Clara细胞10-kDa蛋白介导的呼吸道上皮细胞抗炎作用机制研究
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摘要
第一部分Clara细胞10-kDa蛋白在呼吸道上皮细胞炎症过程中的作用
实验一人CC10基因真核表达载体的构建及鉴定
背景：慢性鼻-鼻窦炎和鼻息肉是鼻腔鼻窦的慢性炎症性疾病，它们的发病机制尚未完全阐明。Clara细胞10-kD蛋白(CC10)是具有抗炎和免疫调节作用的多功能蛋白质。既往研究表明CC10在慢性鼻-鼻窦炎和鼻息肉低表达，可能在疾病的发生发展中起重要作用，但其具体作用机制尚未阐明。基因转染是研究蛋白质功能的重要手段，为研究CC10蛋白在呼吸道炎症性疾病中的作用，本实验构建人CC10真核表达载体，为下一步研究提供重要的帮助。
目的：构建及鉴定人CC10基因真核细胞表达载体。
方法：采用RT-PCR法，从人下鼻甲组织的总RNA中扩增含人CC10编码区全长的cDNA片段，将其连接到pcDNA3.1／V5-His TOPO TA载体中，脂质体法转染CC10质粒到支气管上皮细胞BEAS-2B，免疫荧光细胞化学法及Western blot法检测CC10蛋白的表达。
结果：用菌液PCR法和酶切鉴定质粒并测序，人CC10基因成功克隆到真核细胞表达载体pcDNA3.1中，体外转染CC10质粒的BEAS-2B细胞中CC10蛋白表达明显增高。
结论：成功构建了CC10基因的真核细胞表达载体pcDNA3.1-hCC10，并获得表达。
实验二Clara细胞10-kDa蛋白在呼吸道上皮细胞中发挥抗炎作用
背景：Clara细胞10-kD蛋白(CC10)是具有抗炎和免疫调节作用的多功能蛋白质，既往研究表明CC10在呼吸道炎症性疾病中起重要作用。人类支气管上皮细胞BEAS-2B细胞系被广泛接受的用于研究呼吸道上皮细胞的模型，基因转染是研究蛋白质功能的重要手段。为研究CC10蛋白在呼吸道炎症性疾病中的作用，本研究以细胞试验为模型，比较未转染与转染了CC10质粒的BEAS-2B细胞系对炎性细胞因子的反应，探讨CC10在呼吸道炎症性疾病中的作用。
目的：用细胞因子IL-1β刺激BEAS-2B细胞建立呼吸道上皮细胞炎症模型，并探讨CC10蛋白能否在呼吸道上皮细胞系炎症模型中起作用。
方法：以细胞试验为模型，用pcDNA3.1或CC10质粒转染BEAS-2B细胞，48小时后再用炎性细胞因子白细胞介素-1(IL-1β，10 ng／ml)作用6 h，采用实时定量(real-time)逆转录聚合酶链反应(reverse transcription polymerase chain reaction，RT-PCR)，酶联免疫吸附试验(ELISA)检测各组下游基因白细胞介素-8(IL-8)的变化。
结果：IL-8在BEAS-2B细胞中基础表达水平较低，转染空质粒和CC10质粒对IL-8的表达无影响，而与空白对照组相比，转染空质粒组的BEAS-2B细胞在IL-1β刺激6 h后IL-8mRNA上调达150倍，刺激24 h后蛋白上调达62倍，转染CC10质粒的BEAS-2B细胞明显抑制IL-1β诱导的IL-8表达，其对mRNA和蛋白表达的抑制分别达5倍和2倍，差异均有统计学意义(P＜0.05)。
结论：CC10可抑制IL-1β诱导的支气管上皮细胞BEAS-2B IL-8 mRNA和蛋白的表达，CC10蛋白在呼吸道上皮细胞中发挥抗炎作用。
第二部分Clara细胞10-kDa蛋白在呼吸道上皮细胞发挥抗炎作用的机制研究
背景：Clara细胞10-kD蛋白(CC10)是具有抗炎和免疫调节作用的多功能蛋白质。前期试验发现CC10在呼吸道上皮细胞可抑制IL-1β诱导BEAS-2B表达IL-8，但CC10在呼吸道发挥抗炎作用的具体机制还不清楚。IL-1β在呼吸道炎症中可激活核转录因子κB(NF-κB)，而IL-8基因的表达亦受NF-κB的调控。因此我们推测CC10在呼吸道上皮细胞发挥的抗炎作用是通过抑制NF-κB的活化来实现。
目的：确定CC10在呼吸道上皮细胞抑制IL-1β诱导BEAS-2B表达IL-8是否通过抑制NF-κB的活性来介导，并阐明其作用机制。
方法：采用报告荧光基因和Western blot方法，对CC10转染的BEAS-2B细胞在加入IL-1β刺激后NF-κB的活性变化进行检测，然后用Western blot方法检测NF-κB信号通路上游关键因子p-IκB-α和p-IKKα／β，最后用免疫共沉淀法检测NF-κB亚单位p65蛋白和CC10蛋白是否有相互作用。
结果：报告荧光基因检测结果显示BEAS-2B细胞在加入10 ng／ml的IL-1β作用4 h后NF-κB的活性与空白对照相比上调达6.6倍，而转染CC10质粒后这种上调效应被抑制，NF-κB的活性明显下调，达64.7％(P＜0.05)。用Western blot方法分别检测BEAS-2B细胞内总的p65在IL-1β刺激和转染前后无变化，BEAS-2B细胞在IL-1β刺激后核内p65蛋白迅速上调，而转染CC10质粒后，核内p65蛋白减少。进一步检测NF-κB信号通路上游关键蛋白p-IκB-α和p-IKKα／β发现，CC10转染后的BEAS-2B细胞与空质粒转染后的细胞在IL-1β作用后p-IκB-α减少，而p-IKKα／β的量则没有变化。最后用免疫共沉淀法未发现CC10和p65蛋白间有直接作用。
结论：CC10抑制IL-1β诱导BEAS-2B表达IL-8是通过抑制核转录因子κB来起作用，CC10抑制NF-κB的活性的作用机制是抑制NF-κB活化的关键蛋白IκB-α的磷酸化。
PartⅠThe effect of Clara cell 10-kDa protein inairway epithelium inflammation
ExperimentⅠConstruction and identification the expression vector ofhuman Clara cell 10-kd protein gene
Background: Chronic sinusitis and nasal polyps are chronic inflammatory diseases innasal cavity and nasal sinus. The pathogenesis of them has not been elucidated by now. Claracell 10-kd protein (CC10) is a multifunction protein with anti-inflammatory andimmunomodulatory effects. Previous research has demonstrated that CC10 is downregulatedin chronic sinusitis and nasal polyps, but how the CC10 protein functions on these diseasesremain unclear. Gene transfection is an important means to study the function of protein. Tostudy the function of CC10 protein on airway inflammatory diseases, we construct CC10plasmid which can be expressed in eukaryotic cell, it is helpful for further research.
Objective: To construct and identify the expression vector of human Clara cell 10-kdprotein gene.
Methods: The cDNA fragment that contains the full coding region of CC10 gene wasacquired from human inferior turbinate tissue, and then the cDNA was ligated topcDNA3.1/V5-His TOPO TA vector. CC 10 plasmid was transfected to bronchi epithelial cellline BEAS-2B by liposome mediated gene transfer method. The expression level of CC10protein was detected by the techniques of immunofluorescence and western blot.
Results: After the identification of PCR and restriction enzymes analysis, therecombinant plasmid was sequenced and confirmed which contained the correct and entirenucleotide sequence of the CC10 DNA. The CC10 protein was expressed in BEAS-2B cellsafter being transfected with reconstructive plasmid.
Conclusion: The human CC10 expression plasmid was successfully constructed andacquired stably protein expression in BEAS-2B cell line.
ExperimentⅡThe Clara cell 10-kDa protein functions as an anti-inflammationfactor in airway epithelium
Background: Clara cell 10-kd protein (CC10) is a multifunction protein withanti-inflammatory and immunomodulatory effects. Previous research had demonstrated thatCC10 plays an important role in airway inflammation. Human bronchial epithelial cell lineBEAS-2B is a widespread used model for study of aiway epithelial cell, and gene transfectionis an important means to study the function of protein. To elucidate the function of CC10 inairway inflammation, in this study, we transfected the bronchial epithelial cell line BEAS-2Bwith mock or CC10 plasmid, and compared the response of them after the treatment withIL-1β.
Objective: To set up a model of alway epithelium inflammation by using the cytokineIL-1βstimulate the BEAS-2B cell line, and to elucidate whether the CC10 protein plays apotential role in this model.
Methods: The bronchial epithelial cell line BEAS-2B was transfected with pcDNA3.1 orCC10 plasmid for 48 hours, and then the cells were treated with 10 ng/ml IL-1βfor 6 hours,the downstream gene IL-8 mRNA and protein levels were detected by the methods ofreal-time reverse transcription polymerase chain reaction and enzyme linked immunosorbentassay.
Results: The expression of IL-8 in BEAS-2B cells was low, neither pcDNA3.1 norCC10 plasmid had any effect on IL-8 expression. Compared with controls, the IL-8 mRNAwas upregulated up to 150-fold in BEAS-2B cells trasfectd with mock and stimulated withIL-1βfor 6 hours, and the protein level was also upregulated up to 62-fold after beingstimulated with IL-1βfor 24 hours. However, the CC10 protein could inhibit the IL-1βinduced IL-8 expression in BEAS-2B, the IL-8 mRNA and protein expression weresignificantly downregulated at 5-fold and 2-fold, respectively (P＜0.05).
Conclusion: The human CC10 protein can inhibit the IL-1βinduced IL-8 expression inBEAS-2B and may play an anti-inflammation role in aiway epithelium.
PartⅡThe mechanism of Clara cell 10-kDa protein functions as ananti-inflammation factor in airway epithelium
Background: Clara cell 10-kd protein (CC10) is a multifunction protein withanti-inflammatory and immunomodulatory effects. Previous research had demonstrated thatCC10 protein can inhibit the IL-1βinduced IL-8 expression in BEAS-2B and may play ananti-inflammation role in aiway epithelium, but the detailed mechanism of CC10 fuctions asan anti-inflammation factor remains unknown. Because NF-κB can be activated by IL-1βinaiway inflammation and IL-8 gene expression is also regulated by NF-κB. So, we assumeCC10 fuctions as an anti-inflammation factor in aiway epithelium is through inhibiting theactivation of NF-κB.
Objective: To ensure wherther CC10 can suppress the activation of NF-κB in airwayepithelium inflammation and identify the detailed mechanism.
Methods: We first detected the NF-κB activity in BEAS-2B cells after transfection withmock or CC10 plasmid and stimulated with IL-1βby the means of luciferase report genetransfection and western blot. Then we detected the important proteins p-IκB-αand p-IKKα/βin NF-κB signal pathway. Eventually we determined wherther CC10 can directly interactionwith p65 by the means of co-immunoprecipitation.
Results: The activity of NF-κB was up-regulated up to 6.6-fold in BEAS-2B cells aftertreatment with 10 ng/ml IL-1β, and this ascensus can be significantly inhibited by CC10, thedecrease was to 64.7% (P＜0.05). The total p65 protein expression level was not changed inIL-1βstimulated BEAS-2B cells after transfection with mock or CC10, but the nuclear p65protein in BEAS-2B was immediataly increased after IL-1βstimulation compared with controls, howerer, when tranfected with CC10 plasmid, this increase was also attenuated.Similarly with nuclear p65 protein, the p-IκB-αprotein was also immediataly increased afterIL-1βstimulation compared with controls, and can be attenuated by CC10, but the p-IKKα/βprotein after IL-1βstimulation was not changed in BEAS-2B after being transfeced withmock and CC10 plasmid. Finally, the result of co-immunoprecipitation demonstrated thatthere was no direct interaction between CC 10 and p65.
Conclusion: The CC10 protein can inhibit the activation of NF-κB and fuctions as ananti-inflammation factor in alway epithelium, this effect is via inhibiting the phosphorylationof IκB-α.
实验一人CC10基因真核表达载体的构建及鉴定
背景：慢性鼻-鼻窦炎和鼻息肉是鼻腔鼻窦的慢性炎症性疾病，它们的发病机制尚未完全阐明。Clara细胞10-kD蛋白(CC10)是具有抗炎和免疫调节作用的多功能蛋白质。既往研究表明CC10在慢性鼻-鼻窦炎和鼻息肉低表达，可能在疾病的发生发展中起重要作用，但其具体作用机制尚未阐明。基因转染是研究蛋白质功能的重要手段，为研究CC10蛋白在呼吸道炎症性疾病中的作用，本实验构建人CC10真核表达载体，为下一步研究提供重要的帮助。
目的：构建及鉴定人CC10基因真核细胞表达载体。
方法：采用RT-PCR法，从人下鼻甲组织的总RNA中扩增含人CC10编码区全长的cDNA片段，将其连接到pcDNA3.1／V5-His TOPO TA载体中，脂质体法转染CC10质粒到支气管上皮细胞BEAS-2B，免疫荧光细胞化学法及Western blot法检测CC10蛋白的表达。
结果：用菌液PCR法和酶切鉴定质粒并测序，人CC10基因成功克隆到真核细胞表达载体pcDNA3.1中，体外转染CC10质粒的BEAS-2B细胞中CC10蛋白表达明显增高。
结论：成功构建了CC10基因的真核细胞表达载体pcDNA3.1-hCC10，并获得表达。
实验二Clara细胞10-kDa蛋白在呼吸道上皮细胞中发挥抗炎作用
背景：Clara细胞10-kD蛋白(CC10)是具有抗炎和免疫调节作用的多功能蛋白质，既往研究表明CC10在呼吸道炎症性疾病中起重要作用。人类支气管上皮细胞BEAS-2B细胞系被广泛接受的用于研究呼吸道上皮细胞的模型，基因转染是研究蛋白质功能的重要手段。为研究CC10蛋白在呼吸道炎症性疾病中的作用，本研究以细胞试验为模型，比较未转染与转染了CC10质粒的BEAS-2B细胞系对炎性细胞因子的反应，探讨CC10在呼吸道炎症性疾病中的作用。
目的：用细胞因子IL-1β刺激BEAS-2B细胞建立呼吸道上皮细胞炎症模型，并探讨CC10蛋白能否在呼吸道上皮细胞系炎症模型中起作用。
方法：以细胞试验为模型，用pcDNA3.1或CC10质粒转染BEAS-2B细胞，48小时后再用炎性细胞因子白细胞介素-1(IL-1β，10 ng／ml)作用6 h，采用实时定量(real-time)逆转录聚合酶链反应(reverse transcription polymerase chain reaction，RT-PCR)，酶联免疫吸附试验(ELISA)检测各组下游基因白细胞介素-8(IL-8)的变化。
结果：IL-8在BEAS-2B细胞中基础表达水平较低，转染空质粒和CC10质粒对IL-8的表达无影响，而与空白对照组相比，转染空质粒组的BEAS-2B细胞在IL-1β刺激6 h后IL-8mRNA上调达150倍，刺激24 h后蛋白上调达62倍，转染CC10质粒的BEAS-2B细胞明显抑制IL-1β诱导的IL-8表达，其对mRNA和蛋白表达的抑制分别达5倍和2倍，差异均有统计学意义(P＜0.05)。
结论：CC10可抑制IL-1β诱导的支气管上皮细胞BEAS-2B IL-8 mRNA和蛋白的表达，CC10蛋白在呼吸道上皮细胞中发挥抗炎作用。
第二部分Clara细胞10-kDa蛋白在呼吸道上皮细胞发挥抗炎作用的机制研究
背景：Clara细胞10-kD蛋白(CC10)是具有抗炎和免疫调节作用的多功能蛋白质。前期试验发现CC10在呼吸道上皮细胞可抑制IL-1β诱导BEAS-2B表达IL-8，但CC10在呼吸道发挥抗炎作用的具体机制还不清楚。IL-1β在呼吸道炎症中可激活核转录因子κB(NF-κB)，而IL-8基因的表达亦受NF-κB的调控。因此我们推测CC10在呼吸道上皮细胞发挥的抗炎作用是通过抑制NF-κB的活化来实现。
目的：确定CC10在呼吸道上皮细胞抑制IL-1β诱导BEAS-2B表达IL-8是否通过抑制NF-κB的活性来介导，并阐明其作用机制。
方法：采用报告荧光基因和Western blot方法，对CC10转染的BEAS-2B细胞在加入IL-1β刺激后NF-κB的活性变化进行检测，然后用Western blot方法检测NF-κB信号通路上游关键因子p-IκB-α和p-IKKα／β，最后用免疫共沉淀法检测NF-κB亚单位p65蛋白和CC10蛋白是否有相互作用。
结果：报告荧光基因检测结果显示BEAS-2B细胞在加入10 ng／ml的IL-1β作用4 h后NF-κB的活性与空白对照相比上调达6.6倍，而转染CC10质粒后这种上调效应被抑制，NF-κB的活性明显下调，达64.7％(P＜0.05)。用Western blot方法分别检测BEAS-2B细胞内总的p65在IL-1β刺激和转染前后无变化，BEAS-2B细胞在IL-1β刺激后核内p65蛋白迅速上调，而转染CC10质粒后，核内p65蛋白减少。进一步检测NF-κB信号通路上游关键蛋白p-IκB-α和p-IKKα／β发现，CC10转染后的BEAS-2B细胞与空质粒转染后的细胞在IL-1β作用后p-IκB-α减少，而p-IKKα／β的量则没有变化。最后用免疫共沉淀法未发现CC10和p65蛋白间有直接作用。
结论：CC10抑制IL-1β诱导BEAS-2B表达IL-8是通过抑制核转录因子κB来起作用，CC10抑制NF-κB的活性的作用机制是抑制NF-κB活化的关键蛋白IκB-α的磷酸化。
PartⅠThe effect of Clara cell 10-kDa protein inairway epithelium inflammation
ExperimentⅠConstruction and identification the expression vector ofhuman Clara cell 10-kd protein gene
Background: Chronic sinusitis and nasal polyps are chronic inflammatory diseases innasal cavity and nasal sinus. The pathogenesis of them has not been elucidated by now. Claracell 10-kd protein (CC10) is a multifunction protein with anti-inflammatory andimmunomodulatory effects. Previous research has demonstrated that CC10 is downregulatedin chronic sinusitis and nasal polyps, but how the CC10 protein functions on these diseasesremain unclear. Gene transfection is an important means to study the function of protein. Tostudy the function of CC10 protein on airway inflammatory diseases, we construct CC10plasmid which can be expressed in eukaryotic cell, it is helpful for further research.
Objective: To construct and identify the expression vector of human Clara cell 10-kdprotein gene.
Methods: The cDNA fragment that contains the full coding region of CC10 gene wasacquired from human inferior turbinate tissue, and then the cDNA was ligated topcDNA3.1/V5-His TOPO TA vector. CC 10 plasmid was transfected to bronchi epithelial cellline BEAS-2B by liposome mediated gene transfer method. The expression level of CC10protein was detected by the techniques of immunofluorescence and western blot.
Results: After the identification of PCR and restriction enzymes analysis, therecombinant plasmid was sequenced and confirmed which contained the correct and entirenucleotide sequence of the CC10 DNA. The CC10 protein was expressed in BEAS-2B cellsafter being transfected with reconstructive plasmid.
Conclusion: The human CC10 expression plasmid was successfully constructed andacquired stably protein expression in BEAS-2B cell line.
ExperimentⅡThe Clara cell 10-kDa protein functions as an anti-inflammationfactor in airway epithelium
Background: Clara cell 10-kd protein (CC10) is a multifunction protein withanti-inflammatory and immunomodulatory effects. Previous research had demonstrated thatCC10 plays an important role in airway inflammation. Human bronchial epithelial cell lineBEAS-2B is a widespread used model for study of aiway epithelial cell, and gene transfectionis an important means to study the function of protein. To elucidate the function of CC10 inairway inflammation, in this study, we transfected the bronchial epithelial cell line BEAS-2Bwith mock or CC10 plasmid, and compared the response of them after the treatment withIL-1β.
Objective: To set up a model of alway epithelium inflammation by using the cytokineIL-1βstimulate the BEAS-2B cell line, and to elucidate whether the CC10 protein plays apotential role in this model.
Methods: The bronchial epithelial cell line BEAS-2B was transfected with pcDNA3.1 orCC10 plasmid for 48 hours, and then the cells were treated with 10 ng/ml IL-1βfor 6 hours,the downstream gene IL-8 mRNA and protein levels were detected by the methods ofreal-time reverse transcription polymerase chain reaction and enzyme linked immunosorbentassay.
Results: The expression of IL-8 in BEAS-2B cells was low, neither pcDNA3.1 norCC10 plasmid had any effect on IL-8 expression. Compared with controls, the IL-8 mRNAwas upregulated up to 150-fold in BEAS-2B cells trasfectd with mock and stimulated withIL-1βfor 6 hours, and the protein level was also upregulated up to 62-fold after beingstimulated with IL-1βfor 24 hours. However, the CC10 protein could inhibit the IL-1βinduced IL-8 expression in BEAS-2B, the IL-8 mRNA and protein expression weresignificantly downregulated at 5-fold and 2-fold, respectively (P＜0.05).
Conclusion: The human CC10 protein can inhibit the IL-1βinduced IL-8 expression inBEAS-2B and may play an anti-inflammation role in aiway epithelium.
PartⅡThe mechanism of Clara cell 10-kDa protein functions as ananti-inflammation factor in airway epithelium
Background: Clara cell 10-kd protein (CC10) is a multifunction protein withanti-inflammatory and immunomodulatory effects. Previous research had demonstrated thatCC10 protein can inhibit the IL-1βinduced IL-8 expression in BEAS-2B and may play ananti-inflammation role in aiway epithelium, but the detailed mechanism of CC10 fuctions asan anti-inflammation factor remains unknown. Because NF-κB can be activated by IL-1βinaiway inflammation and IL-8 gene expression is also regulated by NF-κB. So, we assumeCC10 fuctions as an anti-inflammation factor in aiway epithelium is through inhibiting theactivation of NF-κB.
Objective: To ensure wherther CC10 can suppress the activation of NF-κB in airwayepithelium inflammation and identify the detailed mechanism.
Methods: We first detected the NF-κB activity in BEAS-2B cells after transfection withmock or CC10 plasmid and stimulated with IL-1βby the means of luciferase report genetransfection and western blot. Then we detected the important proteins p-IκB-αand p-IKKα/βin NF-κB signal pathway. Eventually we determined wherther CC10 can directly interactionwith p65 by the means of co-immunoprecipitation.
Results: The activity of NF-κB was up-regulated up to 6.6-fold in BEAS-2B cells aftertreatment with 10 ng/ml IL-1β, and this ascensus can be significantly inhibited by CC10, thedecrease was to 64.7% (P＜0.05). The total p65 protein expression level was not changed inIL-1βstimulated BEAS-2B cells after transfection with mock or CC10, but the nuclear p65protein in BEAS-2B was immediataly increased after IL-1βstimulation compared with controls, howerer, when tranfected with CC10 plasmid, this increase was also attenuated.Similarly with nuclear p65 protein, the p-IκB-αprotein was also immediataly increased afterIL-1βstimulation compared with controls, and can be attenuated by CC10, but the p-IKKα/βprotein after IL-1βstimulation was not changed in BEAS-2B after being transfeced withmock and CC10 plasmid. Finally, the result of co-immunoprecipitation demonstrated thatthere was no direct interaction between CC 10 and p65.
Conclusion: The CC10 protein can inhibit the activation of NF-κB and fuctions as ananti-inflammation factor in alway epithelium, this effect is via inhibiting the phosphorylationof IκB-α.
引文
1. Gliklich RE, Metson R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol Head Neck Surg 1995; 113:104-109.
2. Bernstein JM. The molecular biology of nasal polyposis. Current allergy and asthma reports 2001; 1:262-267.
3. Norlander T, Westrin KM, Stierna P. The inflammatory response of the sinus and nasal mucosa during sinusitis: implications for research and therapy. Acta oto-laryngologica 1994; 515:38-44.
4. Liu Z, Kim J, Sypek JP et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. The Journal of allergy and clinical immunology 2004;114:783-790.
5. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhino sinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
6. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
7. Hay JG, Danel C, Chu CS, Crystal RG Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 1995;268:L565-75.
8. Thomas NS, Holgate ST. Genes for asthma on chromosome 11: an update. Clin Exp Allergy 1998; 28:387-91.
9. Wang SZ, Rosenberger CL, Bao YX, Stark JM, Harrod KS. Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus infection. J Immunol 2003; 171:1051-60.
10. Rossini GP, Fayard JM, Tessier C, Laugier C. Binding and internalization of extracellular type-Ⅰphospholipase A2 in uterine stromal cells. Biochem J 1996; 315 (Pt 3):1007-14.
11. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30: 469-475.
12. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
13. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
14. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
15. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc 2004; 1:93-8.
16. Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002; 169:4572-8.
17. Becker S, Quay J, Koren HS, Haskill JS. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol Lung Cell Mol Physiol 1994; 266:L278-86.
18. Cromwell O, Hamid Q, Corrigan CJ, Barkans J, Meng Q, Collins PD, et al. Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumour necrosis factor-alpha. Immunology 1992; 77:330-7.
19. Holgate ST, Lackie PM, Davies DE, Roche WR, Walls AF. The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma. Clin Exp Allergy 1999; 29(suppl 2):90-5.
20. Sanders SP, Siekierski ES, Richards SM, Porter JD, Imani F, and Proud D. Rhinovirus infection induces expression of type 2 nitric oxide synthase in human respiratory epithelial cells in vitro and in vivo. J Allergy Clin Immunol 2001; 107:235-43.
21. Zhu Z, Tang W, Gwaltney JM Jr, Wu Y, Elias JA. Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB. Am J Physiol Lung Cell Mol Physiol 1997; 273:L814-24.
1. Jacob A, Faddis BT, Chole RA. Chronic bacterial rhinosinusitis: description of a mouse model. Arch Otolaryngol Head Neck Surg, 2001, 127:657-664.
2. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, and Nicklas RA, et al. Rhinosinusitis: establishing definitions for clinical research and patient care. J Allergy Clin Immunol 2004; 114:155-212.
3. Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl 2007:1-136.
4. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
5. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30:469-475.
6. Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG, et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783-790.
7. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
8. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B, et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
9. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
10. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N, et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
11. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. The New England journal of medicine 1999; 340:197-206.
12. Pilon AL. Rationale for the development of recombinant human CC10 as a therapeutic for inflammatory and fibrotic disease. Annals of the New York Academy of Sciences 2000; 923:280-299.
13. Mukherjee AB, Kundu GC, Mantile-Selvaggi Get al. Uteroglobin: a novel cytokine? Cell Mol Life Sci 1999; 55:771-787.
14. Shijubo N, Kawabata I, Sato N, Itoh Y. Clinical aspects of Clara cell 10-kDa protein/uteroglobin (secretoglobin 1A1). Current pharmaceutical design 2003; 9:1139-1149.
15. Benson M, Fransson M, Martinsson T, Naluai AT, Uddman R, Cardell LO. Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy 2007; 62:178-183.
16. Hay JG, Danel C, Chu CS, Crystal RG. Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 1995;268:L565-75.
17. Singh G, Katyal SL, Brown WE, Phillips S, Kennedy AL, Anthony J, et al. Amino-acid and cDNA nucleotide sequences of human Clara cell 10 kDa protein. Biochim Biophys Acta 1988; 950:329-37.
18. Pattabiraman N, Matthews JH, Ward KB, Mantile-Selvaggi G, Miele L, Mukherjee AB. Crystal structure analysis of recombinant human uteroglobin and molecular modeling of ligand binding. Ann N Y Acad Sci 2000; 923:113-27.
19. Matthews JH, Pattabiraman N, Ward KB, Mantile G, Miele L, Mukherjee AB. Crystallization and characterization of the recombinant human Clara cell 10-kDa protein. Proteins 1994; 20:191-6.
1. Gibson PG, Simpson LJ, Saltos N. Heterogeneity of airwayinflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001; 119(5):1329-1336.
2. Shute JK, Vrugt B, Lindley IJ, Holgate ST, Bron A, Aalbers R, et al.Free and complexed interleukin-8 in blood and bronchial mucosa in asthma. Am J Respir Crit Care Med 1997; 155(6): 1877-1883.
3. Chanez P, Enander I, Jones I, Godard P, Bousquet J. Interleukin 8 in bronchoalveolar lavage of asthmatic and chronic bronchitis patients. Int Arch Allergy Immunol 1996; 111(1):83-88.
4. Teran LM, Johnston SL, Schroder JM, Church MK, Holgate ST. Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus-induced asthma. Am J Respir Crit Care Med 1997; 155(4): 1362-1366.
5. Wark PA, Johnston SL, Moric I, Simpson JL, Hensle MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002; 19(1):68-75.
6. Borish L, Mascali JJ, Dishuck J, Beam WR, Martin RJ, Rosenwasser LJ. Detection of alveolar macrophage-derived IL-1 beta in asthma. Inhibition with corticosteroids. J Immunol 1992; 149(9):3078-3082.
7. Sousa AR, Lane SJ, Nakhosteen JA, Lee TH, Poston RN. Expression of interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic bronchial epithelium. Am J Respir Crit Care Med 1996; 154(4 Pt 1):1061-1066.
8. Tomita K, Tanigawa T, Yajima H, Fukutani K, Matsumoto Y, Tanaka Y, et al. Identification and characterization of monocyte subpopulations from patients with bronchial asthma. J Allergy Clin Immunol 1995; 96(2):230-238.
9. de Kluijver J, Grunberg K, Pons D, de Klerk EP, Dick CR, Sterk PJ, et al. Interleukin-1 beta and interleukin-lra levels in nasal lavages during experimental rhinovirus infection in asthmatic and nonasthmatic subjects. Clin Exp Allergy 2003; 33(10):1415-1418.
10. Nakae S, Komiyama Y, Yokoyama H, Nambu A, Umeda M, Iwase M. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int Immunol 2003; 15(4):483-490.
11. Schmitz N, Kurrer M, Kopf M. The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model. Eur J Immunol 2003; 33(4):991-1000.
12. Griego SD, Weston CB, Adams JL, Tal-Singer R, Dillon SB. Role of p38 mitogen-activated protein kinase in rhinovirus-induced cytokine production by bronchial epithelial cells. J Immunol 2000; 165(9): 5211-5220.
13. Yamaya M, Sekizawa K, Suzuki T, Yamada N, Furukawa M, Ishizuka S, et al. Infection of human respiratory submucosal glands with rhinovirus: effects on cytokine and ICAM-1 production. Am J Physiol 1999; 277(2 Pt 1):L362-L371.
14. Oltmanns U, Issa R, Sukkar MB, John M, Chung KF. Role of c-jun Nterminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells. Br J Pharmacol 2003; 139(6):1228-1234.
15. Wuyts WA, Vanaudenaerde BM, Dupont LJ, Demedts MG, Verleden GM. Modulation by cAMP of IL-1 beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells. Eur Respir J 2003; 22(2):220-226.
16. Lee SA, Fitzgerald SM, Huang SK, Li C, Chi DS, Krishnaswamy G. Molecular regulation of IL-13 and MCP-1 expression in human mast cells by IL-1beta. Am J Respir Cell Mol 2004.
17. Manni A, Kleimberg J, Ackerman V, Bellini A, Patalano F, Mattoli S. Inducibility of RANTES mRNA by IL-lbeta in human bronchial epithelial cells is associated with increased NF-kappaB DNA binding activity. Biochem Biophys Res Commun 1996; 220(1): 120-124.
18. Marini M, Soloperto M, Mezzetti M, Fasoli A, Mattoli S. Interleukin-1 binds to specific receptors on human bronchial epithelial cells and upregulates granulocyte/macrophage colonystimulating factor synthesis and release. Am J Respir Cell Mol Biol 1991; 4(6):519-524.
19. Hashimoto S, Matsumoto K, Gon Y, Maruoka S, Kujime K, Hayashi S, et al. kinase regulates TNF alpha-, IL-1 alpha- and PAF induced RANTES and GM-CSF production by human bronchial epithelial cells. Clin Exp Allergy 2000; 30(1):48-55.
20. Matsumoto K, Hashimoto S, Gon Y, Nakayama T, Horie T. Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway. J Allergy Clin Immunol 1998; 101(6 Pt 1):825-831.
21. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
22. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30:469-475.
23. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. The New England journal of medicine 1999; 340:197-206.
24. Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG, et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783-790.
25. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
26. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54(9):825-857.
27. Shute J. Interleukin-8 is a potent eosinophil chemo-attractant. Clin Exp Allergy 1994; 24(3):203-206.
28. Pilon AL. Rationale for the development of recombinant human CC10 as a therapeutic for inflammatory and fibrotic disease. Annals of the New York Academy of Sciences 2000; 923:280-299.
29. Mukherjee AB, Kundu GC, Mantile-Selvaggi Get al. Uteroglobin: a novel cytokine? Cell Mol Life Sci 1999; 55:771-787.
30. Shijubo N, Kawabata I, Sato N, Itoh Y. Clinical aspects of Clara cell 10-kDa protein/uteroglobin (secretoglobin 1A1). Current pharmaceutical design 2003; 9:1139-1149.
31. Benson M, Fransson M, Martinsson T, Naluai AT, Uddman R, Cardell LO. Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy 2007; 62:178-183.
32. Wang SZ, Rosenberger CL, Bao YX, Stark JM, Harrod KS. Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus
??infection. J Immunol 2003; 171:1051-60.
33. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
34. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
35. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
36. Edwardsa MR, Mukaidab N, Johnsonc M, Johnstona SL. IL-1β induces IL-8 in bronchial cells via NF-kB and NF-IL6transcription factors and can be suppressed by glucocorticoids. Pulmonary Pharmacology & Therapeutics 2005; 18; 337-345.
37. Newton R, Stevens DA, Hart LA, Lindsay M, Adcock IM, Barnes PJ. Superinduction of COX-2 mRNA by cycloheximide and interleukin-lbeta involves increased transcription and correlates with increased NF-kappaB and JNK activation. FEBS Lett 1997; 418(1-2):135-8.
38. Kim YD, Kwon EJ, Park DW, Song SY, Yoon SK, Baek SH. Interleukin-lbeta induces MUC2 and MUC5AC synthesis through cyclooxygenase-2 in NCI-H292 cells. Mol Pharmacol 2002; 62(5): 1112-8.
1. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc 2004; 1:93-8.
2. Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002; 169:4572-8.
3. Mutsaers SE, Bishop JE, McGrouther G, Laurent GJ. Mechanisms of tissue repair: from wound healing to fibrosis. Int J Biochem Cell Biol 1997; 29:5-17.
4. Becker S, Quay J, Koren HS, Haskill JS. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol Lung Cell Mol Physiol 1994; 266:L278-86.
5. Cromwell O, Hamid Q, Corrigan CJ, Barkans J, Meng Q, Collins PD, et al. Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1beta and rumour necrosis factor-alpha. Immunology 1992; 77:330-7.
6. Holgate ST, Lackie PM, Davies DE, Roche WR, Walls AF. The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma. Clin Exp Allergy 1999; 29(suppl 2):90-5.
7. Zhu Z, Tang W, Gwaltney JM Jr, Wu Y, Elias JA. Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB. Am J Physiol Lung Cell Mol Physiol 1997; 273:L814-24.
8. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, Nicklas RA et al. Rhinosinusitis: establishing definitions for clinical research and patient care. J Allergy Clin Immunol 2004; 114:155-212.
9. Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl 2007; 20:1-136.
10. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
11. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30: 469-475.
12. Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783-790.
13. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
14. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates T(H)2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
15. Mandal AK, Zhang Z. Ray R, Choi MS, Chowdhury B, Pattabiraman N et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
16. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
17. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54(9):825-857. 18. Shute J. Interleukin-8 is a potent eosinophil chemo-attractant. Clin Exp Allergy 1994; 24(3):203-206.
19. Newton R, Stevens DA, Hart LA, Lindsay M, Adcock IM, Barnes PJ. Superinduction of COX-2 mRNA by cycloheximide and interleukin-1beta involves increased transcription and correlates with increased NF-kappaB and JNK activation. FEBS Lett 1997; 418(1-2):135-8.
20. Oltmanns U, Issa R, Sukkar MB, John M, Chung KF. Role of c-jun Nterminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells. Br J Pharmacol 2003; 139(6): 1228-1234.
21. Hashimoto S, Matsumoto K, Gon Y, Maruoka S, Kujime K, Hayashi S, et al. kinase regulates TNF alpha-, IL-1 alpha- and PAF induced RANTES and GM-CSF production by human bronchial epithelial cells. Clin Exp Allergy 2000; 30(1):48-55.
22. Matsumoto K, Hashimoto S, Gon Y, Nakayama T, Horie T. Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway. J Allergy Clin Immunol 1998; 101(6 Pt 1):825-831.
23. Kim YD, Kwon EJ, Park DW, Song SY, Yoon SK, Baek SH. Interleukin-1beta induces MUC2 and MUC5AC synthesis through cyclooxygenase-2 in NCI-H292 cells. Mol Pharmacol 2002, 62(5): 1112-8.
24. Hay JG, Danel C, Chu CS, Crystal RG Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 1995;268:L565-75.
25. Thomas NS, Holgate ST. Genes for asthma on chromosome 11: an update. Clin Exp Allergy 1998; 28:387-91.
26. Mukaida N, Shiroo M, Matsushima K. Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8. J Immunol 1989; 143(4):1366-71.
27. Flohe L, Brigelius Flohe R, Saliou C, et al. Redox regulation of NF-kappa B activation. Free Radic Biol Med, 1997, 22 (6): 1115-1126.
28. MayMJ, Ghosh S. Signal transduction through NF- kappa B. Immunol Today, 1998, 19(2): 80-88.
29. Popescu FD. New asthma drugs acting on gene expression. J Cell Mol Med 2003, 7(4):475-86.
30. Hayden MS, Ghosh S. Signaling to NF-kappaB, Genes Dev 2004, 18(18): 2195-2224.
1. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 1986, 46: 705-716.
2. Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol, 1996, 14: 649-683.
3. Xiao W. Advances in NF kappaB signaling transduction and transcription. Cell Mol Immunol 2004; 1 (6): 425-435.
4. Karin M, Yamamoto Y, Wang QM. The IKK NF- kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 2004; 3(1):17-26.
5. Aggarwal BB, Takada Y, Shishodia S, et al. Nuclear transcription factor NF- kappa B: role in biology and medicine. Indian J Exp Biol 2004; 42(4):341-353.
6. Flohe L, Brigelius Flohe R, Saliou C, et al. Redox regulation of NF-kappa B activation. Free Radic Biol Med, 1997, 22 (6): 1115-1126.
7. MayMJ, Ghosh S. Signal transduction through NF- kappa B. Immunol Today, 1998, 19(2): 80-88.
8. Baeuerle PA. IkB-NF-kB structures: at the interface of inflammationcontrol. Cell, 1998, 95:729-731.
9. Hayden MS, Ghosh S. Signaling to NF-kappaB, Genes Dev 2004, 18(18): 2195-2224.
10. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha induced cell death. Science 1996; 274(5288):782- 784.
11. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 1995; 9(22):2723- 2735.
12. Miller BS, Zandi E. Complete reconstitution of human IkappaB kinase (IKK) complex in yeast. Assessment of its stoichiometry and the role of IKKgamma on the complex activity in the absence of stimulation. J Biol Chem 2001; 276(39):36320- 36326.
13. Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends in biochemical sciences 2004; 29:72-79.
14. Zandi E, Rothwarf DM, Delhase M, et al. The Ikappa B kinase complex (IKK) contains two kinase subunits. IKKα and IKKβ, necessary for IkappaB phosphorylation and NF kappa B activation. Cell, 1997, 91 (2): 243-252.
15. Woronicz JD, GAO X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF - kappa B activation and complex formation with IkappaB kinase-alpha and NIK. Science 1997; 278 (5339):866- 869.
16. Cohen L, Henzel WJ, Baeuerle PA. IKAP is a scaffold protein of the IkappaB kinase complex. Nature 1998; 395(6699):292- 296.
17. Rothwarf DM, Zandi E, Natoli G, et al. IKK-gamma is an essential regulatory subunit of the Ikappa B kinase complex. Nature, 1998, 395 (6699):297-300.
18. Delhase M, Hayakawa M, Chen Y, et al. Positive and negative regulation of I kappa B kinase activity through IKKbeta subunit phosphorylation. Science, 1999, 284(5412):309-313.
19. Yang, L, Colin, L, Zhang, DH, et al. Essential role of nuclear factor kappaB in the induction of eosinophilia in allergic airway inflammation. J Exp Med, 1998, 188(9), 1739-1750.
20. Das J, Chen CH, Yang L, et al. A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation Nat Immunol 2001, 2(1), 45-50.
21. Donovan CE, Mark DA, He HZ, et al. NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation. J Immunol 1999,163,6827-6833.
22. Hart LA, Krishnan VL, Adcock IM, et al. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med 1998, 158(5), 1585-1592.
23. Gagliardo R, Chanez P, Mathieu M, Bruno A, Costanzo G, Gougat C, Vachier I, Bousquet J, Bonsignore G, Vignola AM. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med. 2003, 168 (10), 1190-1198.
24. Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, and Janssen Heininger YM. NF-kappa B activation in airways modulates allergic inflammation but not hyperresponsiveness. J Immunol 2004; 173:7003-7009.
25. Jany B, Betz R, Schreck R. Activation of the transcription factor NF-kappa B in human tracheobronchial epithelial cells by inflammatory stimuli. Eur Respir J 1995; 8:387-391
26. Chabot FM. A role for transcription factor NF-kappa B in inflammation. Inflamm Res, 1997, 46(1): 1-2.
27. Lee JI, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target. J Clin Pharmacol, 1998, 38(11): 981-993.
28. Obata H, Biro S, Arima N, et al. NF-kappa B is induced in the nuclei of cultured rat aortic smooth muscle cells by stimulation of various growth factors. Biochem Biophys Res
??Commun, 1996, 224(1): 27-32.
29. Chetta A, Zanini A, Foresi A, et al.Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone. Am J Respir Crit Care Med, 2003, 167(5): 751-757.
30. Wang XT, Liu PY, Tang JB, et al. PDGF Gene therapy enhances expression of VEGF and bFGF genes and activates the NF-κB gene in signal pathways in ischemic flaps. Plast Reconstr Surg, 2006, 117(1): 129-137.
31. Yamashita N, Sekine K, Miyasaka T, et al. Platelet-derived growth factor is involved in the augmentation of airway responsiveness through remodeling of airways in diesel exhaust particulate-treated mice. J Allergy Clin Immunol, 2001, 107(1): 135-142.
32. Malmastrom J, Tufvesson E, Lofdahl CG.Activation of platelet-derived growth factor pathway in human asthmatic pulmonary-derived mesenchymal cells. Ectrophoresis, 2003, 24(1-2): 276-285.
33. Blackwell TS, Holden EP, Blackwell TR, DeLarco JE, Christman JW. Cytokine-induced neutrophil chemoattractant mediates neutrophilic alveolitis in rats: association with nuclear factor kappa B activation. American journal of respiratory cell and molecular biology 1994; 11:464-472.
34. Le Tulzo Y, Shenkar R, Kaneko Det al. Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression. The Journal of clinical investigation 1997; 99:1516-1524.
35. Simeonova PP, Luster MI. Asbestos induction of nuclear transcription factors and interleukin 8 gene regulation. American journal of respiratory cell and molecular biology 1996; 15:787-795.
36. Schwartz MD, Moore EE, Moore FAet al. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Critical care medicine 1996; 24:1285-1292.
37. Antal JM, Divis LT, Erzurum SC, Wiedemann HP, Thomassen MJ. Surfactant suppresses NF-kappa B activation in human monocytic cells. American journal of respiratory cell and molecular biology 1996; 14:374-379.
38. Wong HR, Ryan M, Wispe JR. Stress response decreases NF-kappaB nuclear translocation and increases I-kappaBalpha expression in A549 cells. The Journal of clinical investigation 1997; 99:2423-2428.
39. Das J, Chen C H, Yang L, et al. A critical role for NF-kappaB in GATA3 expression and Th2 differentiation in allergic airway inflammation. Nat Immunol, 2001, 2: 45-50.
40. Artis D ,Shapira S ,Mason N ,et al. Differential requirement for NF-kappaB family members in control of helminth infection and intestinal inflammation. J Immunol, 2002, 169:4481 -4487.
41. Pai S Y, Ho I C. c2Rel delivers a one-two punch in Thlcell differentiation. J Clin Invest, 2002,110:741 -742.
42. Liou H C, Hsia C Y. Distinctions between c-Rel andother NF-kappaB proteins in immunity and disease. Bioessays, 2003, 25:767 - 780.
43. Hilliard B A , Mason N ,Xu L ,et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J Clin Invest, 2002, 110:843 - 850.
44. Li-Weber M , Giaisi M , Baumann S , et al. NF-kappa B synergizes with NF-AT and NF-IL6 in activation of the IL-4 gene in T cells. Eur J Immunol, 2004, 34: 1111 -1118.
45. Tokuyama K, Nishimura H , Iizuka K, et al. Effect s of Y227632 , a Rho/Rho kinase inhibitor , on leukotriene D(4)- and histamine-induced airflow obstruction and airway microvascular leakage in guinea pigs in vivo. Pharmacology, 2002, 64:189 - 195.
46. Adachi T, Alum R. The mechanism of IL-5 signal transduction.Am J Physiol, 1998, 275(1):c623.
47. Sha WC. Regulation of immune responses by NF-KB/Rel transcription factors. J Exp Med. 1998, 187:143-146.
48. Vandenbroeck K, Alloza I, Gadina M, et al. Inhibiting cytokines of the interleukin-12
??family: recent advances and novelchallenges. J Pharmacol, 2004, 56:145 - 160.
49. Li-Weber M, Glaisi M, Baumann S, et al. NF-Kappa B synergizes with NF-AT and NF-IL6 in activation of the IL-4 gene in T-cell. Eur J Immunol, 2004, 34:1111 - 1118.
50. Ramis I, Bioque G, Lorente Jet al. Constitutive nuclear factor-kappaB activity in human upper airway tissues and nasal epithelial cells. Eur Respir J 2000; 15:582-589.
51. Takeno S, Hirakawa K, Ueda T, Furukido K, Osada R, Yajin K. Nuclear factor-kappa B activation in the nasal polyp epithelium: relationship to local cytokine gene expression. The Laryngoscope 2002; 112:53-58.
52. Wilson SJ, Leone BA, Anderson D, Manning A, Holgate ST. Immunohistochemical analysis of the activation of NF-kappaB and expression of associated cytokines and adhesion molecules in human models of allergic inflammation. The Journal of pathology 1999; 189:265-272.
53. Johan L , Ingalill R , Mathias T , et al. Glucocorticoid effects on NF-kappaB binding in the t ranscription of the ICAM-1 gene. Diochem Biophys Res Commun, 2000, 273:1008-1014.
54. Nissen R M, Yamamoto K R. The glucocorticoid receptor inhibits NF kappaB by interfering with serine22 phosphorylation of the RNA polymerase Ⅱ carboxy terminal domain. Genes Dev, 2000, 14:2314 - 2329.
55. HandelML. T ranscrip tion factors A P21 and N F2kappa B: where steroids meet the gold standard of anti-rheumatic drugs. Infiamm Res, 1997, 46: 282-286
56. Beauparlant P, Hiscott J, Crepieux P, et al. Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection. Cytoki & Grow Fact Rev, 1997,7:175-190
57. Barnes PJ, Kairn M. Nuclear factor kappa B: a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med, 1997, 336: 1066-1071
2. Bernstein JM. The molecular biology of nasal polyposis. Current allergy and asthma reports 2001; 1:262-267.
3. Norlander T, Westrin KM, Stierna P. The inflammatory response of the sinus and nasal mucosa during sinusitis: implications for research and therapy. Acta oto-laryngologica 1994; 515:38-44.
4. Liu Z, Kim J, Sypek JP et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. The Journal of allergy and clinical immunology 2004;114:783-790.
5. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhino sinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
6. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
7. Hay JG, Danel C, Chu CS, Crystal RG Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 1995;268:L565-75.
8. Thomas NS, Holgate ST. Genes for asthma on chromosome 11: an update. Clin Exp Allergy 1998; 28:387-91.
9. Wang SZ, Rosenberger CL, Bao YX, Stark JM, Harrod KS. Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus infection. J Immunol 2003; 171:1051-60.
10. Rossini GP, Fayard JM, Tessier C, Laugier C. Binding and internalization of extracellular type-Ⅰphospholipase A2 in uterine stromal cells. Biochem J 1996; 315 (Pt 3):1007-14.
11. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30: 469-475.
12. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
13. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
14. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
15. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc 2004; 1:93-8.
16. Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002; 169:4572-8.
17. Becker S, Quay J, Koren HS, Haskill JS. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol Lung Cell Mol Physiol 1994; 266:L278-86.
18. Cromwell O, Hamid Q, Corrigan CJ, Barkans J, Meng Q, Collins PD, et al. Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumour necrosis factor-alpha. Immunology 1992; 77:330-7.
19. Holgate ST, Lackie PM, Davies DE, Roche WR, Walls AF. The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma. Clin Exp Allergy 1999; 29(suppl 2):90-5.
20. Sanders SP, Siekierski ES, Richards SM, Porter JD, Imani F, and Proud D. Rhinovirus infection induces expression of type 2 nitric oxide synthase in human respiratory epithelial cells in vitro and in vivo. J Allergy Clin Immunol 2001; 107:235-43.
21. Zhu Z, Tang W, Gwaltney JM Jr, Wu Y, Elias JA. Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB. Am J Physiol Lung Cell Mol Physiol 1997; 273:L814-24.
1. Jacob A, Faddis BT, Chole RA. Chronic bacterial rhinosinusitis: description of a mouse model. Arch Otolaryngol Head Neck Surg, 2001, 127:657-664.
2. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, and Nicklas RA, et al. Rhinosinusitis: establishing definitions for clinical research and patient care. J Allergy Clin Immunol 2004; 114:155-212.
3. Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl 2007:1-136.
4. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
5. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30:469-475.
6. Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG, et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783-790.
7. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
8. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B, et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
9. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
10. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N, et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
11. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. The New England journal of medicine 1999; 340:197-206.
12. Pilon AL. Rationale for the development of recombinant human CC10 as a therapeutic for inflammatory and fibrotic disease. Annals of the New York Academy of Sciences 2000; 923:280-299.
13. Mukherjee AB, Kundu GC, Mantile-Selvaggi Get al. Uteroglobin: a novel cytokine? Cell Mol Life Sci 1999; 55:771-787.
14. Shijubo N, Kawabata I, Sato N, Itoh Y. Clinical aspects of Clara cell 10-kDa protein/uteroglobin (secretoglobin 1A1). Current pharmaceutical design 2003; 9:1139-1149.
15. Benson M, Fransson M, Martinsson T, Naluai AT, Uddman R, Cardell LO. Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy 2007; 62:178-183.
16. Hay JG, Danel C, Chu CS, Crystal RG. Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 1995;268:L565-75.
17. Singh G, Katyal SL, Brown WE, Phillips S, Kennedy AL, Anthony J, et al. Amino-acid and cDNA nucleotide sequences of human Clara cell 10 kDa protein. Biochim Biophys Acta 1988; 950:329-37.
18. Pattabiraman N, Matthews JH, Ward KB, Mantile-Selvaggi G, Miele L, Mukherjee AB. Crystal structure analysis of recombinant human uteroglobin and molecular modeling of ligand binding. Ann N Y Acad Sci 2000; 923:113-27.
19. Matthews JH, Pattabiraman N, Ward KB, Mantile G, Miele L, Mukherjee AB. Crystallization and characterization of the recombinant human Clara cell 10-kDa protein. Proteins 1994; 20:191-6.
1. Gibson PG, Simpson LJ, Saltos N. Heterogeneity of airwayinflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001; 119(5):1329-1336.
2. Shute JK, Vrugt B, Lindley IJ, Holgate ST, Bron A, Aalbers R, et al.Free and complexed interleukin-8 in blood and bronchial mucosa in asthma. Am J Respir Crit Care Med 1997; 155(6): 1877-1883.
3. Chanez P, Enander I, Jones I, Godard P, Bousquet J. Interleukin 8 in bronchoalveolar lavage of asthmatic and chronic bronchitis patients. Int Arch Allergy Immunol 1996; 111(1):83-88.
4. Teran LM, Johnston SL, Schroder JM, Church MK, Holgate ST. Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus-induced asthma. Am J Respir Crit Care Med 1997; 155(4): 1362-1366.
5. Wark PA, Johnston SL, Moric I, Simpson JL, Hensle MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002; 19(1):68-75.
6. Borish L, Mascali JJ, Dishuck J, Beam WR, Martin RJ, Rosenwasser LJ. Detection of alveolar macrophage-derived IL-1 beta in asthma. Inhibition with corticosteroids. J Immunol 1992; 149(9):3078-3082.
7. Sousa AR, Lane SJ, Nakhosteen JA, Lee TH, Poston RN. Expression of interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic bronchial epithelium. Am J Respir Crit Care Med 1996; 154(4 Pt 1):1061-1066.
8. Tomita K, Tanigawa T, Yajima H, Fukutani K, Matsumoto Y, Tanaka Y, et al. Identification and characterization of monocyte subpopulations from patients with bronchial asthma. J Allergy Clin Immunol 1995; 96(2):230-238.
9. de Kluijver J, Grunberg K, Pons D, de Klerk EP, Dick CR, Sterk PJ, et al. Interleukin-1 beta and interleukin-lra levels in nasal lavages during experimental rhinovirus infection in asthmatic and nonasthmatic subjects. Clin Exp Allergy 2003; 33(10):1415-1418.
10. Nakae S, Komiyama Y, Yokoyama H, Nambu A, Umeda M, Iwase M. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int Immunol 2003; 15(4):483-490.
11. Schmitz N, Kurrer M, Kopf M. The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model. Eur J Immunol 2003; 33(4):991-1000.
12. Griego SD, Weston CB, Adams JL, Tal-Singer R, Dillon SB. Role of p38 mitogen-activated protein kinase in rhinovirus-induced cytokine production by bronchial epithelial cells. J Immunol 2000; 165(9): 5211-5220.
13. Yamaya M, Sekizawa K, Suzuki T, Yamada N, Furukawa M, Ishizuka S, et al. Infection of human respiratory submucosal glands with rhinovirus: effects on cytokine and ICAM-1 production. Am J Physiol 1999; 277(2 Pt 1):L362-L371.
14. Oltmanns U, Issa R, Sukkar MB, John M, Chung KF. Role of c-jun Nterminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells. Br J Pharmacol 2003; 139(6):1228-1234.
15. Wuyts WA, Vanaudenaerde BM, Dupont LJ, Demedts MG, Verleden GM. Modulation by cAMP of IL-1 beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells. Eur Respir J 2003; 22(2):220-226.
16. Lee SA, Fitzgerald SM, Huang SK, Li C, Chi DS, Krishnaswamy G. Molecular regulation of IL-13 and MCP-1 expression in human mast cells by IL-1beta. Am J Respir Cell Mol 2004.
17. Manni A, Kleimberg J, Ackerman V, Bellini A, Patalano F, Mattoli S. Inducibility of RANTES mRNA by IL-lbeta in human bronchial epithelial cells is associated with increased NF-kappaB DNA binding activity. Biochem Biophys Res Commun 1996; 220(1): 120-124.
18. Marini M, Soloperto M, Mezzetti M, Fasoli A, Mattoli S. Interleukin-1 binds to specific receptors on human bronchial epithelial cells and upregulates granulocyte/macrophage colonystimulating factor synthesis and release. Am J Respir Cell Mol Biol 1991; 4(6):519-524.
19. Hashimoto S, Matsumoto K, Gon Y, Maruoka S, Kujime K, Hayashi S, et al. kinase regulates TNF alpha-, IL-1 alpha- and PAF induced RANTES and GM-CSF production by human bronchial epithelial cells. Clin Exp Allergy 2000; 30(1):48-55.
20. Matsumoto K, Hashimoto S, Gon Y, Nakayama T, Horie T. Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway. J Allergy Clin Immunol 1998; 101(6 Pt 1):825-831.
21. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
22. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30:469-475.
23. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. The New England journal of medicine 1999; 340:197-206.
24. Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG, et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783-790.
25. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
26. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54(9):825-857.
27. Shute J. Interleukin-8 is a potent eosinophil chemo-attractant. Clin Exp Allergy 1994; 24(3):203-206.
28. Pilon AL. Rationale for the development of recombinant human CC10 as a therapeutic for inflammatory and fibrotic disease. Annals of the New York Academy of Sciences 2000; 923:280-299.
29. Mukherjee AB, Kundu GC, Mantile-Selvaggi Get al. Uteroglobin: a novel cytokine? Cell Mol Life Sci 1999; 55:771-787.
30. Shijubo N, Kawabata I, Sato N, Itoh Y. Clinical aspects of Clara cell 10-kDa protein/uteroglobin (secretoglobin 1A1). Current pharmaceutical design 2003; 9:1139-1149.
31. Benson M, Fransson M, Martinsson T, Naluai AT, Uddman R, Cardell LO. Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy 2007; 62:178-183.
32. Wang SZ, Rosenberger CL, Bao YX, Stark JM, Harrod KS. Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus
??infection. J Immunol 2003; 171:1051-60.
33. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
34. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
35. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
36. Edwardsa MR, Mukaidab N, Johnsonc M, Johnstona SL. IL-1β induces IL-8 in bronchial cells via NF-kB and NF-IL6transcription factors and can be suppressed by glucocorticoids. Pulmonary Pharmacology & Therapeutics 2005; 18; 337-345.
37. Newton R, Stevens DA, Hart LA, Lindsay M, Adcock IM, Barnes PJ. Superinduction of COX-2 mRNA by cycloheximide and interleukin-lbeta involves increased transcription and correlates with increased NF-kappaB and JNK activation. FEBS Lett 1997; 418(1-2):135-8.
38. Kim YD, Kwon EJ, Park DW, Song SY, Yoon SK, Baek SH. Interleukin-lbeta induces MUC2 and MUC5AC synthesis through cyclooxygenase-2 in NCI-H292 cells. Mol Pharmacol 2002; 62(5): 1112-8.
1. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc 2004; 1:93-8.
2. Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002; 169:4572-8.
3. Mutsaers SE, Bishop JE, McGrouther G, Laurent GJ. Mechanisms of tissue repair: from wound healing to fibrosis. Int J Biochem Cell Biol 1997; 29:5-17.
4. Becker S, Quay J, Koren HS, Haskill JS. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol Lung Cell Mol Physiol 1994; 266:L278-86.
5. Cromwell O, Hamid Q, Corrigan CJ, Barkans J, Meng Q, Collins PD, et al. Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1beta and rumour necrosis factor-alpha. Immunology 1992; 77:330-7.
6. Holgate ST, Lackie PM, Davies DE, Roche WR, Walls AF. The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma. Clin Exp Allergy 1999; 29(suppl 2):90-5.
7. Zhu Z, Tang W, Gwaltney JM Jr, Wu Y, Elias JA. Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB. Am J Physiol Lung Cell Mol Physiol 1997; 273:L814-24.
8. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, Nicklas RA et al. Rhinosinusitis: establishing definitions for clinical research and patient care. J Allergy Clin Immunol 2004; 114:155-212.
9. Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl 2007; 20:1-136.
10. Singh G, Katyal SL. Clara cell proteins. Ann N Y Acad Sci 2000; 923:43-58.
11. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000; 30: 469-475.
12. Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG et al. Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 2004; 114:783-790.
13. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B et al. Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 2004; 114:664-670.
14. Johansson S, Wennergren G, Aberg N, Rudin A. Clara cell 16-kd protein downregulates T(H)2 differentiation of human naive neonatal T cells. J Allergy Clin Immunol 2007; 120:308-314.
15. Mandal AK, Zhang Z. Ray R, Choi MS, Chowdhury B, Pattabiraman N et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 2004; 199:1317-1330.
16. Liu Z, Lu X, Zhang XH et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy 2009; 64:149-157.
17. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54(9):825-857. 18. Shute J. Interleukin-8 is a potent eosinophil chemo-attractant. Clin Exp Allergy 1994; 24(3):203-206.
19. Newton R, Stevens DA, Hart LA, Lindsay M, Adcock IM, Barnes PJ. Superinduction of COX-2 mRNA by cycloheximide and interleukin-1beta involves increased transcription and correlates with increased NF-kappaB and JNK activation. FEBS Lett 1997; 418(1-2):135-8.
20. Oltmanns U, Issa R, Sukkar MB, John M, Chung KF. Role of c-jun Nterminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells. Br J Pharmacol 2003; 139(6): 1228-1234.
21. Hashimoto S, Matsumoto K, Gon Y, Maruoka S, Kujime K, Hayashi S, et al. kinase regulates TNF alpha-, IL-1 alpha- and PAF induced RANTES and GM-CSF production by human bronchial epithelial cells. Clin Exp Allergy 2000; 30(1):48-55.
22. Matsumoto K, Hashimoto S, Gon Y, Nakayama T, Horie T. Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway. J Allergy Clin Immunol 1998; 101(6 Pt 1):825-831.
23. Kim YD, Kwon EJ, Park DW, Song SY, Yoon SK, Baek SH. Interleukin-1beta induces MUC2 and MUC5AC synthesis through cyclooxygenase-2 in NCI-H292 cells. Mol Pharmacol 2002, 62(5): 1112-8.
24. Hay JG, Danel C, Chu CS, Crystal RG Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 1995;268:L565-75.
25. Thomas NS, Holgate ST. Genes for asthma on chromosome 11: an update. Clin Exp Allergy 1998; 28:387-91.
26. Mukaida N, Shiroo M, Matsushima K. Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8. J Immunol 1989; 143(4):1366-71.
27. Flohe L, Brigelius Flohe R, Saliou C, et al. Redox regulation of NF-kappa B activation. Free Radic Biol Med, 1997, 22 (6): 1115-1126.
28. MayMJ, Ghosh S. Signal transduction through NF- kappa B. Immunol Today, 1998, 19(2): 80-88.
29. Popescu FD. New asthma drugs acting on gene expression. J Cell Mol Med 2003, 7(4):475-86.
30. Hayden MS, Ghosh S. Signaling to NF-kappaB, Genes Dev 2004, 18(18): 2195-2224.
1. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 1986, 46: 705-716.
2. Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol, 1996, 14: 649-683.
3. Xiao W. Advances in NF kappaB signaling transduction and transcription. Cell Mol Immunol 2004; 1 (6): 425-435.
4. Karin M, Yamamoto Y, Wang QM. The IKK NF- kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 2004; 3(1):17-26.
5. Aggarwal BB, Takada Y, Shishodia S, et al. Nuclear transcription factor NF- kappa B: role in biology and medicine. Indian J Exp Biol 2004; 42(4):341-353.
6. Flohe L, Brigelius Flohe R, Saliou C, et al. Redox regulation of NF-kappa B activation. Free Radic Biol Med, 1997, 22 (6): 1115-1126.
7. MayMJ, Ghosh S. Signal transduction through NF- kappa B. Immunol Today, 1998, 19(2): 80-88.
8. Baeuerle PA. IkB-NF-kB structures: at the interface of inflammationcontrol. Cell, 1998, 95:729-731.
9. Hayden MS, Ghosh S. Signaling to NF-kappaB, Genes Dev 2004, 18(18): 2195-2224.
10. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha induced cell death. Science 1996; 274(5288):782- 784.
11. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 1995; 9(22):2723- 2735.
12. Miller BS, Zandi E. Complete reconstitution of human IkappaB kinase (IKK) complex in yeast. Assessment of its stoichiometry and the role of IKKgamma on the complex activity in the absence of stimulation. J Biol Chem 2001; 276(39):36320- 36326.
13. Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends in biochemical sciences 2004; 29:72-79.
14. Zandi E, Rothwarf DM, Delhase M, et al. The Ikappa B kinase complex (IKK) contains two kinase subunits. IKKα and IKKβ, necessary for IkappaB phosphorylation and NF kappa B activation. Cell, 1997, 91 (2): 243-252.
15. Woronicz JD, GAO X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF - kappa B activation and complex formation with IkappaB kinase-alpha and NIK. Science 1997; 278 (5339):866- 869.
16. Cohen L, Henzel WJ, Baeuerle PA. IKAP is a scaffold protein of the IkappaB kinase complex. Nature 1998; 395(6699):292- 296.
17. Rothwarf DM, Zandi E, Natoli G, et al. IKK-gamma is an essential regulatory subunit of the Ikappa B kinase complex. Nature, 1998, 395 (6699):297-300.
18. Delhase M, Hayakawa M, Chen Y, et al. Positive and negative regulation of I kappa B kinase activity through IKKbeta subunit phosphorylation. Science, 1999, 284(5412):309-313.
19. Yang, L, Colin, L, Zhang, DH, et al. Essential role of nuclear factor kappaB in the induction of eosinophilia in allergic airway inflammation. J Exp Med, 1998, 188(9), 1739-1750.
20. Das J, Chen CH, Yang L, et al. A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation Nat Immunol 2001, 2(1), 45-50.
21. Donovan CE, Mark DA, He HZ, et al. NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation. J Immunol 1999,163,6827-6833.
22. Hart LA, Krishnan VL, Adcock IM, et al. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med 1998, 158(5), 1585-1592.
23. Gagliardo R, Chanez P, Mathieu M, Bruno A, Costanzo G, Gougat C, Vachier I, Bousquet J, Bonsignore G, Vignola AM. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med. 2003, 168 (10), 1190-1198.
24. Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, and Janssen Heininger YM. NF-kappa B activation in airways modulates allergic inflammation but not hyperresponsiveness. J Immunol 2004; 173:7003-7009.
25. Jany B, Betz R, Schreck R. Activation of the transcription factor NF-kappa B in human tracheobronchial epithelial cells by inflammatory stimuli. Eur Respir J 1995; 8:387-391
26. Chabot FM. A role for transcription factor NF-kappa B in inflammation. Inflamm Res, 1997, 46(1): 1-2.
27. Lee JI, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target. J Clin Pharmacol, 1998, 38(11): 981-993.
28. Obata H, Biro S, Arima N, et al. NF-kappa B is induced in the nuclei of cultured rat aortic smooth muscle cells by stimulation of various growth factors. Biochem Biophys Res
??Commun, 1996, 224(1): 27-32.
29. Chetta A, Zanini A, Foresi A, et al.Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone. Am J Respir Crit Care Med, 2003, 167(5): 751-757.
30. Wang XT, Liu PY, Tang JB, et al. PDGF Gene therapy enhances expression of VEGF and bFGF genes and activates the NF-κB gene in signal pathways in ischemic flaps. Plast Reconstr Surg, 2006, 117(1): 129-137.
31. Yamashita N, Sekine K, Miyasaka T, et al. Platelet-derived growth factor is involved in the augmentation of airway responsiveness through remodeling of airways in diesel exhaust particulate-treated mice. J Allergy Clin Immunol, 2001, 107(1): 135-142.
32. Malmastrom J, Tufvesson E, Lofdahl CG.Activation of platelet-derived growth factor pathway in human asthmatic pulmonary-derived mesenchymal cells. Ectrophoresis, 2003, 24(1-2): 276-285.
33. Blackwell TS, Holden EP, Blackwell TR, DeLarco JE, Christman JW. Cytokine-induced neutrophil chemoattractant mediates neutrophilic alveolitis in rats: association with nuclear factor kappa B activation. American journal of respiratory cell and molecular biology 1994; 11:464-472.
34. Le Tulzo Y, Shenkar R, Kaneko Det al. Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression. The Journal of clinical investigation 1997; 99:1516-1524.
35. Simeonova PP, Luster MI. Asbestos induction of nuclear transcription factors and interleukin 8 gene regulation. American journal of respiratory cell and molecular biology 1996; 15:787-795.
36. Schwartz MD, Moore EE, Moore FAet al. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Critical care medicine 1996; 24:1285-1292.
37. Antal JM, Divis LT, Erzurum SC, Wiedemann HP, Thomassen MJ. Surfactant suppresses NF-kappa B activation in human monocytic cells. American journal of respiratory cell and molecular biology 1996; 14:374-379.
38. Wong HR, Ryan M, Wispe JR. Stress response decreases NF-kappaB nuclear translocation and increases I-kappaBalpha expression in A549 cells. The Journal of clinical investigation 1997; 99:2423-2428.
39. Das J, Chen C H, Yang L, et al. A critical role for NF-kappaB in GATA3 expression and Th2 differentiation in allergic airway inflammation. Nat Immunol, 2001, 2: 45-50.
40. Artis D ,Shapira S ,Mason N ,et al. Differential requirement for NF-kappaB family members in control of helminth infection and intestinal inflammation. J Immunol, 2002, 169:4481 -4487.
41. Pai S Y, Ho I C. c2Rel delivers a one-two punch in Thlcell differentiation. J Clin Invest, 2002,110:741 -742.
42. Liou H C, Hsia C Y. Distinctions between c-Rel andother NF-kappaB proteins in immunity and disease. Bioessays, 2003, 25:767 - 780.
43. Hilliard B A , Mason N ,Xu L ,et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J Clin Invest, 2002, 110:843 - 850.
44. Li-Weber M , Giaisi M , Baumann S , et al. NF-kappa B synergizes with NF-AT and NF-IL6 in activation of the IL-4 gene in T cells. Eur J Immunol, 2004, 34: 1111 -1118.
45. Tokuyama K, Nishimura H , Iizuka K, et al. Effect s of Y227632 , a Rho/Rho kinase inhibitor , on leukotriene D(4)- and histamine-induced airflow obstruction and airway microvascular leakage in guinea pigs in vivo. Pharmacology, 2002, 64:189 - 195.
46. Adachi T, Alum R. The mechanism of IL-5 signal transduction.Am J Physiol, 1998, 275(1):c623.
47. Sha WC. Regulation of immune responses by NF-KB/Rel transcription factors. J Exp Med. 1998, 187:143-146.
48. Vandenbroeck K, Alloza I, Gadina M, et al. Inhibiting cytokines of the interleukin-12
??family: recent advances and novelchallenges. J Pharmacol, 2004, 56:145 - 160.
49. Li-Weber M, Glaisi M, Baumann S, et al. NF-Kappa B synergizes with NF-AT and NF-IL6 in activation of the IL-4 gene in T-cell. Eur J Immunol, 2004, 34:1111 - 1118.
50. Ramis I, Bioque G, Lorente Jet al. Constitutive nuclear factor-kappaB activity in human upper airway tissues and nasal epithelial cells. Eur Respir J 2000; 15:582-589.
51. Takeno S, Hirakawa K, Ueda T, Furukido K, Osada R, Yajin K. Nuclear factor-kappa B activation in the nasal polyp epithelium: relationship to local cytokine gene expression. The Laryngoscope 2002; 112:53-58.
52. Wilson SJ, Leone BA, Anderson D, Manning A, Holgate ST. Immunohistochemical analysis of the activation of NF-kappaB and expression of associated cytokines and adhesion molecules in human models of allergic inflammation. The Journal of pathology 1999; 189:265-272.
53. Johan L , Ingalill R , Mathias T , et al. Glucocorticoid effects on NF-kappaB binding in the t ranscription of the ICAM-1 gene. Diochem Biophys Res Commun, 2000, 273:1008-1014.
54. Nissen R M, Yamamoto K R. The glucocorticoid receptor inhibits NF kappaB by interfering with serine22 phosphorylation of the RNA polymerase Ⅱ carboxy terminal domain. Genes Dev, 2000, 14:2314 - 2329.
55. HandelML. T ranscrip tion factors A P21 and N F2kappa B: where steroids meet the gold standard of anti-rheumatic drugs. Infiamm Res, 1997, 46: 282-286
56. Beauparlant P, Hiscott J, Crepieux P, et al. Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection. Cytoki & Grow Fact Rev, 1997,7:175-190
57. Barnes PJ, Kairn M. Nuclear factor kappa B: a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med, 1997, 336: 1066-1071