因素方差分析法；以Bonferroni法进行多重比较。用单侧或双侧t检验单独比较两组间差异。P<0.05示有统计学差异。
结果
1、25D3诱导16-HBE细胞TSLP的表达
不同浓度的25D3(50-1000nM)处理后,16-HBE细胞的细胞活力没有受到任何影响。根据剂量-效应曲线,TSLP的mRNA水平在25D3的100nM浓度时显著增加。并且随着25D3的浓度增力P,TSLP的nRNA水平不断增加,在500nM处达到峰值。因此,500nM浓度被选做后续实验。时间-反应结果表明(刺激条件：500nM25D3,持续2-24h)TSLP的mRNA表达和蛋白质的水平显著上调。
2、25D3诱导16-HBE细胞VDUP1的表达
25D3刺激0.5-24h后,细胞内VDUP1的mRNA和蛋白质的表达水平。结果表明,与对照组相比,500nM25D3刺激2-24h后,细胞内VDUP1的mRNA表达和蛋白质表达水平显著上调。
3、下调VDUP1的蛋白表达
针对VDUP1合成了三种siRNA (siRNA1和siRNA2, siRNA3)(详见材料与方法)。从转染的siRNA2或siRNA3的细胞裂解液中发现VDUP1水平降低。这种现象在siRNA3中更加明显,与对照组相比,VDUP1的表达减少了35%,VDUP1siRNA3被选做后续实验。
4、VDUP1的沉默降低了在16-HBE细胞中25D3介导的TSLP的合成
采用VDUP1siRNA来抑制16-HBE细胞中VDUP1的表达。用siRNA转染的细胞存活率大于90%。在同样浓度D3(500nM)刺激下,经siRNA处理后的VDUP1沉默的细胞,其TSLP的mRNA和蛋白表达水平都有显著降低。
5、la-羟化酶抑制后限制了16-HBE细胞中25D3活化为1,25D3,并且减弱了TSLP的表达
25D3存在时,16-HBE细胞可以不经任何刺激的情况下,将25D3活化为1,25D3。经1000nM伊曲康唑预处理的16-HBE细胞,25D3活化为1,25D3的能力显著降低。在1000nM伊曲康唑预处理后,由25D3介导的TSLP的mRNA和蛋白水平显著降低。
6、VDUP1的沉默降低了16-HBE细胞中1,25D3介导的TSLP的表达水平
不同浓度的1,25D3(0.1-100nM)中,16-HBE细胞活力没有变化。根据剂量-效应曲线,1,25D3在0.1nM处,TSLP的nRNA和蛋白水平显著增加,并在50nM处达到峰值。而当同样在50nM浓度的1,25D3时,TSLP的mRNA和蛋白质的表达水平在2h时显著增加,并在12h处达到峰值。50nM浓度的1,25D3刺激6h后,测得、/DUP1的mRNA的表达水平。结果表明,在16-HBE细胞中,与对照组相比,在50nM终浓度的1,25D3刺激6h后,VDUP1的mRNA的表达显著上调。与对照组siRNA处理过的细胞相比,经由50nM浓度的1,25D3处理后的细胞,当VDUP1基因沉默表达时,其TSLP的mRNA和蛋白水平显著降低。以上结果显示,在16-HBE细胞中,1,25D3是经由VDUP1通路介导TSLP的表达。
7、1a-羟化酶的抑制对在16-HBE细胞中1,25D3诱导的TSLP表达水平没有明显的影响
1000nM的伊曲康唑预处理16-HBE细胞,仍然会有1,25D3介导生成TSLP。这进一步支持了16-HBE细胞在维生素D活化并介导TSLP表达通路中,1α-羟化酶并未发挥作用。
结论
1、非活化的25D3和活化的1,25D3都可以介导16-HBE细胞中TSLP的表达；
2、1α-羟化酶经伊曲康唑抑制后,部分抑制了25D3(而不是1,25D3)的TSLP在16-HBE细胞中的表达；
3、与25D3相比,极低浓度的1,25D3更能显著增加TSLP在气道上皮细胞中的表达；
4、维生素D对TSLP基因表达的影响是间接的。
Introduction
Bronchial asthma is a chronic inflammatory disease in airways, which are related to airway inflammatory cells, cell structure and cytokines. In1990, the collaborative group of pediatric asthma investigated children aged0to14from27provinces, showing a prevalence of asthma in children of0.09%-2.60%, with an average0.91percent. In2000, the prevalence was surveyed again and found it was increased to0.12%-3.34%, with an average of1.54%, comparing with the result10years ago, the average increase rate was64.84%. Many patients are suffered from asthma in different ways in their daily life. According to WHO, in the world the number of disability years is estimated to reach15million due to the asthma, which accounting for about1%of the total global health burden. Economic burden brought about by the asthma hospitalization and drug use in terms of direct medical costs, such as lost income and non-normal or death caused by indirect non-medical costs are quite large. Although the number of new treatments and methods have been confirmed in clinical treatments, but there are many problems need to be solved. On the one hand, a lot of treatment did not manage the root of asthma, some showed various reversal effects. On the other hand there are a number of different side effects of treatment, and some also need to continue to monitor the drug concentration of patients, which caused great inconvenience. Therefore, explore more effective means to treat is still urgent, discover and explore the way asthma occurred may be a nice choice.
Emerging evidence indicates that vitamin D insufficiency is associated with several lung diseases, including asthma and chronic obstructive pulmonary disease (COPD), which may be associated with impaired pulmonary function, and the increased incidence of inflammation and infection. The exact underlying mechanisms are unknown; however, vitamin D appears to affect the function of inflammatory and structural cells, including lymphocytes, dendritic cells, monocytes and epithelial cells, la-hydroxylase is responsible for the final and rate-limiting step in the synthesis of active1,25-dihydroxyvitamin D3(1,25D3) from the circulating or storage form,25-hydroxyvitamin D3(25D3).In2008, Hansdottir et al reported that airway epithelial cells express la-hydroxylase and are able to convert vitamin D from an inactive form into an active one, and that vitamin D affects the expression of vitamin D-driven genes that play a major role in host defense. The expression of la-hydroxylase in airway epithelial cells suggests a broader role of vitamin D in respiratory diseases.
Airway epithelial cells are not only physical barriers to invaders, but also produce cytokines, such as thymic stromal lymphopoietin (TSLP) in response to allergens. Thymic stromal lymphopoietin (TSLP) is a novel interleukin-7(IL-7) similar cytokines, which plays important roles in allergic inflammation and asthma as a pleiotropic cytokine in lungs. Recent research has focused on TSLP production mechanism, which helps us to clarify how TSLP bronchial asthma and development works. The overexpression of the TSLP gene in airway epithelial cells has been shown to lead to asthma and TSLP has been suggested to play an important role in the initiation and maintenance of the allergic immune response. TSLP expression has been shown tobe induced by1,25D3in SCC25human epithelial tumor cells (derived from a tongue squamous cell carcinoma). It has also been demonstrated that the topical application of1,25D3leads to the induction of TSLP expression in mouse epidermal keratinocytes. However, whether vitamin D affects the expression of TSLP in human bronchial epithelial (HBE) cells remains unresolved.
Vitamin D3upregulated protein1(VDUP1) is an endogenous inhibitor of thioredoxin. VDUP1was originally identifi ed as a differentially expressed gene in1,25D3-treated HL-60leukemia cells. It is cytoplasmically located and has been shown to play a multifunctional role in a variety of cellular responses. Recently, VDUP1has been shown to play a role in vascular endothelial growth factor (VEGF)-and interleukin-1β-mediated signal transduction pathways. However, little is known about the expression of VDUP1in bronchial epithelial cells and its involvement in the activation of these cells.
In this study, to determine whether vitamin D enhances the expression of TSLP in airway epithelial cells and whether VDUP1is involved in this process,16-HBE cells were used. This SV40large T antigen-transformed bronchial epithelial cell line is widely used for the investigation of the functional properties of bronchial epithelial cells. The results from this study demonstrate that TSLP expression can be manipulated by both inactive and active vitamin D via the VDUP1pathway, therefore suggesting a novel mechanism by which vitamin D regulates immune function in the lungs.
Materials and methods
Cell culture, treatment and transfection.16-HBE bronchial epithelial cells were cultured in MEM growth medium supplemented with10%fetal calf serum and maintained at37℃in a humidifi ed incubator in the presence of5%CO2. Cells were cultured for at least2days prior to stimulation with25D3and1,25D3for6h with or without pre-treatment with1,000nM itraconazole for2h.
The sequence of the VDUP1-targeting small interfering RNA (siRNA) was as follows:siRNA1sense,5'-GUCAGAGG CAAUCAUAUUATT-3'and antisense,5'-UAAUAUGAUUG CCUCUGACTG-31; siRNA2sense,5'-CUGUGAAGGUGA UGAUAUUTT-3'and antisense,5'-AAUCUCAUCACCUUC ACAGTT-3'; siRNA3sense,5'-GAAACAAAUAUGAGUACAATT-3'andantisense,5'-UUGUACUCAUAUUUGUUU CCA-3';and negative control (NO)sense, 5'-UUCUCCGAAC GUGUCACGUTT-3'and antisense,5'-ACGUGACACGUU CGGAGAATT-3'. The16-HBE cells were seeded at a density of1.2x105cells/well in12-well culture plates and cultured for2days. Cells that were40-60%confluent, were transfected with5nM VDUP1-specific siRNA or control siRNA using the HiPerFect transfection reagent. The viability of the cells was determined by MTT assay. The transfected cells were cultured for an additional48h and then stimulated with500nM25D3and50nM1,25D3for6h.
Quantitative determination of1,25D3.1,25D3was quantifi ed using an enzyme immunoassay kit for1,25D3.
RNA isolation and real-time polymerase chain reaction (PCR). Gene expression was analyzed by real-time RT-PCR using SYBR(?) Premix Ex TaqTM and the Mx3005p real-time qPCR system. Total RNA was extracted with RNAisoPLUS following the manufacturer's instructions and cDNA was synthesized from500ng of RNA using the PrimeScriptTM RT kit. The qRT-PCR reaction mixture contained1X SYBR Premix Ex Taq,200nM forward and reverse primers and2μl cDNA in a fi nal volume of25μ1. The primers used were:human TSLP (forward,5'-GCCC AGGCTATTCGGAAAC-31and reverse,5'-GAAGCGACG CCACAATCC-31) VDUP1(forward,5'-ACTCGTGTCAAAG CCGTTAGGA-3'and reverse,5'-AGCTCAAAGCCGAACTT GTACTCA-31) and β-actin (forward,5'-GTGGACATCCGC AAAGAC-3'and reverse,5'-GAAAGGGTGTAACGC AACT-3'). The cycle threshold (Ct) values were used to calculate the relative expression levels of the messenger RNA (mRNA). The expression levels of all genes were normalized to the expression of a reference gene (β-actin)
Western blot analysis. The cells were washed3times with phosphate-buffered saline (PBS) and disrupted in ice-cold lysis buffer (20mM Tris,20mM P-glycerophosphate,150mM NaCl,3mM EDTA,3mM EGTA,1mM Na3VO4,0.5%Nonidet P-40and1mM dithiothreitol). The protein concentration of the lysates was determined using the Bradford protein assay was separated on a10%SDS-polyacrylamide gel and transferred onto a PVDF membrane. The membrane was blocked with5%skim milk in Tris-buffered saline with Tween-20(TBST)(50mM Tris-HCl, pH7.5,150mM NaCl and0.05%Tween-20) for1h at room temperature and then incubated overnight with rabbit anti-human VDUP1polyclonal antibody1:600at4℃. The membrane was washed with TBST (3x15-min washes) and incubated in anti-rabbit IgG secondary antibody conjugated with horseradish peroxidase1:5,000for1h at room temperature. Protein signal was detected using the SuperECL system and detected by radiography. The immunoreactive bands were visualized using a Kodak2000M camera. An anti-GAPDH goat polyclonal antibody was used to confirm equal loading.
TSLP enzyme-linked immunosorbent assay (ELISA). TSLP in culture supernatants were detected by ELISA and the data were normalized to the total protein amounts in the samples, as determined by Bradford assay. The minimal detectable level of TSLP was31.25pg/ml.
Statistical analysis. Data are presented as the means±SEM. Differences among multiple groups were assessed for statistical signifi cance by one-way analysis of variance; Bonferroni's method was used for multiple comparisons. When2groups were being compared we used a one-or two-tailed Student's t-test depending on the hypothesis in question. A P-value<0.05was considered to indicate a statistically significant difference.
Results
1.25D3induces TSLP expression in16-HBE cells.
To determine whether inactive25D3affects TSLP expression in airway epithelial cells, we first investigated the effects of25D3on the viability of16-HBE cells. We found no loss in cell viability when the16-HBE cells were stimulated with various concentrations of25D3(50-1,000nM). Based on our concentration-response curve, TSLP mRNA levels significantly increased at concentrations of100nM and peaked at concentrations500nM25D3. Therefore, we used the concentration of500nM in the subsequent experiments. The time-response results revealed that TSLP mRNA and protein levels were significantly upregulated in the cells stimulated with500nM25D3for2to24h.
2.25D3induces VDUP1expression in16-HBE cells. The mRNA and protein expression of VDUP1following treatment with25D3from0.5to24h were determined. The results indicated that VDUP1mRNA and protein expression was significantly upregulated in the16-HBE cells treated with500nM25D3for2to24h when compared with the untreated cells.
3.VDUP1silencing by RNAi.
To determine the biological function of VDUP1, its expression was silenced by RNA interference. Three RNA duplexes (siRNA1, siRNA2and siRNA3) directed against VDUP1were synthesized (see Materials and methods). Extracts prepared from the cells transfected with either the siRNA2or siRNA3duplex showed reduced VDUP1levels. This effect was more pronounced with the use of siRNA3, wherein VDUP1expression was<35%of the control. siRNAl and siRNA2reduced VDUP1expression to40-80%of the control. Therefore, we selected VDUP1siRNA3in the subsequent experiments.
4. Silencing of VDUP1decreases25D3-induced TSLP production in16-HBE cells.
To elucidate the mechanism behind the25D3-induced TSLP production, we investigated whether VDUP1is involved in this process. We used VDUP1siRNA3to suppress VDUP1expression in the16-HBE cells. The viability of the cells was>90%in the siRNA-transfected cells. We observed a significantly lower level of TSLP mRNA and protein expression in the VDUP1-silenced cells when compared with the control siRNA-treated cells following treatment with500nM25D3.
5. Inhibition of la-hydroxylase blocks the conversion of25D3to1,25D3andattenuates the upregulation of TSLP expression in16-HBE cells.
To determine the effect of1,25D3, the16-HBE cells were first treated with increasing concentrations of25D3, and the levels of1,25D3in the supernatants were measured after24h. Consistent with a previous study, our results indicated that the16-HBE cells converted25D3to1,25D3when exposed to25D3without other stimuli. To further link the enzymatic machinery expressed by16-HBE cells to the1, 25D3generation and induction of TSLP expression, we used a chemical inhibitor of la-hydroxylase, itraconazole. Pre-treatment of the16-HBE cells with itraconazole (1,000nM) significantly reduced their ability to convert25D3to1,25D3. We then examined the effects of itraconazole on the induction of TSLP by25D3. The results revealed that in the presence of itraconazole (1,000nM), there was a signifi cantly lower production of TSLP mRNA and protein by25D3. These results indicate that in the presence of itraconazole, less25D3is being converted to1,25D3, resulting in a reduced production of TSLP.
6. VDUP1silencing decreases1,25D3-induced TSLP expression in16-HBE cells.
To further investigate the effect of active vitamin D on TSLP expression in airway epithelial cells, we directly used1,25D3as the stimulator. We found no loss in cellviability when the16-HBE cells were stimulated with various concentrations of1,25D3(0.1to100nM). Based on the concentration-response curve, TSLP mRNA and protein levels significantly increased at0.1nM, and peaked at concentrations of50nM1,25D3. The levels of TSLP mRNA and protein expression significantly increased at2h and peaked at12h in the cells exposed to50nM1,25D3. To determine the role of VDUP1in this process, we examined the mRNA expression level of VDUP1at the same time following treatment with50nM1,25D3for6h and VDUP1was also manipulated via the siRNA-mediated silencing of VDUP1. The results revealed that VDUP1mRNA expression was significantly upregulated in the16-HBE cells treated with50nM1,25D3for6h when compared with the untreated cells. In comparison with the control siRNA-treated cells, following treatment with50nM1,25D3, we observed a significantly lower level of TSLP mRNA and protein in the cells in which VDUP1was silenced. These results suggest that the VDUP1pathway is involved in the1,25D3-induced TSLP expression in16-HBE cells.
7. Inhibition of1α-hydroxylase exerts no effects on1,25D3-induced TSLP expression in16-HBE cells.
To confirm the specificity of the TSLP production induced by1,25D3, we treated the cells with itraconazole, as well as1,25D3. We found that in the presence of itraconazole (1,000nM), a similar induction of TSLP by1,25D3was obsevered. This further supports our primary hypothesis that1αhydroxylase converts inactive vitamin D to active vitamin D and induces TSLP expression in16-HBE cells.
Conclusion
1. Both inactive25D3and active1,25D3induce TSLP expression in16-HBE cells;
2. The inhibition of1α-hydroxylase by itraconazole partially suppresses the25D3-but not the1,25D3-induced TSLP expression in16-HBE cells.
3.0.1nM1,25D3significantly increased the expression of TSLP in airway epithelial cells, not25D3;
4. The effect of vitamin D on TSLP gene expression may be an indirect effect.
引文
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