前B细胞增强因子对IL-1β介导的肺上皮和内皮细胞的炎症和通透性的调节
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摘要
前B细胞克隆增强因子(Pre-B-cell colony-enhancing factor,PBEF)基因最早是从激活的外周血淋巴细胞的cDNA文库中克隆获得。它作为B细胞早期分化的一种生长因子,可以增强IL-7和干细胞因子(SCF)促进前B细胞向B细胞转化的能力。研究发现当细胞处于增殖状态时,PBEF主要分布在胞浆,处于非增殖状态时,则主要出现在胞核内,从而认为PBEF是与细胞周期有关的细胞内蛋白。在炎症细胞因子如IL-β, TNF-α促使中性粒细胞生存期延长的过程中,细胞内PBEF表达明显增多;通过RNAi技术抑制PBEF的表达后,可以完全抵消炎性细胞因子针对中性粒细胞的抗凋亡作用。在妊娠过程中,PBEF在胎膜表面大量表达能使IL-6和IL-8表达增加,这可能在自然分娩和感染性流产中起了重要的作用。PBEF还具有烟酰胺磷酸核糖转移酶的活性,参与NAD+的生物合成,通过调节NAD+依赖蛋白脱乙酰基酶(Sir)-2的活性,促进血管平滑肌细胞的成熟。最近研究表明,PBEF具有很好的类胰岛素活性,可以降低血浆葡萄糖水平,增加机体对胰岛素的敏感性。因此,PBEF是一个具有多种重要生物学功能的蛋白,在体内许多的生理性和病理性过程中发挥着重要的作用,已成为许多医学领域中重要的研究对象。
急性肺损伤(ALI)是指由心源性以外的各种肺内外致病因素所导致的急性、进行性缺氧性呼吸衰竭。严重的ALI或ALI的最终严重阶段被定义为急性呼吸窘迫综合征(ARDS)。ALI/ARDS主要病理特征为肺微血管通透性增高而导致的肺泡渗出液中富含蛋白质的肺水肿及透明膜形成,并伴有肺间质纤维化。由肺内炎症细胞(如嗜中性粒细胞、巨噬细胞)和细胞因子(如IL-1β、IL-8)为主导的肺内炎症反应失控导致的肺泡毛细血管膜损伤是形成肺毛细血管通透性增高肺水肿的病理基础。目前ARDS的病死率为50-90%,究其原因,主要是由于ARDS发病机理错综复杂,迄今尚未完全阐明。
我们以前通过对动物ALI的模型进行研究,发现PBEF的基因表达在血清、支气管肺泡灌洗液以及肺组织中的表达明显增加。通过对人类PBEF基因近端启动子区域的单核苷酸多态性(SNP)分析,我们发现在SNP T-1001G和C-1543T中GC单倍体ALI的发病率显著增加,报告基因分析显示SNP C-1543T中T的变异可以显著降低PBEF的转录。此外,凝血酶所引起的PBEF表达的增加以及内皮细胞屏障的功能障碍,可能是急性肺损伤发生的重要机制。综上,这些研究结果提示PBEF可能是急性肺损伤一个新的生物学标志物。
本实验目的在于通过研究PBEF在IL-1β介导的肺血管内皮细胞和肺泡上皮细胞的炎症和通透性中的调节作用,进一步探讨PBEF在ALI发病中确切的分子机制。本实验研究了转录抑制剂对IL-1β刺激后的A549和HPAEC细胞中PBEF基因mRNA表达的影响;通过凝胶迁移滞后实验分析了转录因子与PBEF基因启动子区域SNP C-1535T的结合能力;将PBEF基因的cDNA和PBEF的siRNA转染到人肺腺癌上皮细胞(A549)和人肺动脉内皮细胞(HPAEC)中,观察了PBEF过表达和PBEF表达下调对细胞IL-8的分泌以及细胞通透性的影响;我们还研究了PBEF的表达对于其它的炎性细胞因子比如IL-16和CCR3基因表达的影响。为此做了以下的一些工作:
1.通过蛋白免疫印迹(western blotting)的方法,对IL-1β诱导的A549细胞中PBEF蛋白表达的剂量依赖性与时间依赖性进行了分析。结果显示,IL-1β诱导A549细胞中PBEF蛋白的表达呈时间依赖性,并且在5至25 ng/ml浓度范围内,IL-1β均可使PBEF蛋白的表达显著增加。
2.用转录抑制剂-放线菌素D处理IL-1β刺激后A549和HPAEC细胞,通过RT-PCR半定量的方法分析了转录抑制剂对PBEF基因mRNA表达的影响。结果显示,IL-1β可以显著增加A549和HPAEC细胞中PBEF基因mRNA的表达,这在一定程度上是由于IL-1β可以增加PBEF基因的转录所致。
3.通过凝胶迁移滞后实验分析了转录因子与PBEF基因启动子区域SNP C-1535T的结合能力。结果显示,PBEF基因启动子区域C -1535T中T的变异可以改变一个未知的转录因子与PBEF基因启动子的亲和力,降低PBEF基因的转录,进而减少基因的表达。
4.将PBEF基因的cDNA和PBEF的siRNA转染到A549和HPAEC细胞中,观察了PBEF过表达和PBEF表达下调对细胞IL-8表达的影响。结果显示,PBEF过表达可以显著增加IL-1β刺激后的A549和HPAEC细胞中IL-8的分泌;而PBEF的siRNA所引起的PBEF表达下调则可以显著降低IL-1β刺激后的A549和HPAEC细胞中IL-8的分泌。这些结果表明PBEF作为IL-1β所引发的炎症反应中一个重要的炎性细胞因子,通过调节IL-8的表达,在ALI的发病机制中起着重要的作用。
5.将PBEF基因的cDNA和PBEF的siRNA转染到A549和HPAEC细胞中,观察了PBEF过表达和PBEF表达下调对其它的炎性细胞因子比如IL-16和CCR3基因表达的影响。结果显示,PBEF表达下调可以降低IL-1β刺激后的A549细胞中IL-16和CCR3基因mRNA表达,而PBEF过表达则可以增加IL-1β刺激后的A549细胞中IL-16和CCR3基因mRNA表达。这些结果提示PBEF可能在炎性通路中是一个重要的信号传递者或是始发者,它作为一个炎性细胞因子,可以通过调节其它的炎性细胞因子的表达,在肺部炎症反应中起着重要的作用。
6.将PBEF基因的cDNA和PBEF的siRNA转染到A549和HPAEC细胞中,观察了PBEF过表达和PBEF表达下调对细胞通透性的影响。结果显示,PBEF过表达可以使IL-1β刺激后的A549和HPAEC细胞通透性分别增加44%和65%,而PBEF表达下调可以使IL-1β刺激后的A549和HPAEC细胞通透性分别降低29%和24%。这些结果表明PBEF可能在内皮细胞和上皮细胞屏障功能的调节中起着重要的作用。
以上结果表明,PBEF作为IL-1β所引发的炎症反应中一个重要的炎性细胞因子在肺部炎症以及肺血管内皮以及肺泡上皮细胞屏障功能的调节中发挥着重要的功能。这为进一步了解PBEF的生物学功能和其在ALI发病中确切的分子机制以及为PBEF的临床应用提供了有价值的实验依据和线索。
Pre-B-cell colony-enhancing factor was first identified as a protein that was secreted by activated lymphocytesin bone marrow stromal cells and that synergized with IL-7 and stem cell factor (SCF) to stimulate early stage B cell formation. PBEF in non-proliferating cells is more abundant in the cells nuclei than in the cytoplasma, whereas in proliferating cells this distribution is inverse, suggesting that PBEF is a cell cycle-associated protein. IL-1βand TNF-α, inflammatory mediators known to inhibit neutrophil apoptosis, lead to an increased PBEF transcription in neutrophils and monocytes. The inhibition of apoptosis by these inflammatory stimuli is abrogated by blocking PBEF translation. PBEF is constitutively expressed by the fetal membranes during pregnancy. It increases the expression of IL-6 and IL-8 and is important in both normal spontaneous labor and infection-induced preterm labor. PBEF acts as a nicotinamide phosphoribosyltransferase involoved in nicotinamide adenine dinucleotide (NAD+) synthesis. This activity is shown to be important for vascular smooth muscle cell (SMC) maturation. PBEF has recently been identified as a new adipokine which exerts insulin-mimetic effects and has a physiological role in lowing plasma glucose levels and improvement of insulin sensitivity. Therefore, PBEF as a multifunctional protein is critically involved in many physiological and pathological processes.
Acute lung injury (ALI) is characterized by pulmonary inflammation, non-cardiogenic edema, and severe systemic hypoxemia. Acute respiratory distress syndrome (ARDS) is the severe form of ALI. One of the earliest manifestations of ALI is a diffuse intense inflammatory process and damage to both endothelial and epithelial cell barriers, resulting in marked extravasation of vascular fluid into the alveolar airspace. A number of inflammatory cells and cytokines including neutrophils, macrophages, IL-1βand IL-8 can induce or aggravate the inflammation of endothelial and epithelial cells, leading to this barrier dysfunctions.The mortality and morbidity of ALI/ARDS remain high since the etiology and molecular pathogenesis are still incompletely understood.
In our previous study on animal models of ALI, we identified pre-B-cell colony enhancing factor as a significantly upregulated gene in ALI. We discovered single nucleotide polymorphisms in the human PBEF gene promoter. Moreover we found that carriers of the haplotype GC from SNPs T-1001G and C-1543T had a 7.7-fold higher risk of ALI. The T variant from the SNP C-1535T resulted in a significant decrease in the transcription rate (1.8-fold) by the reporter gene assay. We further found that a reduction in PBEF protein expression by siRNA significantly attenuated pulmonary artery endothelial cell barrier dysfunction induced by the potent edemagenic agent, thrombin, reflected by reductions in transendothelial electric resistance. Taken together, these results strongly indicate PBEF as a potential novel candidate gene and biomarker in ALI.
The objective of this study was to further elucidate the role of PBEF in pulmonary inflammation and permeability using pulmonary cells as cell models since increased vascular and epithelial cell inflammation and permeability processes are important features of ALI. We investigated the molecular mechanism by which IL-1βinduces the expression of PBEF in pulmonary vascular endothelial cells. We assessed the effect of PBEF knockdown with PBEF siRNA and PBEF overexpression on basal and IL-1β-mediated pulmonary epithelial cell (A549) and human pulmonary artery endothelial cell (HPAEC) IL-8 production and permeability by in vitro cell permeability assay. We also examined the role of PBEF expression on other inflammatory cytokines such as IL-16 and CCR3. The main work is as followings:
1. Dose-response and time-course of IL-1βinduced PBEF protein expression in A549 cells were analyzed by Western blotting. The results demonstrated that IL-1βsignificantly increased PBEF protein expression in a time-dependent manner and cell lysate PBEF expression was significantly increased with different dose treatments of IL-1β(5 to 25 ng/ml).
2. The mRNA levels of HPAEC cells treated for 4 h with IL1-βin the presence or absence of actinomycin D, a transcription inhibitor were assessed by RT-PCR. The results showed that simultaneous treatment of HPAEC with IL1-βplus act D prevented the IL1-βinduction of PBEF mRNA, supporting that IL1-βinduces the transcription of PBEF gene. The data indicates that a transcriptional regulation mechanism is at least in part responsible for the IL-1βinduced up-regulation of the PBEF gene expression.
3. EMSA analyzed whether the T-variant altered the binding affinity to any transcription factor, which may underlie its effect on the decrease in the transcription of PBEF gene expression. The results revealed that -1535 T-variant in the human PBEF gene promoter has less binding to an unknown transcription factor than the common -1535 C-allele, this difference became more pronounced after the IL1-βor TNFαtreatment. The altered transcriptional factor binding may underlie the reduced expression of PBEF and thus less susceptibility to acute lung injury in those -1535T carriers.
4. A549 cells and HPAEC were transiently transfected with pCAGGS-hPBEF or PBEF stealth siRNA in order to increase or knock down PBEF expression. Then we assessed the effect of PBEF knockdown and PBEF overexpression on IL-8 production in the basal and IL-1β-mediated A549 cells and HPAEC. The results demonstrated that knockdown of PBEF expression by PBEF siRNA significantly blunted IL-1β-stimulated IL-8 secretion and its production in the A549 cells and HPAEC, and PBEF-overexpression augmented IL-8 secretion and its production from A549 cells, suggesting that PBEF may be a target of IL-1βinvolved in the inflammatory process during the pathogenesis of ALI.
5. The role of PBEF expression on other inflammatory cytokines such as IL-16 and CCR3 was examined by RT-PCR. The results showed that the knockdown of PBEF in A549 cells attenuated IL-1β-stimulated increase of IL-16 and CCR3 gene expression, while the overexpression of PBEF in A549 cells promoted IL-1β-stimulated increase of IL-16 and CCR3 gene expression at mRNA level. These data implicate PBEF might be an important“master” signal transducer or initiator in the inflammation pathway to regulate the synthesis of some inflammatory cytokines and PBEF could play a critical role as an inflammatory cytokine during the pathogenesis of ALI.
6. The effect of PBEF knockdown and PBEF overexpression permeability on cell permeability in the basal and IL-1β-mediated A549 cells and HPAEC was investigated by in vitro cell permeability assay. The results demonstrated that the overexpression of PPEF significantly augmented IL-1βmediated cell permeability by 44% in A549 cells and 65% in endothelial cells; the knockdown of PBEF expression significantly attenuated IL-1β-induced cell permeability by 29% in epithelial cells and 24% in endothelial cells. These results indicate that overexpression of PBEF in A549 cells and HPAEC augmented IL-1βinduced lung epithelial cell barrier dysfunction and thus increased cell permeability in vitro.
These results suggest that PBEF may play a critical role as an inflammatory cytokine in the development of pulmonary inflammation and dysregulation of pulmonary vascular endothelial and alveolar epithelial cell barriers, which may be an important mechanism underlying PBEF in the pathogenesis of ALI. These results lend further support that PBEF may represent a new diagnostic and therapeutic target in ALI.
急性肺损伤(ALI)是指由心源性以外的各种肺内外致病因素所导致的急性、进行性缺氧性呼吸衰竭。严重的ALI或ALI的最终严重阶段被定义为急性呼吸窘迫综合征(ARDS)。ALI/ARDS主要病理特征为肺微血管通透性增高而导致的肺泡渗出液中富含蛋白质的肺水肿及透明膜形成,并伴有肺间质纤维化。由肺内炎症细胞(如嗜中性粒细胞、巨噬细胞)和细胞因子(如IL-1β、IL-8)为主导的肺内炎症反应失控导致的肺泡毛细血管膜损伤是形成肺毛细血管通透性增高肺水肿的病理基础。目前ARDS的病死率为50-90%,究其原因,主要是由于ARDS发病机理错综复杂,迄今尚未完全阐明。
我们以前通过对动物ALI的模型进行研究,发现PBEF的基因表达在血清、支气管肺泡灌洗液以及肺组织中的表达明显增加。通过对人类PBEF基因近端启动子区域的单核苷酸多态性(SNP)分析,我们发现在SNP T-1001G和C-1543T中GC单倍体ALI的发病率显著增加,报告基因分析显示SNP C-1543T中T的变异可以显著降低PBEF的转录。此外,凝血酶所引起的PBEF表达的增加以及内皮细胞屏障的功能障碍,可能是急性肺损伤发生的重要机制。综上,这些研究结果提示PBEF可能是急性肺损伤一个新的生物学标志物。
本实验目的在于通过研究PBEF在IL-1β介导的肺血管内皮细胞和肺泡上皮细胞的炎症和通透性中的调节作用,进一步探讨PBEF在ALI发病中确切的分子机制。本实验研究了转录抑制剂对IL-1β刺激后的A549和HPAEC细胞中PBEF基因mRNA表达的影响;通过凝胶迁移滞后实验分析了转录因子与PBEF基因启动子区域SNP C-1535T的结合能力;将PBEF基因的cDNA和PBEF的siRNA转染到人肺腺癌上皮细胞(A549)和人肺动脉内皮细胞(HPAEC)中,观察了PBEF过表达和PBEF表达下调对细胞IL-8的分泌以及细胞通透性的影响;我们还研究了PBEF的表达对于其它的炎性细胞因子比如IL-16和CCR3基因表达的影响。为此做了以下的一些工作:
1.通过蛋白免疫印迹(western blotting)的方法,对IL-1β诱导的A549细胞中PBEF蛋白表达的剂量依赖性与时间依赖性进行了分析。结果显示,IL-1β诱导A549细胞中PBEF蛋白的表达呈时间依赖性,并且在5至25 ng/ml浓度范围内,IL-1β均可使PBEF蛋白的表达显著增加。
2.用转录抑制剂-放线菌素D处理IL-1β刺激后A549和HPAEC细胞,通过RT-PCR半定量的方法分析了转录抑制剂对PBEF基因mRNA表达的影响。结果显示,IL-1β可以显著增加A549和HPAEC细胞中PBEF基因mRNA的表达,这在一定程度上是由于IL-1β可以增加PBEF基因的转录所致。
3.通过凝胶迁移滞后实验分析了转录因子与PBEF基因启动子区域SNP C-1535T的结合能力。结果显示,PBEF基因启动子区域C -1535T中T的变异可以改变一个未知的转录因子与PBEF基因启动子的亲和力,降低PBEF基因的转录,进而减少基因的表达。
4.将PBEF基因的cDNA和PBEF的siRNA转染到A549和HPAEC细胞中,观察了PBEF过表达和PBEF表达下调对细胞IL-8表达的影响。结果显示,PBEF过表达可以显著增加IL-1β刺激后的A549和HPAEC细胞中IL-8的分泌;而PBEF的siRNA所引起的PBEF表达下调则可以显著降低IL-1β刺激后的A549和HPAEC细胞中IL-8的分泌。这些结果表明PBEF作为IL-1β所引发的炎症反应中一个重要的炎性细胞因子,通过调节IL-8的表达,在ALI的发病机制中起着重要的作用。
5.将PBEF基因的cDNA和PBEF的siRNA转染到A549和HPAEC细胞中,观察了PBEF过表达和PBEF表达下调对其它的炎性细胞因子比如IL-16和CCR3基因表达的影响。结果显示,PBEF表达下调可以降低IL-1β刺激后的A549细胞中IL-16和CCR3基因mRNA表达,而PBEF过表达则可以增加IL-1β刺激后的A549细胞中IL-16和CCR3基因mRNA表达。这些结果提示PBEF可能在炎性通路中是一个重要的信号传递者或是始发者,它作为一个炎性细胞因子,可以通过调节其它的炎性细胞因子的表达,在肺部炎症反应中起着重要的作用。
6.将PBEF基因的cDNA和PBEF的siRNA转染到A549和HPAEC细胞中,观察了PBEF过表达和PBEF表达下调对细胞通透性的影响。结果显示,PBEF过表达可以使IL-1β刺激后的A549和HPAEC细胞通透性分别增加44%和65%,而PBEF表达下调可以使IL-1β刺激后的A549和HPAEC细胞通透性分别降低29%和24%。这些结果表明PBEF可能在内皮细胞和上皮细胞屏障功能的调节中起着重要的作用。
以上结果表明,PBEF作为IL-1β所引发的炎症反应中一个重要的炎性细胞因子在肺部炎症以及肺血管内皮以及肺泡上皮细胞屏障功能的调节中发挥着重要的功能。这为进一步了解PBEF的生物学功能和其在ALI发病中确切的分子机制以及为PBEF的临床应用提供了有价值的实验依据和线索。
Pre-B-cell colony-enhancing factor was first identified as a protein that was secreted by activated lymphocytesin bone marrow stromal cells and that synergized with IL-7 and stem cell factor (SCF) to stimulate early stage B cell formation. PBEF in non-proliferating cells is more abundant in the cells nuclei than in the cytoplasma, whereas in proliferating cells this distribution is inverse, suggesting that PBEF is a cell cycle-associated protein. IL-1βand TNF-α, inflammatory mediators known to inhibit neutrophil apoptosis, lead to an increased PBEF transcription in neutrophils and monocytes. The inhibition of apoptosis by these inflammatory stimuli is abrogated by blocking PBEF translation. PBEF is constitutively expressed by the fetal membranes during pregnancy. It increases the expression of IL-6 and IL-8 and is important in both normal spontaneous labor and infection-induced preterm labor. PBEF acts as a nicotinamide phosphoribosyltransferase involoved in nicotinamide adenine dinucleotide (NAD+) synthesis. This activity is shown to be important for vascular smooth muscle cell (SMC) maturation. PBEF has recently been identified as a new adipokine which exerts insulin-mimetic effects and has a physiological role in lowing plasma glucose levels and improvement of insulin sensitivity. Therefore, PBEF as a multifunctional protein is critically involved in many physiological and pathological processes.
Acute lung injury (ALI) is characterized by pulmonary inflammation, non-cardiogenic edema, and severe systemic hypoxemia. Acute respiratory distress syndrome (ARDS) is the severe form of ALI. One of the earliest manifestations of ALI is a diffuse intense inflammatory process and damage to both endothelial and epithelial cell barriers, resulting in marked extravasation of vascular fluid into the alveolar airspace. A number of inflammatory cells and cytokines including neutrophils, macrophages, IL-1βand IL-8 can induce or aggravate the inflammation of endothelial and epithelial cells, leading to this barrier dysfunctions.The mortality and morbidity of ALI/ARDS remain high since the etiology and molecular pathogenesis are still incompletely understood.
In our previous study on animal models of ALI, we identified pre-B-cell colony enhancing factor as a significantly upregulated gene in ALI. We discovered single nucleotide polymorphisms in the human PBEF gene promoter. Moreover we found that carriers of the haplotype GC from SNPs T-1001G and C-1543T had a 7.7-fold higher risk of ALI. The T variant from the SNP C-1535T resulted in a significant decrease in the transcription rate (1.8-fold) by the reporter gene assay. We further found that a reduction in PBEF protein expression by siRNA significantly attenuated pulmonary artery endothelial cell barrier dysfunction induced by the potent edemagenic agent, thrombin, reflected by reductions in transendothelial electric resistance. Taken together, these results strongly indicate PBEF as a potential novel candidate gene and biomarker in ALI.
The objective of this study was to further elucidate the role of PBEF in pulmonary inflammation and permeability using pulmonary cells as cell models since increased vascular and epithelial cell inflammation and permeability processes are important features of ALI. We investigated the molecular mechanism by which IL-1βinduces the expression of PBEF in pulmonary vascular endothelial cells. We assessed the effect of PBEF knockdown with PBEF siRNA and PBEF overexpression on basal and IL-1β-mediated pulmonary epithelial cell (A549) and human pulmonary artery endothelial cell (HPAEC) IL-8 production and permeability by in vitro cell permeability assay. We also examined the role of PBEF expression on other inflammatory cytokines such as IL-16 and CCR3. The main work is as followings:
1. Dose-response and time-course of IL-1βinduced PBEF protein expression in A549 cells were analyzed by Western blotting. The results demonstrated that IL-1βsignificantly increased PBEF protein expression in a time-dependent manner and cell lysate PBEF expression was significantly increased with different dose treatments of IL-1β(5 to 25 ng/ml).
2. The mRNA levels of HPAEC cells treated for 4 h with IL1-βin the presence or absence of actinomycin D, a transcription inhibitor were assessed by RT-PCR. The results showed that simultaneous treatment of HPAEC with IL1-βplus act D prevented the IL1-βinduction of PBEF mRNA, supporting that IL1-βinduces the transcription of PBEF gene. The data indicates that a transcriptional regulation mechanism is at least in part responsible for the IL-1βinduced up-regulation of the PBEF gene expression.
3. EMSA analyzed whether the T-variant altered the binding affinity to any transcription factor, which may underlie its effect on the decrease in the transcription of PBEF gene expression. The results revealed that -1535 T-variant in the human PBEF gene promoter has less binding to an unknown transcription factor than the common -1535 C-allele, this difference became more pronounced after the IL1-βor TNFαtreatment. The altered transcriptional factor binding may underlie the reduced expression of PBEF and thus less susceptibility to acute lung injury in those -1535T carriers.
4. A549 cells and HPAEC were transiently transfected with pCAGGS-hPBEF or PBEF stealth siRNA in order to increase or knock down PBEF expression. Then we assessed the effect of PBEF knockdown and PBEF overexpression on IL-8 production in the basal and IL-1β-mediated A549 cells and HPAEC. The results demonstrated that knockdown of PBEF expression by PBEF siRNA significantly blunted IL-1β-stimulated IL-8 secretion and its production in the A549 cells and HPAEC, and PBEF-overexpression augmented IL-8 secretion and its production from A549 cells, suggesting that PBEF may be a target of IL-1βinvolved in the inflammatory process during the pathogenesis of ALI.
5. The role of PBEF expression on other inflammatory cytokines such as IL-16 and CCR3 was examined by RT-PCR. The results showed that the knockdown of PBEF in A549 cells attenuated IL-1β-stimulated increase of IL-16 and CCR3 gene expression, while the overexpression of PBEF in A549 cells promoted IL-1β-stimulated increase of IL-16 and CCR3 gene expression at mRNA level. These data implicate PBEF might be an important“master” signal transducer or initiator in the inflammation pathway to regulate the synthesis of some inflammatory cytokines and PBEF could play a critical role as an inflammatory cytokine during the pathogenesis of ALI.
6. The effect of PBEF knockdown and PBEF overexpression permeability on cell permeability in the basal and IL-1β-mediated A549 cells and HPAEC was investigated by in vitro cell permeability assay. The results demonstrated that the overexpression of PPEF significantly augmented IL-1βmediated cell permeability by 44% in A549 cells and 65% in endothelial cells; the knockdown of PBEF expression significantly attenuated IL-1β-induced cell permeability by 29% in epithelial cells and 24% in endothelial cells. These results indicate that overexpression of PBEF in A549 cells and HPAEC augmented IL-1βinduced lung epithelial cell barrier dysfunction and thus increased cell permeability in vitro.
These results suggest that PBEF may play a critical role as an inflammatory cytokine in the development of pulmonary inflammation and dysregulation of pulmonary vascular endothelial and alveolar epithelial cell barriers, which may be an important mechanism underlying PBEF in the pathogenesis of ALI. These results lend further support that PBEF may represent a new diagnostic and therapeutic target in ALI.
引文
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