胞内DNA感受器DAI在慢性鼻—鼻窦炎及鼻息肉发病机制中作用的研究
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摘要
第一部分
胞内DNA感受器DAI在慢性鼻-鼻窦炎和鼻息肉组织中的表达
目的
研究DNA依赖的干扰素调节因子激活物(DNA-dependent activator of IFN-regulatory factors,DAI) mRNA以及蛋白在慢性鼻-鼻窦炎、鼻息肉和正常下鼻甲鼻黏膜组织的表达及表达程度的差异,探讨其在慢性鼻-鼻窦炎、和鼻息肉发病机制中的作用。
方法
RT-PCR检测DAI在人类支气管上皮细胞系BEAS-2B细胞及慢性鼻-鼻窦炎、鼻息肉和正常下鼻甲鼻黏膜组织的表达。real time RT-PCR技术和免疫组织化学法(IHC)分别检测慢性鼻-鼻窦炎、鼻息肉和下鼻甲黏膜组织中DAI的表达水平。
结果
DAI mRNA及蛋白在BEAS-2B细胞、慢性鼻-鼻窦炎、慢性鼻-鼻窦炎合并鼻息肉和下鼻甲组织中均有表达,real-time RT-PCR及免疫组化显示慢性鼻-鼻窦炎和鼻息肉组织DAI的表达水平明显低于下鼻甲组织,而以慢性鼻-鼻窦炎组织中下降更为明显。
结论
DAI mRNA及蛋白在慢性鼻-鼻窦炎、鼻息肉和正常下鼻甲黏膜上皮细胞内均有表达,且表达量不同,差异有统计学意义,提示DAI可能在慢性鼻-鼻窦炎的发病机制中起重要作用。
第二部分
双链DNA对BEAS-2B细胞及体外培养的鼻粘膜组织块的影响
目的
1观察双链DNA分子poly(dA-dT).poly(dT-dA)是否能够诱导BEAS-2B细胞产生I型干扰素及DAI。
2了解dsDNA刺激BEAS-2B细胞后所产生各细胞因子的影响,探讨其相互作用。
3使用鼻粘膜组织块体外培养研究dsDNA对鼻粘膜组织中相关细胞因子的影响,探讨DNA受体DAI分子在慢性鼻-鼻窦炎、鼻息肉急性复发中的作用。
方法
1 poly(dA-dT).poly(dT-dA)转染BEAS-2B细胞,real time RT-PCR检测相关细胞因子的表达水平,western blot检测DAI的表达。
2 dsDNA转染体外培养的鼻粘膜组织块,real time RT-PCR检测相关细胞因子的表达水平。
结果
1 poly(dA-dT).poly(dT-dA)能够诱导BEAS-2B细胞产生I型干扰素IFN-β,且具有时间与剂量依赖性。dsDNA刺激BEAS-2B细胞后产生的应答中,早期主要表现为促炎因子的升高,后期则以抗炎因子的高表达为主,且dsDNA对抗炎因子的诱导更为明显。
2 dsDNA刺激体外培养的鼻粘膜组织块后,表现为IL-6、IL-8、IP-10、IL-1β及MCP-3的高表达主要出现在NP中;TNF-α、IL-17、IL-22及IFN-λ2的高表达主要出现CRS中;而正常下鼻甲粘膜却对dsDNA的反应性较低。
结论
用dsDNA刺激BEAS-2B细胞后,机体通过自身负反馈调节,最终表现以抗炎作用为主,对机体起保护性作用。在病原微生物刺激后,慢性鼻-鼻窦炎、鼻息肉比正常下鼻甲粘膜组织可能更容易受到影响,导致慢性鼻-鼻窦炎及鼻息肉的急性发作。而上述这些作用,可能正是通过dsDNA的受体DAI发挥作用的。
PartⅠCytosolic DNA Sensor Expression in Chronic RhinoSinusitis and Nasal Polyps
Objective
To study the expression of DAI (DNA-dependent activator of IFN-regulatory factors) mRNA in chronic rhinosinusitis (CRS) and nasal polyps (NPs) ,compared the DAI expression between chronic rhinosinusitis (CRS) and nasal polyps (NPs) patients, and to explored the role of DAI inthepathogenesis of chronic rhinosinusitis (CRS) and nasal polyps (NPs).
Methods
The mRNA expression of DAI in human bronchial epithelial cell line BEAS-2B and tissue were detected by RT-PCR. tissue DAI levels were compared among controls,CRS and NPs patients by means of real time RT-PCR and immunohistochemistry.
Results
The DAI mRNA were expressed in BEAS-2B cells and tissue. The mRNA and protein expression rates of DAI were significant inhibited in both CRS and NPs patients.There were a significant further decrease of DAI expression in CRS patients.
Conclusion
DAI mRNA and protein were expressed in both patients and controls.Significant difference in DAI expression was found between patients and controls.Which may be one of the evidence that DAI may take part in the pathogenesis of CRS and NPs.
PartⅡThe Effect of Double- Standed DNA on BEAS-2B Cells and Nasal Mucosal Tissue Explant Culture
Objective
1 To ensure wherther dsDNA can induced the expression of IFN-βand DAI.
2 To explore the interaction between cytokines when BEAS-2B cells stimulated with dsDNA.
3 Use of nasal mucosal Tissue explant culture study the effect of B-DNA on nasal mucosal tissue related cytokines, explore the role of DAI plays in acute exacerbation of CRS and NPs.
Methods
1 BEAS-2B cells were transfected with poly(dA-dT).poly(dT-dA). Cellular total RNAs were extracted and detected for related cytokines expression by reverse transcription real-time PCR. The expression level of DAI protein was detected by the techniques of western blot.
2 Nasal mucosal Tissue explant culture were transfected with B-DNA, and subjected to reverse transcription real-time PCR analysis to evaluate the expression of related cytokines mRNA.
Results
1 dsDNA was able to induce type I interferon in BEAS-2B cells in a time- and dose-dependent manner. in the early stages, dsDNA-induced high expression of pro-inflammatory factor, and anti-inflammatory factor reached a much higher level in the late stage in BEAS-2B cells.
2 After nasal mucosal Tissue explant culture were transfected with dsDNA, IL-6, IL-8, IP-10, IL-1βand MCP-3 mRNA was greatly high expressed in NPs, TNF-α, IL-17, IL-22 and IFN-λ2 was mainly high expressed in CRS, but was not the normal inferior turbinate mucosa, it have a lowest reactive .
Conclusion
after BEAS-2B stimulated with dsDNA, the body via a negative feedback effect participates in the regulation of inflammatory responses, the anti-inflammatory is the ultimate representation of the feedback regulation. it provides protective effect on the body. when stimulated with pathogenic microorganisms, CRS and NPs may be more vulnerable than normal turbinate mucosa, leading to acute exacerbation of CRS and NPs. The effects mentioned above, it may work through dsDNA receptors DAI.
胞内DNA感受器DAI在慢性鼻-鼻窦炎和鼻息肉组织中的表达
目的
研究DNA依赖的干扰素调节因子激活物(DNA-dependent activator of IFN-regulatory factors,DAI) mRNA以及蛋白在慢性鼻-鼻窦炎、鼻息肉和正常下鼻甲鼻黏膜组织的表达及表达程度的差异,探讨其在慢性鼻-鼻窦炎、和鼻息肉发病机制中的作用。
方法
RT-PCR检测DAI在人类支气管上皮细胞系BEAS-2B细胞及慢性鼻-鼻窦炎、鼻息肉和正常下鼻甲鼻黏膜组织的表达。real time RT-PCR技术和免疫组织化学法(IHC)分别检测慢性鼻-鼻窦炎、鼻息肉和下鼻甲黏膜组织中DAI的表达水平。
结果
DAI mRNA及蛋白在BEAS-2B细胞、慢性鼻-鼻窦炎、慢性鼻-鼻窦炎合并鼻息肉和下鼻甲组织中均有表达,real-time RT-PCR及免疫组化显示慢性鼻-鼻窦炎和鼻息肉组织DAI的表达水平明显低于下鼻甲组织,而以慢性鼻-鼻窦炎组织中下降更为明显。
结论
DAI mRNA及蛋白在慢性鼻-鼻窦炎、鼻息肉和正常下鼻甲黏膜上皮细胞内均有表达,且表达量不同,差异有统计学意义,提示DAI可能在慢性鼻-鼻窦炎的发病机制中起重要作用。
第二部分
双链DNA对BEAS-2B细胞及体外培养的鼻粘膜组织块的影响
目的
1观察双链DNA分子poly(dA-dT).poly(dT-dA)是否能够诱导BEAS-2B细胞产生I型干扰素及DAI。
2了解dsDNA刺激BEAS-2B细胞后所产生各细胞因子的影响,探讨其相互作用。
3使用鼻粘膜组织块体外培养研究dsDNA对鼻粘膜组织中相关细胞因子的影响,探讨DNA受体DAI分子在慢性鼻-鼻窦炎、鼻息肉急性复发中的作用。
方法
1 poly(dA-dT).poly(dT-dA)转染BEAS-2B细胞,real time RT-PCR检测相关细胞因子的表达水平,western blot检测DAI的表达。
2 dsDNA转染体外培养的鼻粘膜组织块,real time RT-PCR检测相关细胞因子的表达水平。
结果
1 poly(dA-dT).poly(dT-dA)能够诱导BEAS-2B细胞产生I型干扰素IFN-β,且具有时间与剂量依赖性。dsDNA刺激BEAS-2B细胞后产生的应答中,早期主要表现为促炎因子的升高,后期则以抗炎因子的高表达为主,且dsDNA对抗炎因子的诱导更为明显。
2 dsDNA刺激体外培养的鼻粘膜组织块后,表现为IL-6、IL-8、IP-10、IL-1β及MCP-3的高表达主要出现在NP中;TNF-α、IL-17、IL-22及IFN-λ2的高表达主要出现CRS中;而正常下鼻甲粘膜却对dsDNA的反应性较低。
结论
用dsDNA刺激BEAS-2B细胞后,机体通过自身负反馈调节,最终表现以抗炎作用为主,对机体起保护性作用。在病原微生物刺激后,慢性鼻-鼻窦炎、鼻息肉比正常下鼻甲粘膜组织可能更容易受到影响,导致慢性鼻-鼻窦炎及鼻息肉的急性发作。而上述这些作用,可能正是通过dsDNA的受体DAI发挥作用的。
PartⅠCytosolic DNA Sensor Expression in Chronic RhinoSinusitis and Nasal Polyps
Objective
To study the expression of DAI (DNA-dependent activator of IFN-regulatory factors) mRNA in chronic rhinosinusitis (CRS) and nasal polyps (NPs) ,compared the DAI expression between chronic rhinosinusitis (CRS) and nasal polyps (NPs) patients, and to explored the role of DAI inthepathogenesis of chronic rhinosinusitis (CRS) and nasal polyps (NPs).
Methods
The mRNA expression of DAI in human bronchial epithelial cell line BEAS-2B and tissue were detected by RT-PCR. tissue DAI levels were compared among controls,CRS and NPs patients by means of real time RT-PCR and immunohistochemistry.
Results
The DAI mRNA were expressed in BEAS-2B cells and tissue. The mRNA and protein expression rates of DAI were significant inhibited in both CRS and NPs patients.There were a significant further decrease of DAI expression in CRS patients.
Conclusion
DAI mRNA and protein were expressed in both patients and controls.Significant difference in DAI expression was found between patients and controls.Which may be one of the evidence that DAI may take part in the pathogenesis of CRS and NPs.
PartⅡThe Effect of Double- Standed DNA on BEAS-2B Cells and Nasal Mucosal Tissue Explant Culture
Objective
1 To ensure wherther dsDNA can induced the expression of IFN-βand DAI.
2 To explore the interaction between cytokines when BEAS-2B cells stimulated with dsDNA.
3 Use of nasal mucosal Tissue explant culture study the effect of B-DNA on nasal mucosal tissue related cytokines, explore the role of DAI plays in acute exacerbation of CRS and NPs.
Methods
1 BEAS-2B cells were transfected with poly(dA-dT).poly(dT-dA). Cellular total RNAs were extracted and detected for related cytokines expression by reverse transcription real-time PCR. The expression level of DAI protein was detected by the techniques of western blot.
2 Nasal mucosal Tissue explant culture were transfected with B-DNA, and subjected to reverse transcription real-time PCR analysis to evaluate the expression of related cytokines mRNA.
Results
1 dsDNA was able to induce type I interferon in BEAS-2B cells in a time- and dose-dependent manner. in the early stages, dsDNA-induced high expression of pro-inflammatory factor, and anti-inflammatory factor reached a much higher level in the late stage in BEAS-2B cells.
2 After nasal mucosal Tissue explant culture were transfected with dsDNA, IL-6, IL-8, IP-10, IL-1βand MCP-3 mRNA was greatly high expressed in NPs, TNF-α, IL-17, IL-22 and IFN-λ2 was mainly high expressed in CRS, but was not the normal inferior turbinate mucosa, it have a lowest reactive .
Conclusion
after BEAS-2B stimulated with dsDNA, the body via a negative feedback effect participates in the regulation of inflammatory responses, the anti-inflammatory is the ultimate representation of the feedback regulation. it provides protective effect on the body. when stimulated with pathogenic microorganisms, CRS and NPs may be more vulnerable than normal turbinate mucosa, leading to acute exacerbation of CRS and NPs. The effects mentioned above, it may work through dsDNA receptors DAI.
引文
1. Scadding GK, Williams A. The burden of allergic rhinitis as reported by UK patients compared with their doctors. Rhinology. 2008; 46(2):99-106.
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3. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature. 2007; 448(7152):501-5.
4. Miyahira AK, Shahangian A, Hwang S, Sun R, Cheng G. TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections. J Immunol. 2009; 182(4):2248-57.
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7. Kuehnemund M, Ismail C, Brieger J, Schaefer D, Mann WJ. Untreated chronic rhinosinusitis: a comparison of symptoms and mediator profiles. Laryngoscope. 2004. 114(3): 561-5.
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2. Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol. 2006; 7(1):40-8.
3. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature. 2007; 448(7152):501-5.
4. Miyahira AK, Shahangian A, Hwang S, Sun R, Cheng G. TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections. J Immunol. 2009; 182(4):2248-57.
5. Rothenburg S, Schwartz T, Koch-Nolte F, Haag F. Complex regulation of the human gene for the Z-DNA binding protein DLM-1. Nucleic Acids Res. 2002. 30(4): 993-1000.
6. Fu Y, Comella N, Tognazzi K, Brown LF, Dvorak HF, Kocher O. Cloning of DLM-1, a novel gene that is up-regulated in activated macrophages, using RNA differential display. Gene. 1999. 240(1): 157-63.
7. Kuehnemund M, Ismail C, Brieger J, Schaefer D, Mann WJ. Untreated chronic rhinosinusitis: a comparison of symptoms and mediator profiles. Laryngoscope. 2004. 114(3): 561-5.
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(2):93-8.
2. Repka-Ramirez S, Naranch K, Park YJ, Clauw D, Baraniuk JN. Cytokines in nasal lavage fluids from acute sinusitis, allergic rhinitis, and chronic fatigue syndrome subjects. Allergy Asthma Proc. 2002; 23(3):185-90.
3. Yasuda K, Yu P, Kirschning CJ, Schlatter B, Schmitz F, Heit A, et al. Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways. J Immunol. 2005; 174(10): 6129-36.
4. 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(2):93-8.
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-1 beta and tumour necrosis factor-alpha. Immunology. 1992; 77(3):330-7.
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