维生素A对肠道树突状细胞的影响与粘膜抗感染免疫的研究
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摘要
目的及意义维生素A(Vitamin A,VA)缺乏仍然是影响我国和发展中国家儿童健康的重要问题.VA营养对于维持粘膜屏障功能具有十分重要的作用,但是VA促进粘膜抗感染免疫功能的机制还有待于进一步阐明。本课题研究了VA营养状态对粘膜树突状细胞(Dendritic Cell,DC)成熟分化和功能的影响,并探讨了其对肠道粘膜抗感染免疫的调节作用.
方法通过建立VA缺乏大鼠模型并诱导肠道感染,应用免疫组化、RT-荧光定量PCR、ELISA,观察粘膜DC数目、成熟度、抗原识别受体表达水平、信号转导以及对Th1/Th2细胞因子蛋白水平和基因转录水平的影响;并观察视黄酸受体(RARs/RXRs)的表达变化.
结果VA缺乏与VA正常大鼠比较:1.肠粘膜DC的数目显著增加,当合并感染时不仅DC数量而且成熟分化也明显增加。2.肠集合淋巴小结中TLR2、TLR4的蛋白表达都明显升高,在合并感染后TLR2的表达上调更明显。3.主要由DC产生的细胞因子IL-12的表达显著增高,伴有肠道感染时IL-12的产生进一步升高;Th1细胞因子IFN-γ和IL-2降低,感染后IFN-γ显著降低;Th2细胞因子IL-10的产生明显下降,在肠道感染时IL-4、IL-6和IL-10都显著下降。4.肠道粘膜RARα、γ和RXRα、β、γ的表达都显著降低,但在感染后这五种视黄酸受体亚型较VA缺乏未感染组显著升高。
结论1.VA缺乏大鼠粘膜DC的增多和活化可能是诱导炎症反应增强,导致粘膜损伤的重要机制之一。2.肠粘膜Th1和Th2细胞因子的产生都显著减少是VA缺乏大鼠粘膜免疫功能降低的重要特征之一。3.对细胞因子产生水平的调节可能是VAD影响粘膜免疫功能,加重粘膜感染损伤的重要机制。4。肠粘膜视黄酸受体的表达不仅与VA营养状态呈正相关变化,而且可能还参与介导VA对粘膜抗感染免疫的调节作用。
Objective Vitamin A deficiency is still a serious problem that impairing the health of children in impoverished area.It has been known that VA plays a very important role in maintain of mucosal barrier,but the mechanisms of VA promote mucosal immunity are uncompleted clear.In this project,we studied effect of VA on the maturation and functions of mucosal dendritic cells(DC),and influence to mucosal immunity,to understand how VA enhances the immunity against infection in mucosa.
Methods A rat model with VA deficiency(VAD)was set up,and intestinal infecions were induced by the oral inoculation of salmonella.By used of immuneohistochemical, RT-quantity PCR,ELISA,the affections of VA on the number and maturation of DC, antigenrecognition receptors and cytokines production,as well as the expressions of retinoic receptors(RARα,β,γ,RXRα,β,γ) in mucosa were detection.
noicResults Compared with the VA normal rats,the numbers of DC in intestinal mucosa were increased in VAD rat,and when infection was complicated with VAD,both of the number and the maturation of DC were promoted.The expressions of TLR2 and TLR4 were elevated in mucosa,and higher expression of TLR2 was found in infected intestinal mucosa of VAD rats.IL-12 production,major from DC,was increased in intestinal mucosa of VAD rats,and more raised when infection was complicated.Productions of Th1 and Th2 cytokines from intestinal mucosa of VAD rats were reduced,and after infection these cytokines were still reduced.The expressions of RARα,RARγand RXRα、β、γwere down-regulated in intestinal mucosa of VAD rats,however,in infected intestinal mucosa these five receptors were up-regulated.
Conclusions 1.The augment of the number and activation ofmucosal DC may play important roles in inflammatory reactions and impairment of mucosa in VAD rats.2.The markedly reduced production of Th1 and Th2 cytokines in intestinal mucosa was one of the important characters of the declined mucosal immunity in VAD rat.3.The regulation of VAD on the production of cytokines by local intestinal mucosa is likely to be an important mechanism of VAD affects intestinal mucosal immunity.4.The expressions of retinoic acid receptors in intestinal mucosa were positive correlated with VA states,and which was likely to involve into the regulation of VA on mucosal immunity.
方法通过建立VA缺乏大鼠模型并诱导肠道感染,应用免疫组化、RT-荧光定量PCR、ELISA,观察粘膜DC数目、成熟度、抗原识别受体表达水平、信号转导以及对Th1/Th2细胞因子蛋白水平和基因转录水平的影响;并观察视黄酸受体(RARs/RXRs)的表达变化.
结果VA缺乏与VA正常大鼠比较:1.肠粘膜DC的数目显著增加,当合并感染时不仅DC数量而且成熟分化也明显增加。2.肠集合淋巴小结中TLR2、TLR4的蛋白表达都明显升高,在合并感染后TLR2的表达上调更明显。3.主要由DC产生的细胞因子IL-12的表达显著增高,伴有肠道感染时IL-12的产生进一步升高;Th1细胞因子IFN-γ和IL-2降低,感染后IFN-γ显著降低;Th2细胞因子IL-10的产生明显下降,在肠道感染时IL-4、IL-6和IL-10都显著下降。4.肠道粘膜RARα、γ和RXRα、β、γ的表达都显著降低,但在感染后这五种视黄酸受体亚型较VA缺乏未感染组显著升高。
结论1.VA缺乏大鼠粘膜DC的增多和活化可能是诱导炎症反应增强,导致粘膜损伤的重要机制之一。2.肠粘膜Th1和Th2细胞因子的产生都显著减少是VA缺乏大鼠粘膜免疫功能降低的重要特征之一。3.对细胞因子产生水平的调节可能是VAD影响粘膜免疫功能,加重粘膜感染损伤的重要机制。4。肠粘膜视黄酸受体的表达不仅与VA营养状态呈正相关变化,而且可能还参与介导VA对粘膜抗感染免疫的调节作用。
Objective Vitamin A deficiency is still a serious problem that impairing the health of children in impoverished area.It has been known that VA plays a very important role in maintain of mucosal barrier,but the mechanisms of VA promote mucosal immunity are uncompleted clear.In this project,we studied effect of VA on the maturation and functions of mucosal dendritic cells(DC),and influence to mucosal immunity,to understand how VA enhances the immunity against infection in mucosa.
Methods A rat model with VA deficiency(VAD)was set up,and intestinal infecions were induced by the oral inoculation of salmonella.By used of immuneohistochemical, RT-quantity PCR,ELISA,the affections of VA on the number and maturation of DC, antigenrecognition receptors and cytokines production,as well as the expressions of retinoic receptors(RARα,β,γ,RXRα,β,γ) in mucosa were detection.
noicResults Compared with the VA normal rats,the numbers of DC in intestinal mucosa were increased in VAD rat,and when infection was complicated with VAD,both of the number and the maturation of DC were promoted.The expressions of TLR2 and TLR4 were elevated in mucosa,and higher expression of TLR2 was found in infected intestinal mucosa of VAD rats.IL-12 production,major from DC,was increased in intestinal mucosa of VAD rats,and more raised when infection was complicated.Productions of Th1 and Th2 cytokines from intestinal mucosa of VAD rats were reduced,and after infection these cytokines were still reduced.The expressions of RARα,RARγand RXRα、β、γwere down-regulated in intestinal mucosa of VAD rats,however,in infected intestinal mucosa these five receptors were up-regulated.
Conclusions 1.The augment of the number and activation ofmucosal DC may play important roles in inflammatory reactions and impairment of mucosa in VAD rats.2.The markedly reduced production of Th1 and Th2 cytokines in intestinal mucosa was one of the important characters of the declined mucosal immunity in VAD rat.3.The regulation of VAD on the production of cytokines by local intestinal mucosa is likely to be an important mechanism of VAD affects intestinal mucosal immunity.4.The expressions of retinoic acid receptors in intestinal mucosa were positive correlated with VA states,and which was likely to involve into the regulation of VA on mucosal immunity.
引文
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