荷斯坦奶牛乳腺上皮细胞β-防御素mRNA的表达及可能信号通路的初步研究
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摘要
防御素是一种富含精氨酸的阳离子低分子短肽,对G+、G-菌,真菌、包膜病毒和螺旋体等都有广谱的杀伤作用。它不仅是新型高效的抗菌多肽,能直接杀菌,抵御入侵机体的病原微生物,而且能调节机体免疫应答、调节组织创伤修复、在介导获得性免疫反应过程中起着重要作用。防御素是动物机体内防御系统中重要的成员,提示防御素可能在奶牛乳腺中抵抗微生物感染、维持乳腺健康方面起着至关重要的作用。在奶牛发生乳腺炎时,防御素应参与了乳腺的防御过程,但防御素产生了怎样的变化,在变化的过程中又是如何调控的仍不清楚。
目前防御素在抗乳腺炎和其防御机制方面的研究报道非常少,而关于β-防御素抗乳腺炎的作用过程更是少之又少,也未见其在奶牛乳腺中的表达调控机制方面的研究。为此我们初步研究了β-防御素基因在奶牛乳腺的表达情况和LPS诱导时β-防御素基因的表达变化及其可能调控的信号通路。其结果如下：
1、克隆了奶牛乳腺组织EBD、TAP、LAP、BNBD4、BNBD5和BNBD7基因。以奶牛乳腺组织为材料,提取乳腺组织总RNA,根据NCBI数据库中牛β-防御素cDNA的保守序列分别设计特异性引物,采用RT-PCR技术扩增基因片段,纯化后连接pMD19-T载体,转化入大肠杆菌后挑取阳性重组质粒测序,测序结果证实EBD、TAP、LAP、 BNBD4、BNBD5和BNBD7在奶牛乳腺组织有表达。
2、建立稳定的奶牛乳腺上皮细胞培养体系,并确定乳腺上皮细胞6种β-防御素基因的表达情况。采用胶原酶消化法和胰蛋白酶选择性消化法对奶牛乳腺上皮细胞进行分离、培养和纯化。对奶牛乳腺上皮细胞进行原代培养以及传1代细胞的传代培养。经形态学、核型分析和运用RT-PCR方法检测α-酪蛋白基因的表达,绘制生长曲线等方法对所培养的奶牛乳腺上皮细胞进行鉴定和分析,结果证实所培养的细胞为上皮细胞,细胞生长状态良好,符合细胞生长规律。在成功培养奶牛乳腺上皮细胞的基础上,提取乳腺上皮细胞总RNA,运用RT-PCR方法扩增6种β-防御素(EBD、BNBD4、BNBD5、BNBD7、LAP、TAP),测序结果证明6种β-防御素基因在奶牛乳腺上皮细胞有表达。
3、获得奶牛乳腺组织与乳腺上皮细胞6种β-防御素mRNA的基础表达水平。通过RT-qPCR方法对6种β-防御素进行扩增及数据统计分析。结果表明,乳腺组织中6种β-防御素基因的相对表达量有显著性差异(P<0.01),仅BNBD4与BNBD5之间的相对表达量没有显著性差异,其中LAP相对表达量最多,BNBD7、EBD、BNBD5、BNBD4次之,TAP的相对表达量最低。奶牛乳腺上皮细胞中6种β-防御素基因mRNA水平的相对表达量有显著性差异(P<0.01),仅EBD与BNBD4之间的相对表达量没有显著性差异,其中LAP相对表达量最多,BNBD7、BNBD5、BNBD4、EBD次之,TAP的相对表达量最低。
4、为了研究乳腺上皮细胞中6种β-防御素mRNA表达水平,我们培养乳腺上皮细胞,添加代表大肠杆菌为主要侵染力的脂多糖(LPS)建立试验性乳腺炎的乳腺上皮细胞模型。首先,确定了最佳的传1代细胞来研究6种β-防御素的表达变化。然后在奶牛乳腺上皮细胞中添加不同剂量(50、100、200、400、800ng/ml) LPS处理不同时间(2、4、8、16、24、48、72h),采用实时RT-qPCR方法检测乳腺上皮细胞中6种β-防御素mRNA的表达水平。结果表明：①乳腺上皮细胞中6种β-防御素mRNA表达量与空白对照组相比存在一定的剂量和时间效应,有些随着浓度增加而表达量增高,如LAP,这可能与其基础表达量有关；在时间上总体趋势是当LPS诱导后主要在8h、48h与72h时相对表达量达到高值,在2h、4h、16h和24h表达量相对较低,推测与其信号通路基因的调控时间相关。②LAP表达量差异较大,增加幅度较高,在奶牛乳腺防御中起重要的防御作用。③乳腺上皮细胞中6种β-防御素mRNA的表达量都显著增加,表明6种β-防御素的表达都呈诱导型表达。
5、确定奶牛乳腺上皮细胞中是否有TLR2、TLR4、NF-κB P65、CREB表达,根据已发表的基因各自序列设计特异性引物,经RT-PCR鉴定及测序证明4种基因在奶牛乳腺上皮细胞可表达。然后采用RT-qPCR技术检测4个基因mRNA的表达变化。结果表明：①LPS刺激后TLRs中TLR2与TLR4的介导作用中,TLR2主要在4h时起介导作用,在2h、8h和48h起部分调控作用；TLR4在除4h外的几个时间段起主要的介导作用。②TLR2与TLR4都介导了LPS刺激时的调控过程,在整个调控过程中以TLR4起主要介导作用。③CREB在与NF-κB并行的信号通路中,CREB和核因子NF-κB都参与了炎症的调控过程。④在调控过程中CREB主要在8h时起调节作用,NF-κB在各时段都有显著性差异,调控增幅较大。⑤脂多糖对于4种调控因子的表达量都有促进作用。
6、为了进一步确定NF-κB途径是否为脂多糖诱导防御素表达的信号通路之一我们在传1代乳腺上皮细胞添加特异性抑制剂PDTC以阻断NF-κB信号通路,然后采用RT-qPCR技术检测BNBD5、BNBD7、TAP、LAP、EBD和BNBD4等基因mRNA表达水平。结果表明：BNBD5、BNBD7、TAP、LAP、EBD和BNBD4mRNA表达量均有下降,在荷斯坦奶牛乳腺上皮细胞中NF-κB为LPS诱导β-防御素基因表达的信号通路之
Defensins are a group of cationic peptide, which contain cysteine-rich, broad-spectrum effect on killing G+, G-bacteria, fungi, enveloped viruses, and spirochetes. It is not only efficient antimicrobial peptides, a direct bactericidal effect against the invading organism pathogenic microorganisms, but also can regulate the immune responsing and tissue repairing, playing an important role in mediating acquired immune response in the process. Due to defensins is the largest members in animal defenses, which indicates that defensins may play crucial role in resisting microbe infection and maintaining breast health. Defensins should participate in mammary gland defense processes, but be unknown to defensins produced what have changed and how to carry out adjusting.
Nowadays there is seldom research of defensins in resistance to mastitis and its defense mechanism. At the same time, the β-defensins resistance to mastitis in the process is very few. Thus, expression of beta defensin and its possible signal pathways by LPS stimulated were studied initially in this paper. The results are listed as follows:
1. At first, to obtain the amplified six kinds of beta defensin (EBD、 BNBD4、 BNBD5、 BNBD7、 LAP、 TAP) gene from the cow mammary gland tissue. Total RNA was extracted from the mammary tissue of a cow and, cDNA encoding beta defensin was amplified by the reverse transcription-PCR (RT-PCR) with the pair of primers which were designed according to the cDNA of NCBI database conserve sequences of reported P-defensins. The objective fragments after purification were connected to the pMD19-T vector, recombinant plasmid positive selection by transformed into Escherichia coli, and samples sequencing. The sequencing results confirmed that the6β-defensins of cloning expressed in mammary gland tissue.
2. To establish stable culture system of mammary epithelium cell in cow and confirm the six kinds of P-defensins expression in mammary epithelial cell. We used collagenase digestion and trypsin chosen digestion method to isolate and purify bovine mammary epithelial cells, and culture the original generation of mammary epithelium cells, at least the cells culture processing to the first filial generation. The consequence shows that it is confirmed that the cultured cells are epithelial cell through the verification from morphological and detecting the expression of a-casein by using RT-PCR method. Analyzing chromosomal karyotype and drawing auxodrome curve to the first filial generation cells are confirm cell growth in good condition and compliance with cell growth law. Total RNA was extracted from the mammary epithelial cells which cultured successfully above and cDNA encoding beta defensin was amplified by the reverse transcription-PCR (RT-PCR). The sequencing results confirmed that the6P-defensins of cloning expressed in mammary epithelial cells.
3. We detected the basic expression of6kinds of (3-defensins in cow breast tissue and mammary epithelial cells by fluorescence quantitative PCR method in order to study the defense functions of defensins. The results showed that the expression of the relative volume of6β-defensins have significant differences (P<0.01), only the relative expression of BNBD4and BNBD5non-significant difference in breast tissue. The result indicated that relative expression quantity of β-defensins to LAP is the highest, to BNBD7、EBD、BNBD5、BNBD4is in the middle, to TAP is the lowest. The results showed that the expression of the relative volume of6β-defensins have significant differences (P<0.01), only the relative expression of BNBD4and EBD non-significant difference in bovine mammary epithelial cells. The relative expression level of LAP is the highest in six β-defensins, BNBD7、BNBD5、BNBD4、EBD is the middle, the TAP is the minimum.
4. After that, establishing mammary epithelial cells model of experimental mastitis by adding LPS produced mainly by E.coli infection in order to studying the six kinds of β-defensins mRNA in mammary epithelial cells. Firstly, we choose the best passage1cells to study changes. The dairy cow mammary epithelial cells were stimulated with different concentration (50,100,200,400and800ng/ml) of LPS. Then the total RNA was extracted after stimulated in seven different times (2,4,8,16,24,48and72h), and the mRNA expression levels of six kinds of β-defensins were evaluated by real-time quantitative PCR. The results show that:①LPS significantly down-regulated a-casein mRNA expression in a time and dose dependent, and the mammary epithelial cells produced a certain inflammatory by adding the LPS. The expression of six kinds of beta-defensins mRNA has significant differences in a time and dose dependent. Some increased with the concentration. The time overall trend of the relative expression is amount high value in8h、48h and72h, and a lower expression level in2h、4h、16h and24h after LPS stimulated mammary epithelial cells.②The expression level differences of LAP gene mRNA is larger and the amplitude is higher than other beta-defensin.③The expression level of the6beta-defensins increased significantly indicated that they are all inducible expression and the increased extent related to the basic expression levels in cow mammary epithelial cells.
5. Initial we determine whether TLR2mRNA、TLR4mRNA、 NF-κB P65mRNA、 and CREB mRNA are expressed in cow mammary epithelial cells. We designed specific primers based on the published TLR2、 TLR4、 NF-κB P65、 and CREB sequence. By RT-PCR analysis and sequencing revealed that these two genes are expressed in cow mammary epithelial cells. Then the expression changes were detected by fluorescence quantitative PCR. The results indicate that:①the regulation of TLR2plays a major role in4h, and partial regulation in2h、8h and48h, at the same time, TLR4play a main role in regulating in several time segment, except4h after LPS stimulated.②TLR2and TLR4of TLRs were involved in the whole regulated process, and TLR4as the main control function.③The results show that CREB and NF-κB were involved in the whole regulated process.④the regulation of CREB plays a major role in8h, and the expression of NF-κB have significant differences in each of the slots.⑤Four kinds of nuclear factors were involved in the expression regulation between LPS and P-defensins.
6. In order to further investigate NF-κB involved mediating the effect of LPS on the expression of defensin (BNBD5、 BNBD7、TAP、 LAP、 EBD and BNBD4) in mammary epithelial cells. The changes in the mRNA expression of BNBD5、 BNBD7、 TAP、LAP、 EBD and BNBD4in mammary epithelial cells treated with estrogen nuclear receptor inhibitor were studied by real-time PCR. The results show:The expression of BNBD5、 BNBD7、 TAP、LAP、EBD and BNBD4mRNA were decreased. The signaling pathway of NF-κB is one of signaling pathways for LPS-induced beta-defensin gene expression in Holstein cow mammary epithelial cells.
目前防御素在抗乳腺炎和其防御机制方面的研究报道非常少,而关于β-防御素抗乳腺炎的作用过程更是少之又少,也未见其在奶牛乳腺中的表达调控机制方面的研究。为此我们初步研究了β-防御素基因在奶牛乳腺的表达情况和LPS诱导时β-防御素基因的表达变化及其可能调控的信号通路。其结果如下：
1、克隆了奶牛乳腺组织EBD、TAP、LAP、BNBD4、BNBD5和BNBD7基因。以奶牛乳腺组织为材料,提取乳腺组织总RNA,根据NCBI数据库中牛β-防御素cDNA的保守序列分别设计特异性引物,采用RT-PCR技术扩增基因片段,纯化后连接pMD19-T载体,转化入大肠杆菌后挑取阳性重组质粒测序,测序结果证实EBD、TAP、LAP、 BNBD4、BNBD5和BNBD7在奶牛乳腺组织有表达。
2、建立稳定的奶牛乳腺上皮细胞培养体系,并确定乳腺上皮细胞6种β-防御素基因的表达情况。采用胶原酶消化法和胰蛋白酶选择性消化法对奶牛乳腺上皮细胞进行分离、培养和纯化。对奶牛乳腺上皮细胞进行原代培养以及传1代细胞的传代培养。经形态学、核型分析和运用RT-PCR方法检测α-酪蛋白基因的表达,绘制生长曲线等方法对所培养的奶牛乳腺上皮细胞进行鉴定和分析,结果证实所培养的细胞为上皮细胞,细胞生长状态良好,符合细胞生长规律。在成功培养奶牛乳腺上皮细胞的基础上,提取乳腺上皮细胞总RNA,运用RT-PCR方法扩增6种β-防御素(EBD、BNBD4、BNBD5、BNBD7、LAP、TAP),测序结果证明6种β-防御素基因在奶牛乳腺上皮细胞有表达。
3、获得奶牛乳腺组织与乳腺上皮细胞6种β-防御素mRNA的基础表达水平。通过RT-qPCR方法对6种β-防御素进行扩增及数据统计分析。结果表明,乳腺组织中6种β-防御素基因的相对表达量有显著性差异(P<0.01),仅BNBD4与BNBD5之间的相对表达量没有显著性差异,其中LAP相对表达量最多,BNBD7、EBD、BNBD5、BNBD4次之,TAP的相对表达量最低。奶牛乳腺上皮细胞中6种β-防御素基因mRNA水平的相对表达量有显著性差异(P<0.01),仅EBD与BNBD4之间的相对表达量没有显著性差异,其中LAP相对表达量最多,BNBD7、BNBD5、BNBD4、EBD次之,TAP的相对表达量最低。
4、为了研究乳腺上皮细胞中6种β-防御素mRNA表达水平,我们培养乳腺上皮细胞,添加代表大肠杆菌为主要侵染力的脂多糖(LPS)建立试验性乳腺炎的乳腺上皮细胞模型。首先,确定了最佳的传1代细胞来研究6种β-防御素的表达变化。然后在奶牛乳腺上皮细胞中添加不同剂量(50、100、200、400、800ng/ml) LPS处理不同时间(2、4、8、16、24、48、72h),采用实时RT-qPCR方法检测乳腺上皮细胞中6种β-防御素mRNA的表达水平。结果表明：①乳腺上皮细胞中6种β-防御素mRNA表达量与空白对照组相比存在一定的剂量和时间效应,有些随着浓度增加而表达量增高,如LAP,这可能与其基础表达量有关；在时间上总体趋势是当LPS诱导后主要在8h、48h与72h时相对表达量达到高值,在2h、4h、16h和24h表达量相对较低,推测与其信号通路基因的调控时间相关。②LAP表达量差异较大,增加幅度较高,在奶牛乳腺防御中起重要的防御作用。③乳腺上皮细胞中6种β-防御素mRNA的表达量都显著增加,表明6种β-防御素的表达都呈诱导型表达。
5、确定奶牛乳腺上皮细胞中是否有TLR2、TLR4、NF-κB P65、CREB表达,根据已发表的基因各自序列设计特异性引物,经RT-PCR鉴定及测序证明4种基因在奶牛乳腺上皮细胞可表达。然后采用RT-qPCR技术检测4个基因mRNA的表达变化。结果表明：①LPS刺激后TLRs中TLR2与TLR4的介导作用中,TLR2主要在4h时起介导作用,在2h、8h和48h起部分调控作用；TLR4在除4h外的几个时间段起主要的介导作用。②TLR2与TLR4都介导了LPS刺激时的调控过程,在整个调控过程中以TLR4起主要介导作用。③CREB在与NF-κB并行的信号通路中,CREB和核因子NF-κB都参与了炎症的调控过程。④在调控过程中CREB主要在8h时起调节作用,NF-κB在各时段都有显著性差异,调控增幅较大。⑤脂多糖对于4种调控因子的表达量都有促进作用。
6、为了进一步确定NF-κB途径是否为脂多糖诱导防御素表达的信号通路之一我们在传1代乳腺上皮细胞添加特异性抑制剂PDTC以阻断NF-κB信号通路,然后采用RT-qPCR技术检测BNBD5、BNBD7、TAP、LAP、EBD和BNBD4等基因mRNA表达水平。结果表明：BNBD5、BNBD7、TAP、LAP、EBD和BNBD4mRNA表达量均有下降,在荷斯坦奶牛乳腺上皮细胞中NF-κB为LPS诱导β-防御素基因表达的信号通路之
Defensins are a group of cationic peptide, which contain cysteine-rich, broad-spectrum effect on killing G+, G-bacteria, fungi, enveloped viruses, and spirochetes. It is not only efficient antimicrobial peptides, a direct bactericidal effect against the invading organism pathogenic microorganisms, but also can regulate the immune responsing and tissue repairing, playing an important role in mediating acquired immune response in the process. Due to defensins is the largest members in animal defenses, which indicates that defensins may play crucial role in resisting microbe infection and maintaining breast health. Defensins should participate in mammary gland defense processes, but be unknown to defensins produced what have changed and how to carry out adjusting.
Nowadays there is seldom research of defensins in resistance to mastitis and its defense mechanism. At the same time, the β-defensins resistance to mastitis in the process is very few. Thus, expression of beta defensin and its possible signal pathways by LPS stimulated were studied initially in this paper. The results are listed as follows:
1. At first, to obtain the amplified six kinds of beta defensin (EBD、 BNBD4、 BNBD5、 BNBD7、 LAP、 TAP) gene from the cow mammary gland tissue. Total RNA was extracted from the mammary tissue of a cow and, cDNA encoding beta defensin was amplified by the reverse transcription-PCR (RT-PCR) with the pair of primers which were designed according to the cDNA of NCBI database conserve sequences of reported P-defensins. The objective fragments after purification were connected to the pMD19-T vector, recombinant plasmid positive selection by transformed into Escherichia coli, and samples sequencing. The sequencing results confirmed that the6β-defensins of cloning expressed in mammary gland tissue.
2. To establish stable culture system of mammary epithelium cell in cow and confirm the six kinds of P-defensins expression in mammary epithelial cell. We used collagenase digestion and trypsin chosen digestion method to isolate and purify bovine mammary epithelial cells, and culture the original generation of mammary epithelium cells, at least the cells culture processing to the first filial generation. The consequence shows that it is confirmed that the cultured cells are epithelial cell through the verification from morphological and detecting the expression of a-casein by using RT-PCR method. Analyzing chromosomal karyotype and drawing auxodrome curve to the first filial generation cells are confirm cell growth in good condition and compliance with cell growth law. Total RNA was extracted from the mammary epithelial cells which cultured successfully above and cDNA encoding beta defensin was amplified by the reverse transcription-PCR (RT-PCR). The sequencing results confirmed that the6P-defensins of cloning expressed in mammary epithelial cells.
3. We detected the basic expression of6kinds of (3-defensins in cow breast tissue and mammary epithelial cells by fluorescence quantitative PCR method in order to study the defense functions of defensins. The results showed that the expression of the relative volume of6β-defensins have significant differences (P<0.01), only the relative expression of BNBD4and BNBD5non-significant difference in breast tissue. The result indicated that relative expression quantity of β-defensins to LAP is the highest, to BNBD7、EBD、BNBD5、BNBD4is in the middle, to TAP is the lowest. The results showed that the expression of the relative volume of6β-defensins have significant differences (P<0.01), only the relative expression of BNBD4and EBD non-significant difference in bovine mammary epithelial cells. The relative expression level of LAP is the highest in six β-defensins, BNBD7、BNBD5、BNBD4、EBD is the middle, the TAP is the minimum.
4. After that, establishing mammary epithelial cells model of experimental mastitis by adding LPS produced mainly by E.coli infection in order to studying the six kinds of β-defensins mRNA in mammary epithelial cells. Firstly, we choose the best passage1cells to study changes. The dairy cow mammary epithelial cells were stimulated with different concentration (50,100,200,400and800ng/ml) of LPS. Then the total RNA was extracted after stimulated in seven different times (2,4,8,16,24,48and72h), and the mRNA expression levels of six kinds of β-defensins were evaluated by real-time quantitative PCR. The results show that:①LPS significantly down-regulated a-casein mRNA expression in a time and dose dependent, and the mammary epithelial cells produced a certain inflammatory by adding the LPS. The expression of six kinds of beta-defensins mRNA has significant differences in a time and dose dependent. Some increased with the concentration. The time overall trend of the relative expression is amount high value in8h、48h and72h, and a lower expression level in2h、4h、16h and24h after LPS stimulated mammary epithelial cells.②The expression level differences of LAP gene mRNA is larger and the amplitude is higher than other beta-defensin.③The expression level of the6beta-defensins increased significantly indicated that they are all inducible expression and the increased extent related to the basic expression levels in cow mammary epithelial cells.
5. Initial we determine whether TLR2mRNA、TLR4mRNA、 NF-κB P65mRNA、 and CREB mRNA are expressed in cow mammary epithelial cells. We designed specific primers based on the published TLR2、 TLR4、 NF-κB P65、 and CREB sequence. By RT-PCR analysis and sequencing revealed that these two genes are expressed in cow mammary epithelial cells. Then the expression changes were detected by fluorescence quantitative PCR. The results indicate that:①the regulation of TLR2plays a major role in4h, and partial regulation in2h、8h and48h, at the same time, TLR4play a main role in regulating in several time segment, except4h after LPS stimulated.②TLR2and TLR4of TLRs were involved in the whole regulated process, and TLR4as the main control function.③The results show that CREB and NF-κB were involved in the whole regulated process.④the regulation of CREB plays a major role in8h, and the expression of NF-κB have significant differences in each of the slots.⑤Four kinds of nuclear factors were involved in the expression regulation between LPS and P-defensins.
6. In order to further investigate NF-κB involved mediating the effect of LPS on the expression of defensin (BNBD5、 BNBD7、TAP、 LAP、 EBD and BNBD4) in mammary epithelial cells. The changes in the mRNA expression of BNBD5、 BNBD7、 TAP、LAP、 EBD and BNBD4in mammary epithelial cells treated with estrogen nuclear receptor inhibitor were studied by real-time PCR. The results show:The expression of BNBD5、 BNBD7、 TAP、LAP、EBD and BNBD4mRNA were decreased. The signaling pathway of NF-κB is one of signaling pathways for LPS-induced beta-defensin gene expression in Holstein cow mammary epithelial cells.
引文
1 马仲华,何飞鸿,陈耀星等.家畜解剖学与组织胚胎学[M].中国农业出版社,第三版
2 赵兴绪主编.兽医产科学,北京：中国农业出版社,2002：457-468
3 齐长明,奶牛疾病学[M].中国农业科学技术出版社,2006
4 李配林,汤天晓,刘颖等.用中西药制剂薄硫膏治疗奶牛乳房炎[J].中兽医医药杂志,1998,17(2)：28
5 马树东,冯丽荣,王梅中.西兽药配合治疗奶牛临床型乳房炎的效果[J].中国奶牛,2000(5)：39-40
6 Axford RFE, Bishop SC, Nicholas FW, et al. Breeding for disease resistance in farm animals [J]. CABI Publishing, Oxon,2000,243-252
7 潘虎,刘纯传,张礼华等.我国部分地区奶牛乳房炎的病因及发病情况调查[J].中国兽医科技,1996,26(2)：16-17
8 DeGraves FJ, Fetrow J. Economics of mastitis and mastitis control [J]. Vet Clin North Am:Food Anim Pract,1993,9:421-434
9 Ruegg PL. Investigation of mastitis problems on farms [J]. Vet Clin North Am:Food Anim Pract,2003,19(1):47-73
10 Bradley AJ. Bovine mastitis:an evolving disease. The Veterinary Journal,2002,164: 116-128
11 Chen Y, Zhao YH, Wu R. In silico cloning of mouse Muc5b gene and upregulation of its expression in mouse asthma model. Am J Respir Crit Care Med,2001,164:1059-1066
12 Almeida RA, Luther DA, Oliver SP. Pathogenic Strategies of mastitis pathogens, http://animalscience.ag.utk.edu/annual-reports_all.html
13 Bayles KW, Wesson CA, Liou LE, et al. Intracellular Staphylococcus aureus escapes the endosomeand induces apoptosis in epithelial cells[J]. Infection and Immunity, 1998,66(1):336-342
14 Hassan AA, Khan IU, Abdulmawjood A, et al. Inter-and intraspecies variations of the 16S-23S rDNA intergenic spacer region of various streptococcal species [J]. Syst Appl Microbiol,2003,26:97-103
15 Almeida RA, Fang W, Oliver SP. Adherence and internalization of Streptococcus uber is to bovine mammary epithelial cells are mediated by host cell proteoglycans [J]. FEMS Microbiol Lett,1999b,177:313-317.
16 Almeida RA, Oliver SP. Interaction of coagulase-negative Staphylococcus species with bovine mammary epithelial cells [J]. Microbial Pathogenesis,2001,31(5): 205-212
17 Almeida RA, Calvinho LF, Oliver SP. Influence of protein kinase inhibitors on Stieptocoeeus aberis internalization into bovine mammary epithelial cells [J]. Microbial Pathogenesis,2000,28:9-16
18 Sears PM, McCarthy KK. Diagnosis of mastitis for therapy decisions [J]. Vet Clin North Am:Food Anim Pract,2003,19(1):93-108
19 Jayarao BM, Wolfgang DR. Bulk-tank milk analysis:A useful tool for improving milk quality and herd udder health. Vet Clin North Am:Food Anim Pract,2003,19(1): 75-92
20赵德明,沈建忠(主译)Rebhun WC(著).奶牛疾病学.北京：中国农业出版社,1999,383-425
21 Dosogne H, Vangroenweghe F, Burvenich C. Potential mechanism of action of J5 vaccine in protection against severe bovine coliform mastitis[J]. Vet Res,2002,33(1): 1-12
22刘本君,葛佳瑞,戴波涛.不同程度奶牛乳腺炎IL-8、TNF-α的研究[J].黑龙江畜牧兽医(科技版),2011,(7)：106-107
23高纯一,祁永锋,丁营兵.公英散加味治疗乳牛乳房炎[J].中国兽医科技,2001(2)：12
24高庆田,朱其苏.“中药乳炎消油剂”临床应用综述[J].中国奶牛,2000(4)：36-37
25张彬,薛明,崔颖等.新兽药消炎醌对乳牛乳腺炎临床治疗试验[J].中国兽医科技,2000(8)：9-12
26潘志明,张小荣,焦新安.作为疫苗和疫苗载体的胞内细菌[J].动物兽医进展,2002,23(3)：107.
27 Leitner G, Yadlin N, Lubashevsy E, et al. Development of a Staphylococcus aureus vaccine against mastitis in dairy cows. Ⅱ. Field trial [J]. Vet Immunol Immunopathol, 2003,93(3-4):153-8
28 Leitner G, Lubashevsky E, Glickman A, et al. Development of a Staphylococcus aureus vaccine against mastitis in dairy cows. Ⅰ. Challenge trials [J]. Vet Immunol Immunopathol,2003,93(1-2):31-8
29 Leitner G, Lubashevsky E, Trainin Z. Staphylococcus aureus vaccine against mastitis in dairy cows, composition and evaluation of its immunogenicity in a mouse model [J]. Vet Immunol Immunopathol,2003,93 (3-4):159-67
30 Finch J, Winter A, Walton A, et al. Further studies on the efficacy of a live vaccine against mastitis caused by Streptococcus uberis [J]. Vaccine,1997,156:1138-1143
31罗金印,郁杰,李新圃等.乳牛乳腺炎多联苗免疫试验[J].中国兽医科技,2002,32(5)：40-41
32 Bradley AJ. Bovine mastitis:an evolving disease [J]. The Veterinary Journal,2002, 164:116-128
33 Kerr D E, Plaut K, Bramley A J, et al. Lysoslaphin expression in mammary glands confers protection against staphylococcal infection in transgenic mice[J]. Nat Biotechnol,2001,19(1):66-70.
34 Pyorala S. New strategies to prevent mastitis [J]. Reprod Dom Anim,2002,37:211-216
35 Yancy R. Vaccines and diagnostic method for bovine mastitis fact and fiction [J]. Adv Vet Med,1999,41:257-273
36 Finch J, Winter A, Walton A, et al. Further studies on the efficacy of efficacy of a live caccine against mastitis caused by Streptococcus uberis [J]. Vaccine, 1997,156:1138-1143
37涂勇,曹贵方.p-防御素-5mRNA在荷斯坦奶牛乳腺上皮细胞中的表达[D].2011：8-9
38易明梅,冯华,朱建国等.生物制剂在奶牛乳房炎防治中的应用[J].中国畜牧兽医,2007,34(5)：37-39
39 Heringstad B, Klemetsdal G, Ruane J. Selection for mastitis resistance in dairy cattle:a review with focus on the situation in the Nordic countries [J]. Livestock Production Science,2000,64:95-96
40 Magnusson U. Breeding for improved disease resistance in organic farming-possibilities and constraints [J], Acta Vet Scand,2001, Suppl.95:59-61
41 Detilleux JC. Genetic factors affecting susceptibility of dairy cows to udder pathogens [J]. Vet Immunol Immunopathol,2002,88:103-110
42 Burton JL, Erskine RJ. Immunity and mastitis:some new ideas for an old disease [J]. Vet Clin North Am:Food Anim Pract,2003,19(1):1-45
43 Rupp R, Boichard D. Genetic parameters for clinical mastitis, somatic cell score, production, udder type traits, and milkinkease in the first lactation Holsteins [J]. J Dairy Sci,1999,82:2198-2202
44 Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense [J]. Annu Rev Immunol,2004,22:181-215. [PubMed:15032578] Comprehensive review of the innate and adaptive immune functions of defensins.
45 Diamond G, Beckloff N, Ryan LK. Host defense peptides in the oral cavity and the lung:similarities and differences, J Dent Res 2008,87:915-927. [PubMed: 18809744]
46 Rehaume LM, Hancock RE, Neutrophil-derived defensins as modulators of innate immune function. Crit Rev Immunol 2008,28:185-200. [PubMed:19024344]
47周雷.几种奶牛乳房炎相关基因在白细胞内的表达及克隆表达[C].甘肃农业大学.2008：4
48陈永辉,钟莲,张胜燕.公英散治疗奶牛乳房炎的临床效果观察[J].中国畜牧兽医,2008,35(5)：82-83
49 Yorma C,Soebah S,Low SM,Zhou L,Liu SP,Li J,Bouerman RW.Defensins :antimicrobial peptides for therapeutic development [J]. Biotechnol J 2007,2 (11):1353-1359
50傅荣昭,李文彬,孙勇如.防御素的研究进展[J].农业生物技术学报,1996,4(12)：348-353
51 李穆然.β-防御素与炎症性肠病[J].国际消化病杂志,2006,26(6)：374-376.
52 Sorensen J L, Cowland J B, Theilgaard-Monch K, et al. Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors [J]. J Immunol.,2003,170(11):5583-5589
53 Yang D, Biragyn A, Kwak LW, Oppenheim JJ. Mammalian defensins in immunity:more than just microbicidal [J]. Trends Immunol 2002,23 (6):291-296
54 Selsted ME, Ouellette AJ Mammalian defensins in the antimicrobial immune response [J]. Nat Immunol 2005,6 (6):551-557
55 Nguyen TX, Cole AM, Lehrer RI Evolution of primate thetadefensins:a serpentine path to a sweet tooth [J]. Peptides 2003,24 (11):1647-1654
56 G. Diamond, N. Beckloff, and L.K. Ryan. Host Defense Peptides in the Oral Cavity and the Lung:Similarities and Differences [J]. J Dent Res.2008,87(10):915-927
57 Gordon B. Mitchell, Muthafar H. Al-Haddawi, Mary Ellen Clark, et al. Effect of Corticosteroids and Neuropep tides on the Expression of Defensins in Bovine Tracheal Epithelial Cells [J]. INFECTION AND IMMUNITY,2007,1325-1334.
58 Suresh Yenugu, Vishnu Chintalgattu, Christopher J Wingard, et al. Identification, cloning and functional characterization of novel beta-defensins in the rat (Rattus norvegicus) [J]. Reproductive Biology and Endocrinology,2006,4:7
59 Yongming Sang, M. Teresa Ortega, Frank Blecha, Om Prakash, and Tonatiuh Melgarejo. Molecular Cloning and Characterization of Three beta-Defensins from Canine Testes[J]. INFECTION AND IMMUNITY,2005,73 (5):2611-2620
60 Gillian Morrison, Fiona Kilanowski, Donald Davidson, and Julia Dorin. Characterization of the Mouse Beta Defensin 1, Defbl, Mutant Mouse Model.[J]. INFECTION AND IMMUNITY,2002,70 (6):3053-3060
61 MICHAEL MATHEWS, HONG PENG JIA, JANET M. GUTHMILLER, GARRETT LOSH, SCOTT GRAHAM, GEORGIA K. JOHNSON, BRIAN F. TACK, AND PAUL B. MCCRAY, JR. Production of beta-Defens in Antimicrobial Peptides by the Oral Mucosa a'nd Salivary Glands [J]. INFECTION AND IMMUNITY,1999,67 (6):2740-2745
62 JISHU SHI, GUOLONG ZHANG, HUA WU, CHRISTOPHER ROSS, FRANK BLECHA, AND TOMAS GANZ. Porcine Epithelial beta-Defensin 1 Is Expressed in the Dorsal Tongue at Antimicrobial Concentrations [J]. INFECTION AND IMMUNITY,1999,67(6):3121-3127
63 Zhou L, Huang LQ, Beuerman RW, et al. Tan D Proteomic analysis of human tears: defensin expression after ocular surface surgery [J]. J Proteome Res,2004,3(3):410-416
64 Schutte BC, McCray PB Beta-defensins in lung host defense [J]. Annu Rev Physiol 2002,64:709-748
65 Valore EV, Park CH, Quayle AJ, et al. Human beta-defensin-1:an antimicrobial peptide of urogenital tissues [J]. J Clin Invest,1998,101(8):1633-1642
66 Harder J, Bartels J, Christophers E, Schroder JM Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic[J]. J Biol Chem,2001,276(8):5707-5713
67 Jia HP, Schuttea BC, Schudye A, et al. Jr Discovery of new human b-defensins using a genomics-based approach [J]. Gene.2001,263:211-218
68 Sumikawa Y, Asada H, Hoshino K, et al. Induction of beta-defensin 3 in keratinocytes stimulated by bacterial lipopeptides through toll-like receptor 2 [J]. Microbes Infect,2006,8 (6):1513-1521
69 Varoga D, Wruck CJ, Tohidnezhad M, et al. Osteoblasts participate in the innate immunity of the bone by producing human beta defensin-3 [J]. Histochem Cell Biol, 2009,131 (2):207-218
70 Harder J, Meyer-Hoffert U, Teran LM, et al. Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-lbeta, but not IL-6, induce human betadefensin-2 in respiratory epithelia [J]. Am J Respir Cell Mol Biol,2000,22(6):714-721
71 Bogefors J, Kvarnhammar AM, Hockerfelt U, et al. Reduced tonsillar expression of human β-defensin 1,2 and 3 in allergic rhinitis [J]. FEMS Immunol Med Microbiol, 2012 Mar 22.10.1111/j.1574-695X.2012.00959. x. [Epub ahead of print] PMID:22444247 [PubMed-as supplied by publisher]
72 Garc i a JR, Jaumann F, Schulz S, Krause A, Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction [J]..Cell Tissue Res,2001a,306(2):257-264
73 Allan M. TORRES, Xiuhong WANG, Jamie I. FLETCHER, Dianne ALEWOOD., Paul F. ALEWOOD. Ross SMITH., Richard J. SIMPSON(?), Graham M. NICHOLSONs, Struan K. SUTHERLAND., Cliff H. GALLAGHER, Glenn F. KING and Philip W. KUCHEL. Solution structure of a defensin-like peptide from platypus venom[J]. Biochem. J.,1999,341:785-794
74 Diamond, G.; Zasloff, M.; Eck, H. et al. Tracheal antimicrobial peptide, a cysteine-rich peptide from mammalian tracheal mucosa:peptide isolation and cloning uf a cDNA [J]. Proceedings of the National Academy of Sciences 1931,88 (9),3952.
75 Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc Natl Acad Sci USA 2005,102:18129-18134. [PubMed:16330776]
76 Rivas-Santiago B, Serrano CJ, Enciso-Moreno JA. Susceptibility to infectious diseases based on antimicrobial peptide production. Infect Immun 2009,77:4690-4695. [PubMed:19703980]
77 Schonwetter, B. S., Stolzenberg, E. D., Zasloff, M. A., Epithelial antibiotics induced at sites of inflammation. Science 1995,267 (5204),1645-1648
78 Selsted, M. E., Tang, Y. Q., Morris., et al. Purification, primary structures, and antibacterial activities of β-defensins, a new family of antimicrobial peptides from bovine neutrophils [J]. Journal of Biological Chemistry 1996,271 (27),16430.
79 Yang D, Biragyn A, Hoover DM, et al. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense [J]. Annu Rev Immunol.,2004,22:181-215
80李宏滨.3个与奶牛乳房炎抗性相关基因的克隆及比较基因组学分析[D].中国农业科学院,2008
81 Ericksen B, Wu Z, Lu W, et al. Antibacterial activity and specificity of the six human alpha-defensins[J]. Antimicrob Agents Chemother,2005,49 (1):269-275
82 Schroder JM, Harder J. Human beta-defensin-2[J]. Int J Biochem Cell Biol,1999, 31(6):645-651
83 Krishnakumari V, Nagaraj R. Interaction of antibacterial peptides spanning the carboxy-terminal region of human betadefensins 1-3 with phospholipids at the air-water interface and inner membrane of E. coli [J]. Peptides,2008,29(1):7-14
84 Nagaoka I, Niyonsaba F, Tsutsumi-Ishi i Y, et al. Evaluation of the effect of human beta-defensins on neutrophil apoptosis [J]. Int Immunol,2008,20(4):543-553
85 Sharma S, Verma I, Khuller GK. Therapeutic potential of human neutrophil peptide 1 against experimental tuberculosis [J]. Antimicrob Agents Chemother,2001, 45(2):639-640
86 Verma C, Seebah S, Low SM, et al. Defensins:antimicrobial peptides for therapeutic development [J]. Biotechnol J,2007,2 (11):1353-1359
87 As hi tani J, Mukae H, Hiratsuka T, et al. Elevated levels of alpha-defensins in plasma and BAL fluid of patients with active pulmonary tuberculosis [J]. Chest,2002, 121(2):519-526
88 Sharma S, Verma I, Khuller GK. Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv:in vitro and ex vivo study [J]. Eur Respir J.,2000,16(1):112-117
89 Rivas-Santiago B, Schwander SK, Sarabia C, et al. Human{beta}-defens in 2 is expressed and associated with Mycobacterium tuberculosis during infection of human alveolar epithelial cells [J]. Infect Immun,2005,73 (8):4505-4511
90 Rivas-Santiago B, Sada E, Tsutsumi V, et al. beta-Defensin gene expression during the course of experimental tuberculosis infection. J Infect Dis,2006,194(5):697-701
91 Wang W, Mulakala C, Ward SC, et al. Retrocyclins kill bacilli and germinating spores of Bacillus anthracis and inactivate anthrax lethal toxin [J]. J Biol Chem.,2006, 281 (43):32755-32764
92 Verma C, Seebah S, Low SM, et al. Defensins:antimicrobial peptides for therapeutic development [J]. Biotechnol J,2007,2(11):1353-1359
93 Feng Z, Jiang B, Chandra J, Ghannoum M, Nelson S, et al. Human beta-defensins: differential activity against Candidal species and regulation by Candida albicans [J]. J Dent Res.,2005,84:445-450
94 Joly S, Organ CC, Johnson GK, et al. Correlation between beta-defensin expression and induction profiles in gingival keratinocytes [J]. Mol Immunol.,2005, 42(9):1073-1084
95 Hazrati E, Galen B, Lu W, et al. Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection [J]. J Immunol.,2006,177(12):8658-8666
96 Wang W, Owen SM, Rudolph DL, et al. Activity of alpha- and theta-defensins against primary isolates of HIV-1 [J]. J Immunol,2004,173 (1):515-520
97 Chang TL, Vargas J, DelPortillo A, et al. Dual role of alpha-defensin-1 inanti-HIV-1 innate immunity[J]. J Clin Invest,2005,115(3):765-773
98 Kreuter A, Skrygan M, Gambichler T, et al. Human papillomavirus-associated induction of human betadefensins in anal intraepithelial neoplasi [J]. Br J Dermatol, 2009,160(6):1197-1205
99 Tarek K. Zaalouk, Mona Bajaj-Elliott, John T. George, and Vincent McDonald. Differential Regulation of beta-Defensin Gene Expression during Cryptosporidium parvum Infect ion [J]. INFECTION AND IMMUNITY,2004,72 (5):2772-2779
100Cole AM, Hong T, Boo LM, et al. Retrocyclin:a primate peptide that protects cells from infection by T-and M-tropic strains of HIV-1 [J]. Proc Natl Acad Sci USA, 2002,99(4):1813-1818
101Munk C, Wei G, Yang OO, et al. The theta-defensin, retrocyclin, inhibits HIV-1 entry [J]. AIDS Res Hum Retioviruses,2003,19(10):875-881
102Leitch GJ, Ceballos CA. role for antimicrobial peptides in intestinal microsporidiosis [J]. Parasitology,2009,136(2):175-181
103Zaalouk TK, Bajaj-Elliott M, George JT, et al. Differential regulation of beta-defensin gene expression during Cryptosporidium parvum infection [J]. Infect Immun,2004,72(5):2772-2779
104 Feng Z, Dubyak GR, Lederman MM, Weinberg A. Cutting edge:human β defensin 3 a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 2006,177:782-786. [PubMed:16818731]
105 Hazrati E, Galen B, Lu W, et al. Human α-and β-defensins block multiple steps in herpes simplex virus infection. J Immunol 2006,177:8658-8666. [PubMed: 17142766]
106 Joly S, Maze C, McCray PB Jr, Guthmiller JM. Human β-defensins 2 and 3 demonstrate strainselective activity against oral microorganisms. J Clin Microbiol 2004, 42:1024-1029. [PubMed:15004048]
107 Karen Taylor, Mark Rolfe, Natal ie Reynolds, Fiona Kilanowski, Uday Pathanial, Dave Clarke, De Yang3, Joost Oppenheim, Kay Samuel, Sarah Howie, Perdita Barran, Derek Macmillan, Dominic Campopiano2 and Julia Dorin. Defensin-related peptide 1 (Defrl) is allelic to Defb8 and chemoattracts immature DC and CD4 T cells independently of CCR6 [J]. Eur. J. Immunol.2009.39:1353-1360
108 Charles E. Shelburne, Wilson A. Coulter, De'Avlin Olguin, et al. Induction of beta-Defensin Resistance in the Oral Anaerobe Porphyromonas gingivalis [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2005,183-187.
109 Lingling Sun, Leon DeMasi, Mark Lafferty, Marco Goicochea, Wuyuan Lu and Alfredo Garzino-Demo. CCR6 mediates the intracellular HIV inhibitory activity of human beta-defensin 2 [J]. Retrovirology,2006,3(1):77
110Tka T, Rahman MM, Battur B, et al. Parasiticidal activity of human alpha-defensin-5 against Toxoplasma gondii [J]. In Vitro Cell Dev Biol Anim Epub, 2010, Feb 5
111 Madison MN, Kleshchenko YY, Nde PN, et al. Human defensin a lpha-1'causes Trypanosoma cruzi membrane pore formation and induces DNA fragmentation, which leads to trypanosome destruction [J]. Infect Imtnun,2007,75 (10):4780-4791
112Ganz T. Defensins:antimicrobial peptides of innate immunity [J]. Nat Rev Immunol. 2003,3(9):710-720
113 T Gambichler, M Skrygan, J Huyn, et al. Pattern of mRNA expression of (3-defensins in basal cell carcinoma[J]. BMC Cancer,2006,6:163
114De Leeuw E, Li C, Zeng P, et al. Functional interaction of human neutrophiI peptide-1 with the cell wall precursor lipid Ⅱ [J]. FEBS Lett,2010,584(8):1543-1548
115 A. FAHLGREN, S. HAMMARSTROM, A. DANIELSSON & M.-L. HAMMARSTROM. beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis[J]. Clin Exp Immunol 2004,137:379-385
116 Brian J. Poindexter, Gordon L. Klein, Stephen M. Milner, and Roger J. Bick. Upregulation of Defensins in Burn Sheep Small Intestine[J]. Open Acess Journal of Plastie Surgery,2009,10:43-55
117 Karl G Kohlgraf, Lindsey C Pingel, Deborah E Dietrich, Kim A Brogden. Defensins as anti-inflammatory compounds and mucosal Adjuvants [J]. Future Microbiol.2010, 5:99-104
118 Beverly A. Dale and L. Page Fredericks. Antimicrobial Peptides in the Oral Environment:Expression and Function in Health and Disease [J]. Curr Issues Mol Biol. 2005,7(2):119-133.
119 J. W. McMichael, A. I. Maxwell, K. Hayashi, K. Taylor, W. A. Wallace, J. R. Govan, J. R. Dorin, and J.-M. Sallenave. Antimicrobial Activity of Murine Lung Cells against Staphylococcus aureus Is Increased In Vitro and In Vivo after Elafin Gene Transfer[J]. INFECTION AND IMMUNITY,2005,73(6):3609-3617
120Mothes H, Melle C, Ernst G, et al. Human Neutrophil Peptides 1-3-earlymarkers in development of colorectal adenomas and carcinomas [J]. Dis Markers,2008, 25(2):123-129
121Droin N, Hendra JB, Ducoroy P, et al. Human defensins as cancer biomarkers and antitumour molecules [J]. J Proteomics,2009,72 (6):918-927
122 Kesting MR, Loeffelbein DJ, Hasler RJ, et al. Expression profile of human beta-defensin 3 in oral squamous cell carcinoma [J]. Cancer Invest.,2009, 27 (5):575-581
123Semple F, Dorin JR. β-Defensins:Multifunctional Modulators of Infection, Inflammation and More?[J]. J Innate Immun.2012 Mar 21. [Epub ahead of print]
124Marin M, Yamamoto Y, Wang QM. The IKK NF- kappa B system:a treasure trove for drug development [J]. Nat Rev Drug Discov,2004,3(1):17-26
125 Young Mee Yoon, Jin Young Lee, Doyoung Yoo, et al. Bacteroides fragil is Enterotoxin Induces Human beta-Defensin-2 Expression in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase/IκB Kinase/NF-κB-Dependent Pathway [J]. INFECTION AND IMMUNITY,2010:2024-2033
126 Cuiming Li Joanne Domenico Yi Jia Josoph J.Lucas Erwin W.Gelfand.NF-κB-Dependent Induction of Cathelicidin-Related Antimicrobial Peptide in Murine Mast Cells by Lipopolysaccharide[J]. Allergy Immunology,2009,150:122-132
127aeuerle PA, Baltimore D. NF-kappa B:ten years after [J]. Cell 1996,87(1):13-20
128叶伟萍,杨祖菁.核因子-κ B p65蛋白在感染性早产孕妇妊娠组织中的表达及意义[J].实用医学杂志,2009,25(4)：557-560
129 Kim HJ, Jung JR, Kim HJ, et al. Expression of human β-defensin-2 in the prostate [J]. BJU Int.2011,107(1):144-9
130Cristina Albanesi, Heather R. Fairchild, Stegania Madonna, et al. IL-4 and IL-12 negatively regulate TNF-α and IFN-γ induced β-defensin Expression through STAT-6, Suppressor of Cytokine Signaling(SOCS)-1, and SOCS-3[J]. The Journal of Immunology,2007,179:984-992.
131 Ravagnan L, Roumier T, and Kroemer G. Mitochondria. The kill organelles and their weapons [J]. J Cell Physiol.,2002,192:131-137
132韩德武等.肠源性内毒素血症与肝病：用衰竭的IEIM学说[M1].北京：中国科学技术出版社,2004
133 Darren Davies, Kieran G Meade, Shan Herath, et al. Toll-like receptor and antimicrobial peptide expression in the bovine endometrium[J]. Reproductive Biology and Endocrinology,2008,6:53
134 Young SL, Lyddon TD, Jorgenson RL, Misfeldt ML:Expression of Toll-like Receptors in human endometrial epithelial cells and cell lines. American Journal of Reproductive Immunology 2004,52:67-73.
135 Aflatoonian R, Tuckerman E, Elliott SL, Bruce C, Aflatoonian A, Li TC, Fazeli A: Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Human Reproduction 2007,22:586-593
136 Jeingmin Song, and Soman N. Abraham. TLR mediated immune responses in the urinary tract [J].Curr opin microbial.2008,11 (1):66-73
137 Samuels son P, Hang L, WulltB, et al. Toll-like receptor 4 express ion and cytokine responses in the human urinary tract mucosa [J]. Infect Immun 2004,72:3179-3186
138 Andersen-Nissen E, Hawm TR, Smith KD, et al. Cutting edge:Tlr5-/-mice are more susceptible to Escherichia coli urinary tract infect ion [J]. J Immunol.,2007, 178:4717-4720. [PubMed:17404249] Using a murine model of UTI, the authors demonstrate for the first time the importance of TLR5 in regulating innate immune response in the urinary tract. Bladders of wild type mice showed high levels of cytokine and chemokine expression in response to flagllin, which was linked to increased inflammation and subsequent bacterial clearance.
139 Zhang D, Zhang G, Hayden MS, et al. A toll-like receptor that prevents infection by uropathogenic bacteria [J]. Science,2004,303:1522-1526,
140Walker W H, Sanborm B M, Habener J F. An isoform of transcription factor CREB expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP induced transcription [J]. Proc Natl Acad Sci USA,1994,91:12423-12427
141 Wu GY, Deiss eroth K, Tsien R W. Activity2dependent CREB phos2 phorylation: Convergence of a fast, sensitive calmod ulin kinase pathway and a slow, less sensitive mitogen2 activated [J]. Proc Natl Acad Sci U SA,2001,98 (5):2808-2813
142Kimiko S, Akira Y, Fumimaro T. Cell cycle regulated phosphorylation of cAMP response element binding protein:Identification novel phosphorylation sites [J]. Biol J, 1999,338 (1):49-54
143 R. Lamprecht, CREB:a message to remember, Cell. Mol. Life Sci.55 (1999) 554-563.
144陈艳杏.17β-雌二醇对亚致死量Aβ1-42所致PC12细胞CREB活性改变的影响[D].华中科技大学,2010
145 M. R. Montminy, L. M. Bilezikjian, Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene[J]. Nature,1987,328:175-178
146 David Moranta, Vero'nica Regueiro, Catalina March, et al. Klebsiella pneumoniae Capsule Polysaccharide Impedes the Expression of beta-Defensins by Airway Epithelial Cells[J]. INFECTION AND IMMUNITY,2010,1135-1146
147 Jessica M. Caverly, Gill Diamond, Jack M. Gallup, Kim A. Brogden, Richard A. Dixon, and Mark R. Ackermann, et al. Coordinated Expression of Tracheal Antimicrobial Peptide and Inflammatory-Response Elements in the Lungs of Neonatal Calves with Acute Bacterial Pneumonia[J]. INFECTION AND IMMUNITY,2003,71(5):2950-2955
148余瑞元,王燕峰,徐长法CREB研究进展[J].中国生物工程杂志,2003,23(1)：39-42,47
149Scheving L A, Cardner W. Circa2dian-regulation of CREB transcrip2tion factor in mouse esophagus [J]. American J Physiol,1998,274 (4PART1):C1011-C1016
150Schmid R S, Graff R D,. Schaler M D, et al. NCAM stimulates the ras2MAPK pathway and CREB phosphorylation in neuronal cells [J]. J Neurobiol,1999,38 (4):542-558
151 White DM, Walker S L, Brenneman D E, et al. CREB contributes to the increased neurite of sensory neurons induced by vasoactive intestinal polypeptide and activity dependent neurotrophic factor [J].Brain Res,2000,868 (1):31-38
152武建明,何洪彬,土长法等,荷斯坦牛中性粒细胞防御素BNBD12基因克隆、原核表达及其抗菌活性分析[C].学术年会,2010：374-377
153王桂荣,严作婷,王东升等,乳牛子宫内膜抗菌肽BNBD5基因的克隆及其原核表达[J].中国兽医科学,2009,39(06)：538-542
154龙晶.牛防御素BNBD5的cDNA克隆及毕赤酵母表达[C].中国农业科学院,2007,25
155 Natal ie L. Reynolds, Mart in De Cecco, Karen Taylor, Chloe Stanton, Fiona Kilanowski, Jason Kalapothakis, Emily Seo, Dusan Uhrin, Dominic Campopiano, John Govan, Derek Macmillan, Perdita Barran, and Julia R. Dorin. Peptide Fragments of a beta-Defensin Derivative with Potent Bactericidal Activity [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2010,4(5):1922-1929
156 Gill Diamond, Nicholas Beckloff, Aaron Weinberg, and Kevin 0. Kisich. The Roles of Antimicrobial Peptides in Innate Host Defense[J]. Curr Pharm Des.2009,15(21): 2377-2392.
157Rooson S, Exner K, Schroer J M, et al. Bovine beta-defensins:Identification and characterization of novel bovine beta-defensin genes and expression in mammary gland tissue [J]. BJU Int.2011,323:1707-1715
158 Pascale Fehlbaum, Meena Rao, Michael Zasloff, and G. Mark Anderson. An essential amino acid induces epithelial beta-defensin expression[J]. PNAS,2000,97(23): 12723-12728
159 Kara Swanson, Stas Gorodetsky, Laura Good, et al. Expression of a beta-Defensin mRNA, Lingual Antimicrobial Peptide, in Bovine Mammary Epithelial Tissue Is Induced by Mastitis[J]. INFECTION AND IMMUNITY,2004,7311-7314
160王艾平,王军平,粟永萍.防御素基因工程制备研究进展[J].微生物学通报,2008,35(3)：436-442
161 KL Piers, MH Brown, RE Hancock. Recombinant DNA procedures for producing small antimicrobial cationic peptides in bacteria [J]. Gene,1993,134(1):7-13.
162 L Zhang, T Falla, M Wu, et al. Determinants of Recombinant Production of Antimicrobial Cationic Peptides and Creation of Peptide Variants in Bacteria [J]. Biochem and Biophy Res Com,1998,247:674-680
163 Chrystelle Derache, Valerie Labas, Vincent Aucagne, et al. Primary Structure and Antibacterial Activity of Chicken Bone Marrow-Derived beta-Defensins[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2009:4647-4655
164 Sergio C, NikolinkaA, IgorZ, eta.l Primate β-defensins Structure,. Function and Evolution [J]. Current Protein and Peptide Science,2005,6(1):7-21
165 Wehkamp J, Schauber J, Stange E F. Defensins and cathelicidins in gastrointestinal infections[J]. Curr Opin Gastroentero,12007,23(1):32-38
166 Bowdish D M, Davidson D J, Hancock R E. Immuno-modulatory properties of defensins and cathelicidins [J]. CurrTopMicrobiol Immuno,12006,306:27-66
167 Cullor J S, Wood S, Smith W, et al. Bactericidal potency and mechanistic specif icity of neutrophil defensins against bovine mastitis pathogens [J]. Vet Microbiol.,1991, 29(1):49-58
168 Selsted ME, Tang YQ, Morris WL. Purification, primary structures, and antibacterial activities of β-defensins, a new family of antimicrobial peptides from bovine neutrophils[J]. J Biol Chem,1993,268(9):6641-6648
169 Roosen S, Exner K, Paul S, et al. Bovine beta-defensins:Identification and characterization of novel bovine β-defensin genes and their express ion in mammary gland tissue[J]. Mamm Genome.,2004,15:834-842
170 Aono S, Li C, Zhang G, et al. Molecular and functional characterization of bovine beta-defensin-1 [J]. Vet Immunol Immunopathol,2006,113(1-2):181-190
171 Fang J, Shi G P, Vaghy P L. Identification of the increased expression of monocyte chemoattractant protein-1, cathepsin S, UPIX-1, and other genes in dystrophin-deficient mouse muscles by suppression subtractive hybridization [J]. J Cell Biochem.,2000,79(1):164-172
172 Goldammer T, Zerbe H, Molenaar A, et al. Mastitis Increases Mammary mRNA Abundance of β-Defensin 5, Toll-Like-Receptor 2 (TLR2), and TLR4 but Not TLR9 in Cattle[J]. Clinical and Diagnostic Laboratory Immunology,2004,11(1):174-185
173 Yang W, Molenaar A, Kurts-Ebert B, et al. NF-kappaB factors are essential, but not the switch, for pathogen-related induction of the bovine beta-defensin 5-encoding gene in mammary epithelial cells [J]. Mol Immunol.,2006,43(3):210-225
174曹随忠,李宏滨,姚学萍,等.奶牛乳房炎抗性基因的反向Northern斑点杂交差异筛选[J].家畜生态学报,2007,28(3)：57-61
175Weichen, Ulrike Syldath, Kerstin Bellmann, et al. Human 60-kDa heat-shock protein: A danger signal to the innate immune system [J]. J. Immunology.1999,162:3212
176 Riollet C, Rainard P, Poutrela B. Cell subpopulations and cytokine expression in cow milk in response to chronic Staphylococcus aureus infection [J]. J Dairy SCI, 2001,84(5):1077-1084
177杨雷,漆世华,刘汉平.猪繁殖与呼吸综合征活疫苗耐热冻干保护剂的试验[J].中国兽医杂志,2011,47(10)：35-37
178刘学进,陈垦,龙友明等,不同浓度脂多糖刺激AR42J细胞对NF-κB及ICAM-1表达的影响[J].广东药学院学报,2007,23(1)：71-75
179顾建车,孙华.脂多糖诱导大鼠心肌细胞NF-κB、IκB-α的表达及意义[J]. J. o f ChineseM icroc irculation Aug 2006,10 (4):266-268
180徐静,张鑫,刘艳杰等.LPS对PC12细胞NF-κB的激活时程[J].大连医科大学学报,2010,32(2)：156-159
181祈春梅.猪CREB家族基因的克隆及表达研究的初步探讨[C].华中农业大学,2009
182查道德.TLR4与NF-κB在非小细胞肺癌组织中的表达及临床意义[C].安徽医科大学,2007
183 Bohnhorst J, Rasmussen T, Moen SH, et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells[J]. Leukemia,2006,20(6):1138-1144
184 Akihiro Sakai, Jiahuai Han, Andrew CB Cato, Shizuo Akira and Jian-Dong Li. Glucocorticoids synergize with IL-1 β to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells [J]. BMC Molecular Biology,2004,5:2
185 Min Yu, Danbing Shao, Jianjun Yang, Shangwu Feng, Jianguo Xu. Ketamine Suppresses Intestinal TLR4 Expression and NF-κB Activity in Lipopolysaccharide-treated Rats[J]. Croat Med J.,2006,47:825-31
186 H. D. BRIGHTBILL, R. L. MODLIN. Toll-like receptors:molecular mechanisms of the mammalian immune response[J]. Immunology 2000,101:1-10
187 Jeongmin Song, and Soman N. Abraham. TLR Mediated Immune Responses in the Urinary Tract [J]. Curr Opin Microbiol.2008,11(1):66-73. doi:10.1016/j. mib.2007.12.001.
188 Manjunatha R. Benakanakere, Jiawei Zhao, Johnah C. Galicia, Michael Martin, Denis F. Kinane Sphingosine Kinase-1 Is Required for Toll Mediated β-Defensin 2 Induction in Human Oral Keratinocytes [J]. PLoS ONE | www.plosone.org July 2010, 5:1-12
189 Diana Legarda, Marcia E. Klein-Patel, Sunghan Yim, Ming H. Yuk, and Gill Diamond. Suppression of NF-κ B-mediated β-defensin gene expression in the mammal ian airway by the Bordetella type Ⅲ secretion system[J]. Cell Microbiol.2005,7(4):489-497
190 Ju SM, Goh AR, Kwon DJ, et al. Extracellular HIV-1 tat induces human beta-defens in-2 production via NF-kappaB/AP-1 dependent pathways in human B cells [J]. Mol Cells, 2012 Mar 23. [Epub ahead of print] PMID:22450687 [PubMed-as supplied by publ isher]
191 Aul R, Armstrong J, Duvoix A, et al. Inhaled LPS challenges in smokers:a study of pulmonary and systemic effects [J]. Br J Clin Pharmacol.2012 Mar 30. doi: 10.1111/j.1365-2125.2012.04287. x. [Epub ahead of print]
192 Yamakawa, M., and Tanaka, H., Immune proteins and their gene expression in the silkworm, Bombyx mori. Dev. Comp. Immunol.,1999,23:281-289
193Pace E, Ferraro M, Minervini MI, et al. Beta Defensin-2 Is Reduced in Central but Not in Distal Airways of Smoker COPD Patients [J]. PLoS One.2012,7(3):e33601. Epub 2012 Mar 16
194 Nadine Steubesand, Karlheinz Kiehne, Gabriele Brunke, et al.The expression of the p-defensins hBD-2 and hBD-3 is differentially regulated by NF-κB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis [J]. BMC Immunology,2009:1-16
195张方,李子玲等.LPS致大鼠肺巨噬细胞NF-κB促进TNF-α分泌[J].中国病理生理杂志,2007,23(2)：1412-1414
196 Gankovskaia OA, Gankovskaia LV, Koval'chuk LV, et al. [Changes in expression level of TLR9 and BD-2 genes in cornea of mice with viral keratitis] [J]. Zh Mikrobiol Epidemiol Immunobiol.,2012 Jan-Feb, (1):80-3. [Article in Russian]
197 Susumu MATSUO, Soh YAMAZAKI, Koichiro TAKESHIGE and Tatsushi MUTA. Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation [J]. Biochem. J.,2007,40(5):605-615
198 Matsusaka, T., Fujikawa, K., Nishio, Y., Mukaida, N., Matsushima, K., Kishimoto, T. and Akira, S. Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl. Acad. Sci. U.S.A.1993,90:10193-10197
199 Zhang, Y. and Rom, W. N. Regulation of the interleukin-1β (IL-1β) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs. Mol. Cell. Biol.1993,13:3831-3837
200 Natsuka, S., Akira, S., Nishio, Y., Hashimoto, S., Sugita, T., Isshiki, H. and Kishimoto, T. Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood,1992,79,460-466
201 Ruddy, M. J., Wong, G. C., Liu, X. L, Yamamoto, H., Kasayama, S., Kirkwood, K. L. and Gaffen, S. L. Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer-binding protein family members. J. Biol. Chem.2004,279,2559-2567
202 Shen, F., Hu, Z., Goswami, J. and'Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 2006,281:24138-241.48
203 Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos.M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beuter.1998. Defective LPS signaling in C3H/HeL and C57BL/10ScCr mice:mutations in Tlr4 gene. Science 282:2085-2088
204 Hoshino, K.,0. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Takeda, and S. Akira.1999. Cutting edge:Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product. J. Immunol.162:3749-3752
205 Shimazu, R., S. Akashi, H. Ogata, Y. Nagai, K. Fukudome, K. Miyake, and M. Kimoto. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med.189:1777-1782
206 Yang, H., D. W. Young, F. Gusovsky, and J. C. Chow.2000. Cel lular events mediated by lipopolysaccharide-stimulated toll-like receptor 4. MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. J. Biol. Chem.275:20861-20866
207 Nagai, Y., S. Akashi, M. Nagafuku, M. Ogata, Y. Iwakura, S. Akira, T. Kitamura, A. Kosugi, M. Kimoto, and K. Miyake.2002. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat. Immunol.3:667-672
208 Weicheng Wu, Raymond D. Mosteller, and Daniel Broek Sphingosine Kinase Protects Lipopolysaccharide-Activated Macrophages from Apoptosis[J]. MOLECULAR AND CELLULAR BIOLOGY, Sept.2004, Vol.24, No.17p.7359-7369
209 T. Goldammer, H. Zerbe, A. Melenaar, et al. Mastitis Increases Mammary mRNA Abundance of beta-Defensin 5, Toll-Like-Receptor 2 (TLR2), and TLR4 but Not TLR9 in Cattle[J]. CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY,2004:174-185
210宋祖军,王少波,王琦等.NF-kB的研究进展[J].世界急危重病医学杂志[J].2007,4(1)：1693-1696
211 Ulich TR, Yin S, Guo K, et a.1 Intratracheal injection of endotoxin and cytokines II, Interleukin-6 and transforming growth factor beta inhibit acute inflammation [J]. Am J Patho,11991,138(5):1097-110
212韦安猛,夏熙郑NF-κB, TNF-α在大鼠慢性阻塞性肺疾病中的作用[J].医药论坛杂志,2006.27(24)：62-63
213 Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences [J]. Cell 1986; 46 (5):705-716
214 Laurence Hoareau, Karima Bencharif, Philippe Rondeau, Ravi Murumalla, Palaniyandi Ravanan, Frank Tallet, Pierre Delarue, Maya Cesari, Regis Rochel, Franck Festy. Signaling pathways involved in LPS induced TNFalpha production in human adipocytes [J]. Iloareau et al. Journal of Inflammation,2010',7:1
215 Pomerantz JL, Baltimore D. Two pathways for NFkB. Mol Cell 2002,10:693-701. [PubMed:12419209
216 Li, Q. and Verma, I. M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2002,2,725-734
217 Hayden, M. S. and Ghosh, S. Signaling to NF-κB. Genes Dev.2004,18,2195-2224
218 Chen, L. F. and Greene, W. C. Shaping the nuclear action of NF-κB. Nat. Rev. Mol. Cell Biol.2004,5,392-401
2 赵兴绪主编.兽医产科学,北京：中国农业出版社,2002：457-468
3 齐长明,奶牛疾病学[M].中国农业科学技术出版社,2006
4 李配林,汤天晓,刘颖等.用中西药制剂薄硫膏治疗奶牛乳房炎[J].中兽医医药杂志,1998,17(2)：28
5 马树东,冯丽荣,王梅中.西兽药配合治疗奶牛临床型乳房炎的效果[J].中国奶牛,2000(5)：39-40
6 Axford RFE, Bishop SC, Nicholas FW, et al. Breeding for disease resistance in farm animals [J]. CABI Publishing, Oxon,2000,243-252
7 潘虎,刘纯传,张礼华等.我国部分地区奶牛乳房炎的病因及发病情况调查[J].中国兽医科技,1996,26(2)：16-17
8 DeGraves FJ, Fetrow J. Economics of mastitis and mastitis control [J]. Vet Clin North Am:Food Anim Pract,1993,9:421-434
9 Ruegg PL. Investigation of mastitis problems on farms [J]. Vet Clin North Am:Food Anim Pract,2003,19(1):47-73
10 Bradley AJ. Bovine mastitis:an evolving disease. The Veterinary Journal,2002,164: 116-128
11 Chen Y, Zhao YH, Wu R. In silico cloning of mouse Muc5b gene and upregulation of its expression in mouse asthma model. Am J Respir Crit Care Med,2001,164:1059-1066
12 Almeida RA, Luther DA, Oliver SP. Pathogenic Strategies of mastitis pathogens, http://animalscience.ag.utk.edu/annual-reports_all.html
13 Bayles KW, Wesson CA, Liou LE, et al. Intracellular Staphylococcus aureus escapes the endosomeand induces apoptosis in epithelial cells[J]. Infection and Immunity, 1998,66(1):336-342
14 Hassan AA, Khan IU, Abdulmawjood A, et al. Inter-and intraspecies variations of the 16S-23S rDNA intergenic spacer region of various streptococcal species [J]. Syst Appl Microbiol,2003,26:97-103
15 Almeida RA, Fang W, Oliver SP. Adherence and internalization of Streptococcus uber is to bovine mammary epithelial cells are mediated by host cell proteoglycans [J]. FEMS Microbiol Lett,1999b,177:313-317.
16 Almeida RA, Oliver SP. Interaction of coagulase-negative Staphylococcus species with bovine mammary epithelial cells [J]. Microbial Pathogenesis,2001,31(5): 205-212
17 Almeida RA, Calvinho LF, Oliver SP. Influence of protein kinase inhibitors on Stieptocoeeus aberis internalization into bovine mammary epithelial cells [J]. Microbial Pathogenesis,2000,28:9-16
18 Sears PM, McCarthy KK. Diagnosis of mastitis for therapy decisions [J]. Vet Clin North Am:Food Anim Pract,2003,19(1):93-108
19 Jayarao BM, Wolfgang DR. Bulk-tank milk analysis:A useful tool for improving milk quality and herd udder health. Vet Clin North Am:Food Anim Pract,2003,19(1): 75-92
20赵德明,沈建忠(主译)Rebhun WC(著).奶牛疾病学.北京：中国农业出版社,1999,383-425
21 Dosogne H, Vangroenweghe F, Burvenich C. Potential mechanism of action of J5 vaccine in protection against severe bovine coliform mastitis[J]. Vet Res,2002,33(1): 1-12
22刘本君,葛佳瑞,戴波涛.不同程度奶牛乳腺炎IL-8、TNF-α的研究[J].黑龙江畜牧兽医(科技版),2011,(7)：106-107
23高纯一,祁永锋,丁营兵.公英散加味治疗乳牛乳房炎[J].中国兽医科技,2001(2)：12
24高庆田,朱其苏.“中药乳炎消油剂”临床应用综述[J].中国奶牛,2000(4)：36-37
25张彬,薛明,崔颖等.新兽药消炎醌对乳牛乳腺炎临床治疗试验[J].中国兽医科技,2000(8)：9-12
26潘志明,张小荣,焦新安.作为疫苗和疫苗载体的胞内细菌[J].动物兽医进展,2002,23(3)：107.
27 Leitner G, Yadlin N, Lubashevsy E, et al. Development of a Staphylococcus aureus vaccine against mastitis in dairy cows. Ⅱ. Field trial [J]. Vet Immunol Immunopathol, 2003,93(3-4):153-8
28 Leitner G, Lubashevsky E, Glickman A, et al. Development of a Staphylococcus aureus vaccine against mastitis in dairy cows. Ⅰ. Challenge trials [J]. Vet Immunol Immunopathol,2003,93(1-2):31-8
29 Leitner G, Lubashevsky E, Trainin Z. Staphylococcus aureus vaccine against mastitis in dairy cows, composition and evaluation of its immunogenicity in a mouse model [J]. Vet Immunol Immunopathol,2003,93 (3-4):159-67
30 Finch J, Winter A, Walton A, et al. Further studies on the efficacy of a live vaccine against mastitis caused by Streptococcus uberis [J]. Vaccine,1997,156:1138-1143
31罗金印,郁杰,李新圃等.乳牛乳腺炎多联苗免疫试验[J].中国兽医科技,2002,32(5)：40-41
32 Bradley AJ. Bovine mastitis:an evolving disease [J]. The Veterinary Journal,2002, 164:116-128
33 Kerr D E, Plaut K, Bramley A J, et al. Lysoslaphin expression in mammary glands confers protection against staphylococcal infection in transgenic mice[J]. Nat Biotechnol,2001,19(1):66-70.
34 Pyorala S. New strategies to prevent mastitis [J]. Reprod Dom Anim,2002,37:211-216
35 Yancy R. Vaccines and diagnostic method for bovine mastitis fact and fiction [J]. Adv Vet Med,1999,41:257-273
36 Finch J, Winter A, Walton A, et al. Further studies on the efficacy of efficacy of a live caccine against mastitis caused by Streptococcus uberis [J]. Vaccine, 1997,156:1138-1143
37涂勇,曹贵方.p-防御素-5mRNA在荷斯坦奶牛乳腺上皮细胞中的表达[D].2011：8-9
38易明梅,冯华,朱建国等.生物制剂在奶牛乳房炎防治中的应用[J].中国畜牧兽医,2007,34(5)：37-39
39 Heringstad B, Klemetsdal G, Ruane J. Selection for mastitis resistance in dairy cattle:a review with focus on the situation in the Nordic countries [J]. Livestock Production Science,2000,64:95-96
40 Magnusson U. Breeding for improved disease resistance in organic farming-possibilities and constraints [J], Acta Vet Scand,2001, Suppl.95:59-61
41 Detilleux JC. Genetic factors affecting susceptibility of dairy cows to udder pathogens [J]. Vet Immunol Immunopathol,2002,88:103-110
42 Burton JL, Erskine RJ. Immunity and mastitis:some new ideas for an old disease [J]. Vet Clin North Am:Food Anim Pract,2003,19(1):1-45
43 Rupp R, Boichard D. Genetic parameters for clinical mastitis, somatic cell score, production, udder type traits, and milkinkease in the first lactation Holsteins [J]. J Dairy Sci,1999,82:2198-2202
44 Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense [J]. Annu Rev Immunol,2004,22:181-215. [PubMed:15032578] Comprehensive review of the innate and adaptive immune functions of defensins.
45 Diamond G, Beckloff N, Ryan LK. Host defense peptides in the oral cavity and the lung:similarities and differences, J Dent Res 2008,87:915-927. [PubMed: 18809744]
46 Rehaume LM, Hancock RE, Neutrophil-derived defensins as modulators of innate immune function. Crit Rev Immunol 2008,28:185-200. [PubMed:19024344]
47周雷.几种奶牛乳房炎相关基因在白细胞内的表达及克隆表达[C].甘肃农业大学.2008：4
48陈永辉,钟莲,张胜燕.公英散治疗奶牛乳房炎的临床效果观察[J].中国畜牧兽医,2008,35(5)：82-83
49 Yorma C,Soebah S,Low SM,Zhou L,Liu SP,Li J,Bouerman RW.Defensins :antimicrobial peptides for therapeutic development [J]. Biotechnol J 2007,2 (11):1353-1359
50傅荣昭,李文彬,孙勇如.防御素的研究进展[J].农业生物技术学报,1996,4(12)：348-353
51 李穆然.β-防御素与炎症性肠病[J].国际消化病杂志,2006,26(6)：374-376.
52 Sorensen J L, Cowland J B, Theilgaard-Monch K, et al. Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors [J]. J Immunol.,2003,170(11):5583-5589
53 Yang D, Biragyn A, Kwak LW, Oppenheim JJ. Mammalian defensins in immunity:more than just microbicidal [J]. Trends Immunol 2002,23 (6):291-296
54 Selsted ME, Ouellette AJ Mammalian defensins in the antimicrobial immune response [J]. Nat Immunol 2005,6 (6):551-557
55 Nguyen TX, Cole AM, Lehrer RI Evolution of primate thetadefensins:a serpentine path to a sweet tooth [J]. Peptides 2003,24 (11):1647-1654
56 G. Diamond, N. Beckloff, and L.K. Ryan. Host Defense Peptides in the Oral Cavity and the Lung:Similarities and Differences [J]. J Dent Res.2008,87(10):915-927
57 Gordon B. Mitchell, Muthafar H. Al-Haddawi, Mary Ellen Clark, et al. Effect of Corticosteroids and Neuropep tides on the Expression of Defensins in Bovine Tracheal Epithelial Cells [J]. INFECTION AND IMMUNITY,2007,1325-1334.
58 Suresh Yenugu, Vishnu Chintalgattu, Christopher J Wingard, et al. Identification, cloning and functional characterization of novel beta-defensins in the rat (Rattus norvegicus) [J]. Reproductive Biology and Endocrinology,2006,4:7
59 Yongming Sang, M. Teresa Ortega, Frank Blecha, Om Prakash, and Tonatiuh Melgarejo. Molecular Cloning and Characterization of Three beta-Defensins from Canine Testes[J]. INFECTION AND IMMUNITY,2005,73 (5):2611-2620
60 Gillian Morrison, Fiona Kilanowski, Donald Davidson, and Julia Dorin. Characterization of the Mouse Beta Defensin 1, Defbl, Mutant Mouse Model.[J]. INFECTION AND IMMUNITY,2002,70 (6):3053-3060
61 MICHAEL MATHEWS, HONG PENG JIA, JANET M. GUTHMILLER, GARRETT LOSH, SCOTT GRAHAM, GEORGIA K. JOHNSON, BRIAN F. TACK, AND PAUL B. MCCRAY, JR. Production of beta-Defens in Antimicrobial Peptides by the Oral Mucosa a'nd Salivary Glands [J]. INFECTION AND IMMUNITY,1999,67 (6):2740-2745
62 JISHU SHI, GUOLONG ZHANG, HUA WU, CHRISTOPHER ROSS, FRANK BLECHA, AND TOMAS GANZ. Porcine Epithelial beta-Defensin 1 Is Expressed in the Dorsal Tongue at Antimicrobial Concentrations [J]. INFECTION AND IMMUNITY,1999,67(6):3121-3127
63 Zhou L, Huang LQ, Beuerman RW, et al. Tan D Proteomic analysis of human tears: defensin expression after ocular surface surgery [J]. J Proteome Res,2004,3(3):410-416
64 Schutte BC, McCray PB Beta-defensins in lung host defense [J]. Annu Rev Physiol 2002,64:709-748
65 Valore EV, Park CH, Quayle AJ, et al. Human beta-defensin-1:an antimicrobial peptide of urogenital tissues [J]. J Clin Invest,1998,101(8):1633-1642
66 Harder J, Bartels J, Christophers E, Schroder JM Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic[J]. J Biol Chem,2001,276(8):5707-5713
67 Jia HP, Schuttea BC, Schudye A, et al. Jr Discovery of new human b-defensins using a genomics-based approach [J]. Gene.2001,263:211-218
68 Sumikawa Y, Asada H, Hoshino K, et al. Induction of beta-defensin 3 in keratinocytes stimulated by bacterial lipopeptides through toll-like receptor 2 [J]. Microbes Infect,2006,8 (6):1513-1521
69 Varoga D, Wruck CJ, Tohidnezhad M, et al. Osteoblasts participate in the innate immunity of the bone by producing human beta defensin-3 [J]. Histochem Cell Biol, 2009,131 (2):207-218
70 Harder J, Meyer-Hoffert U, Teran LM, et al. Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-lbeta, but not IL-6, induce human betadefensin-2 in respiratory epithelia [J]. Am J Respir Cell Mol Biol,2000,22(6):714-721
71 Bogefors J, Kvarnhammar AM, Hockerfelt U, et al. Reduced tonsillar expression of human β-defensin 1,2 and 3 in allergic rhinitis [J]. FEMS Immunol Med Microbiol, 2012 Mar 22.10.1111/j.1574-695X.2012.00959. x. [Epub ahead of print] PMID:22444247 [PubMed-as supplied by publisher]
72 Garc i a JR, Jaumann F, Schulz S, Krause A, Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction [J]..Cell Tissue Res,2001a,306(2):257-264
73 Allan M. TORRES, Xiuhong WANG, Jamie I. FLETCHER, Dianne ALEWOOD., Paul F. ALEWOOD. Ross SMITH., Richard J. SIMPSON(?), Graham M. NICHOLSONs, Struan K. SUTHERLAND., Cliff H. GALLAGHER, Glenn F. KING and Philip W. KUCHEL. Solution structure of a defensin-like peptide from platypus venom[J]. Biochem. J.,1999,341:785-794
74 Diamond, G.; Zasloff, M.; Eck, H. et al. Tracheal antimicrobial peptide, a cysteine-rich peptide from mammalian tracheal mucosa:peptide isolation and cloning uf a cDNA [J]. Proceedings of the National Academy of Sciences 1931,88 (9),3952.
75 Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc Natl Acad Sci USA 2005,102:18129-18134. [PubMed:16330776]
76 Rivas-Santiago B, Serrano CJ, Enciso-Moreno JA. Susceptibility to infectious diseases based on antimicrobial peptide production. Infect Immun 2009,77:4690-4695. [PubMed:19703980]
77 Schonwetter, B. S., Stolzenberg, E. D., Zasloff, M. A., Epithelial antibiotics induced at sites of inflammation. Science 1995,267 (5204),1645-1648
78 Selsted, M. E., Tang, Y. Q., Morris., et al. Purification, primary structures, and antibacterial activities of β-defensins, a new family of antimicrobial peptides from bovine neutrophils [J]. Journal of Biological Chemistry 1996,271 (27),16430.
79 Yang D, Biragyn A, Hoover DM, et al. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense [J]. Annu Rev Immunol.,2004,22:181-215
80李宏滨.3个与奶牛乳房炎抗性相关基因的克隆及比较基因组学分析[D].中国农业科学院,2008
81 Ericksen B, Wu Z, Lu W, et al. Antibacterial activity and specificity of the six human alpha-defensins[J]. Antimicrob Agents Chemother,2005,49 (1):269-275
82 Schroder JM, Harder J. Human beta-defensin-2[J]. Int J Biochem Cell Biol,1999, 31(6):645-651
83 Krishnakumari V, Nagaraj R. Interaction of antibacterial peptides spanning the carboxy-terminal region of human betadefensins 1-3 with phospholipids at the air-water interface and inner membrane of E. coli [J]. Peptides,2008,29(1):7-14
84 Nagaoka I, Niyonsaba F, Tsutsumi-Ishi i Y, et al. Evaluation of the effect of human beta-defensins on neutrophil apoptosis [J]. Int Immunol,2008,20(4):543-553
85 Sharma S, Verma I, Khuller GK. Therapeutic potential of human neutrophil peptide 1 against experimental tuberculosis [J]. Antimicrob Agents Chemother,2001, 45(2):639-640
86 Verma C, Seebah S, Low SM, et al. Defensins:antimicrobial peptides for therapeutic development [J]. Biotechnol J,2007,2 (11):1353-1359
87 As hi tani J, Mukae H, Hiratsuka T, et al. Elevated levels of alpha-defensins in plasma and BAL fluid of patients with active pulmonary tuberculosis [J]. Chest,2002, 121(2):519-526
88 Sharma S, Verma I, Khuller GK. Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv:in vitro and ex vivo study [J]. Eur Respir J.,2000,16(1):112-117
89 Rivas-Santiago B, Schwander SK, Sarabia C, et al. Human{beta}-defens in 2 is expressed and associated with Mycobacterium tuberculosis during infection of human alveolar epithelial cells [J]. Infect Immun,2005,73 (8):4505-4511
90 Rivas-Santiago B, Sada E, Tsutsumi V, et al. beta-Defensin gene expression during the course of experimental tuberculosis infection. J Infect Dis,2006,194(5):697-701
91 Wang W, Mulakala C, Ward SC, et al. Retrocyclins kill bacilli and germinating spores of Bacillus anthracis and inactivate anthrax lethal toxin [J]. J Biol Chem.,2006, 281 (43):32755-32764
92 Verma C, Seebah S, Low SM, et al. Defensins:antimicrobial peptides for therapeutic development [J]. Biotechnol J,2007,2(11):1353-1359
93 Feng Z, Jiang B, Chandra J, Ghannoum M, Nelson S, et al. Human beta-defensins: differential activity against Candidal species and regulation by Candida albicans [J]. J Dent Res.,2005,84:445-450
94 Joly S, Organ CC, Johnson GK, et al. Correlation between beta-defensin expression and induction profiles in gingival keratinocytes [J]. Mol Immunol.,2005, 42(9):1073-1084
95 Hazrati E, Galen B, Lu W, et al. Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection [J]. J Immunol.,2006,177(12):8658-8666
96 Wang W, Owen SM, Rudolph DL, et al. Activity of alpha- and theta-defensins against primary isolates of HIV-1 [J]. J Immunol,2004,173 (1):515-520
97 Chang TL, Vargas J, DelPortillo A, et al. Dual role of alpha-defensin-1 inanti-HIV-1 innate immunity[J]. J Clin Invest,2005,115(3):765-773
98 Kreuter A, Skrygan M, Gambichler T, et al. Human papillomavirus-associated induction of human betadefensins in anal intraepithelial neoplasi [J]. Br J Dermatol, 2009,160(6):1197-1205
99 Tarek K. Zaalouk, Mona Bajaj-Elliott, John T. George, and Vincent McDonald. Differential Regulation of beta-Defensin Gene Expression during Cryptosporidium parvum Infect ion [J]. INFECTION AND IMMUNITY,2004,72 (5):2772-2779
100Cole AM, Hong T, Boo LM, et al. Retrocyclin:a primate peptide that protects cells from infection by T-and M-tropic strains of HIV-1 [J]. Proc Natl Acad Sci USA, 2002,99(4):1813-1818
101Munk C, Wei G, Yang OO, et al. The theta-defensin, retrocyclin, inhibits HIV-1 entry [J]. AIDS Res Hum Retioviruses,2003,19(10):875-881
102Leitch GJ, Ceballos CA. role for antimicrobial peptides in intestinal microsporidiosis [J]. Parasitology,2009,136(2):175-181
103Zaalouk TK, Bajaj-Elliott M, George JT, et al. Differential regulation of beta-defensin gene expression during Cryptosporidium parvum infection [J]. Infect Immun,2004,72(5):2772-2779
104 Feng Z, Dubyak GR, Lederman MM, Weinberg A. Cutting edge:human β defensin 3 a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 2006,177:782-786. [PubMed:16818731]
105 Hazrati E, Galen B, Lu W, et al. Human α-and β-defensins block multiple steps in herpes simplex virus infection. J Immunol 2006,177:8658-8666. [PubMed: 17142766]
106 Joly S, Maze C, McCray PB Jr, Guthmiller JM. Human β-defensins 2 and 3 demonstrate strainselective activity against oral microorganisms. J Clin Microbiol 2004, 42:1024-1029. [PubMed:15004048]
107 Karen Taylor, Mark Rolfe, Natal ie Reynolds, Fiona Kilanowski, Uday Pathanial, Dave Clarke, De Yang3, Joost Oppenheim, Kay Samuel, Sarah Howie, Perdita Barran, Derek Macmillan, Dominic Campopiano2 and Julia Dorin. Defensin-related peptide 1 (Defrl) is allelic to Defb8 and chemoattracts immature DC and CD4 T cells independently of CCR6 [J]. Eur. J. Immunol.2009.39:1353-1360
108 Charles E. Shelburne, Wilson A. Coulter, De'Avlin Olguin, et al. Induction of beta-Defensin Resistance in the Oral Anaerobe Porphyromonas gingivalis [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2005,183-187.
109 Lingling Sun, Leon DeMasi, Mark Lafferty, Marco Goicochea, Wuyuan Lu and Alfredo Garzino-Demo. CCR6 mediates the intracellular HIV inhibitory activity of human beta-defensin 2 [J]. Retrovirology,2006,3(1):77
110Tka T, Rahman MM, Battur B, et al. Parasiticidal activity of human alpha-defensin-5 against Toxoplasma gondii [J]. In Vitro Cell Dev Biol Anim Epub, 2010, Feb 5
111 Madison MN, Kleshchenko YY, Nde PN, et al. Human defensin a lpha-1'causes Trypanosoma cruzi membrane pore formation and induces DNA fragmentation, which leads to trypanosome destruction [J]. Infect Imtnun,2007,75 (10):4780-4791
112Ganz T. Defensins:antimicrobial peptides of innate immunity [J]. Nat Rev Immunol. 2003,3(9):710-720
113 T Gambichler, M Skrygan, J Huyn, et al. Pattern of mRNA expression of (3-defensins in basal cell carcinoma[J]. BMC Cancer,2006,6:163
114De Leeuw E, Li C, Zeng P, et al. Functional interaction of human neutrophiI peptide-1 with the cell wall precursor lipid Ⅱ [J]. FEBS Lett,2010,584(8):1543-1548
115 A. FAHLGREN, S. HAMMARSTROM, A. DANIELSSON & M.-L. HAMMARSTROM. beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis[J]. Clin Exp Immunol 2004,137:379-385
116 Brian J. Poindexter, Gordon L. Klein, Stephen M. Milner, and Roger J. Bick. Upregulation of Defensins in Burn Sheep Small Intestine[J]. Open Acess Journal of Plastie Surgery,2009,10:43-55
117 Karl G Kohlgraf, Lindsey C Pingel, Deborah E Dietrich, Kim A Brogden. Defensins as anti-inflammatory compounds and mucosal Adjuvants [J]. Future Microbiol.2010, 5:99-104
118 Beverly A. Dale and L. Page Fredericks. Antimicrobial Peptides in the Oral Environment:Expression and Function in Health and Disease [J]. Curr Issues Mol Biol. 2005,7(2):119-133.
119 J. W. McMichael, A. I. Maxwell, K. Hayashi, K. Taylor, W. A. Wallace, J. R. Govan, J. R. Dorin, and J.-M. Sallenave. Antimicrobial Activity of Murine Lung Cells against Staphylococcus aureus Is Increased In Vitro and In Vivo after Elafin Gene Transfer[J]. INFECTION AND IMMUNITY,2005,73(6):3609-3617
120Mothes H, Melle C, Ernst G, et al. Human Neutrophil Peptides 1-3-earlymarkers in development of colorectal adenomas and carcinomas [J]. Dis Markers,2008, 25(2):123-129
121Droin N, Hendra JB, Ducoroy P, et al. Human defensins as cancer biomarkers and antitumour molecules [J]. J Proteomics,2009,72 (6):918-927
122 Kesting MR, Loeffelbein DJ, Hasler RJ, et al. Expression profile of human beta-defensin 3 in oral squamous cell carcinoma [J]. Cancer Invest.,2009, 27 (5):575-581
123Semple F, Dorin JR. β-Defensins:Multifunctional Modulators of Infection, Inflammation and More?[J]. J Innate Immun.2012 Mar 21. [Epub ahead of print]
124Marin M, Yamamoto Y, Wang QM. The IKK NF- kappa B system:a treasure trove for drug development [J]. Nat Rev Drug Discov,2004,3(1):17-26
125 Young Mee Yoon, Jin Young Lee, Doyoung Yoo, et al. Bacteroides fragil is Enterotoxin Induces Human beta-Defensin-2 Expression in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase/IκB Kinase/NF-κB-Dependent Pathway [J]. INFECTION AND IMMUNITY,2010:2024-2033
126 Cuiming Li Joanne Domenico Yi Jia Josoph J.Lucas Erwin W.Gelfand.NF-κB-Dependent Induction of Cathelicidin-Related Antimicrobial Peptide in Murine Mast Cells by Lipopolysaccharide[J]. Allergy Immunology,2009,150:122-132
127aeuerle PA, Baltimore D. NF-kappa B:ten years after [J]. Cell 1996,87(1):13-20
128叶伟萍,杨祖菁.核因子-κ B p65蛋白在感染性早产孕妇妊娠组织中的表达及意义[J].实用医学杂志,2009,25(4)：557-560
129 Kim HJ, Jung JR, Kim HJ, et al. Expression of human β-defensin-2 in the prostate [J]. BJU Int.2011,107(1):144-9
130Cristina Albanesi, Heather R. Fairchild, Stegania Madonna, et al. IL-4 and IL-12 negatively regulate TNF-α and IFN-γ induced β-defensin Expression through STAT-6, Suppressor of Cytokine Signaling(SOCS)-1, and SOCS-3[J]. The Journal of Immunology,2007,179:984-992.
131 Ravagnan L, Roumier T, and Kroemer G. Mitochondria. The kill organelles and their weapons [J]. J Cell Physiol.,2002,192:131-137
132韩德武等.肠源性内毒素血症与肝病：用衰竭的IEIM学说[M1].北京：中国科学技术出版社,2004
133 Darren Davies, Kieran G Meade, Shan Herath, et al. Toll-like receptor and antimicrobial peptide expression in the bovine endometrium[J]. Reproductive Biology and Endocrinology,2008,6:53
134 Young SL, Lyddon TD, Jorgenson RL, Misfeldt ML:Expression of Toll-like Receptors in human endometrial epithelial cells and cell lines. American Journal of Reproductive Immunology 2004,52:67-73.
135 Aflatoonian R, Tuckerman E, Elliott SL, Bruce C, Aflatoonian A, Li TC, Fazeli A: Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Human Reproduction 2007,22:586-593
136 Jeingmin Song, and Soman N. Abraham. TLR mediated immune responses in the urinary tract [J].Curr opin microbial.2008,11 (1):66-73
137 Samuels son P, Hang L, WulltB, et al. Toll-like receptor 4 express ion and cytokine responses in the human urinary tract mucosa [J]. Infect Immun 2004,72:3179-3186
138 Andersen-Nissen E, Hawm TR, Smith KD, et al. Cutting edge:Tlr5-/-mice are more susceptible to Escherichia coli urinary tract infect ion [J]. J Immunol.,2007, 178:4717-4720. [PubMed:17404249] Using a murine model of UTI, the authors demonstrate for the first time the importance of TLR5 in regulating innate immune response in the urinary tract. Bladders of wild type mice showed high levels of cytokine and chemokine expression in response to flagllin, which was linked to increased inflammation and subsequent bacterial clearance.
139 Zhang D, Zhang G, Hayden MS, et al. A toll-like receptor that prevents infection by uropathogenic bacteria [J]. Science,2004,303:1522-1526,
140Walker W H, Sanborm B M, Habener J F. An isoform of transcription factor CREB expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP induced transcription [J]. Proc Natl Acad Sci USA,1994,91:12423-12427
141 Wu GY, Deiss eroth K, Tsien R W. Activity2dependent CREB phos2 phorylation: Convergence of a fast, sensitive calmod ulin kinase pathway and a slow, less sensitive mitogen2 activated [J]. Proc Natl Acad Sci U SA,2001,98 (5):2808-2813
142Kimiko S, Akira Y, Fumimaro T. Cell cycle regulated phosphorylation of cAMP response element binding protein:Identification novel phosphorylation sites [J]. Biol J, 1999,338 (1):49-54
143 R. Lamprecht, CREB:a message to remember, Cell. Mol. Life Sci.55 (1999) 554-563.
144陈艳杏.17β-雌二醇对亚致死量Aβ1-42所致PC12细胞CREB活性改变的影响[D].华中科技大学,2010
145 M. R. Montminy, L. M. Bilezikjian, Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene[J]. Nature,1987,328:175-178
146 David Moranta, Vero'nica Regueiro, Catalina March, et al. Klebsiella pneumoniae Capsule Polysaccharide Impedes the Expression of beta-Defensins by Airway Epithelial Cells[J]. INFECTION AND IMMUNITY,2010,1135-1146
147 Jessica M. Caverly, Gill Diamond, Jack M. Gallup, Kim A. Brogden, Richard A. Dixon, and Mark R. Ackermann, et al. Coordinated Expression of Tracheal Antimicrobial Peptide and Inflammatory-Response Elements in the Lungs of Neonatal Calves with Acute Bacterial Pneumonia[J]. INFECTION AND IMMUNITY,2003,71(5):2950-2955
148余瑞元,王燕峰,徐长法CREB研究进展[J].中国生物工程杂志,2003,23(1)：39-42,47
149Scheving L A, Cardner W. Circa2dian-regulation of CREB transcrip2tion factor in mouse esophagus [J]. American J Physiol,1998,274 (4PART1):C1011-C1016
150Schmid R S, Graff R D,. Schaler M D, et al. NCAM stimulates the ras2MAPK pathway and CREB phosphorylation in neuronal cells [J]. J Neurobiol,1999,38 (4):542-558
151 White DM, Walker S L, Brenneman D E, et al. CREB contributes to the increased neurite of sensory neurons induced by vasoactive intestinal polypeptide and activity dependent neurotrophic factor [J].Brain Res,2000,868 (1):31-38
152武建明,何洪彬,土长法等,荷斯坦牛中性粒细胞防御素BNBD12基因克隆、原核表达及其抗菌活性分析[C].学术年会,2010：374-377
153王桂荣,严作婷,王东升等,乳牛子宫内膜抗菌肽BNBD5基因的克隆及其原核表达[J].中国兽医科学,2009,39(06)：538-542
154龙晶.牛防御素BNBD5的cDNA克隆及毕赤酵母表达[C].中国农业科学院,2007,25
155 Natal ie L. Reynolds, Mart in De Cecco, Karen Taylor, Chloe Stanton, Fiona Kilanowski, Jason Kalapothakis, Emily Seo, Dusan Uhrin, Dominic Campopiano, John Govan, Derek Macmillan, Perdita Barran, and Julia R. Dorin. Peptide Fragments of a beta-Defensin Derivative with Potent Bactericidal Activity [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2010,4(5):1922-1929
156 Gill Diamond, Nicholas Beckloff, Aaron Weinberg, and Kevin 0. Kisich. The Roles of Antimicrobial Peptides in Innate Host Defense[J]. Curr Pharm Des.2009,15(21): 2377-2392.
157Rooson S, Exner K, Schroer J M, et al. Bovine beta-defensins:Identification and characterization of novel bovine beta-defensin genes and expression in mammary gland tissue [J]. BJU Int.2011,323:1707-1715
158 Pascale Fehlbaum, Meena Rao, Michael Zasloff, and G. Mark Anderson. An essential amino acid induces epithelial beta-defensin expression[J]. PNAS,2000,97(23): 12723-12728
159 Kara Swanson, Stas Gorodetsky, Laura Good, et al. Expression of a beta-Defensin mRNA, Lingual Antimicrobial Peptide, in Bovine Mammary Epithelial Tissue Is Induced by Mastitis[J]. INFECTION AND IMMUNITY,2004,7311-7314
160王艾平,王军平,粟永萍.防御素基因工程制备研究进展[J].微生物学通报,2008,35(3)：436-442
161 KL Piers, MH Brown, RE Hancock. Recombinant DNA procedures for producing small antimicrobial cationic peptides in bacteria [J]. Gene,1993,134(1):7-13.
162 L Zhang, T Falla, M Wu, et al. Determinants of Recombinant Production of Antimicrobial Cationic Peptides and Creation of Peptide Variants in Bacteria [J]. Biochem and Biophy Res Com,1998,247:674-680
163 Chrystelle Derache, Valerie Labas, Vincent Aucagne, et al. Primary Structure and Antibacterial Activity of Chicken Bone Marrow-Derived beta-Defensins[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2009:4647-4655
164 Sergio C, NikolinkaA, IgorZ, eta.l Primate β-defensins Structure,. Function and Evolution [J]. Current Protein and Peptide Science,2005,6(1):7-21
165 Wehkamp J, Schauber J, Stange E F. Defensins and cathelicidins in gastrointestinal infections[J]. Curr Opin Gastroentero,12007,23(1):32-38
166 Bowdish D M, Davidson D J, Hancock R E. Immuno-modulatory properties of defensins and cathelicidins [J]. CurrTopMicrobiol Immuno,12006,306:27-66
167 Cullor J S, Wood S, Smith W, et al. Bactericidal potency and mechanistic specif icity of neutrophil defensins against bovine mastitis pathogens [J]. Vet Microbiol.,1991, 29(1):49-58
168 Selsted ME, Tang YQ, Morris WL. Purification, primary structures, and antibacterial activities of β-defensins, a new family of antimicrobial peptides from bovine neutrophils[J]. J Biol Chem,1993,268(9):6641-6648
169 Roosen S, Exner K, Paul S, et al. Bovine beta-defensins:Identification and characterization of novel bovine β-defensin genes and their express ion in mammary gland tissue[J]. Mamm Genome.,2004,15:834-842
170 Aono S, Li C, Zhang G, et al. Molecular and functional characterization of bovine beta-defensin-1 [J]. Vet Immunol Immunopathol,2006,113(1-2):181-190
171 Fang J, Shi G P, Vaghy P L. Identification of the increased expression of monocyte chemoattractant protein-1, cathepsin S, UPIX-1, and other genes in dystrophin-deficient mouse muscles by suppression subtractive hybridization [J]. J Cell Biochem.,2000,79(1):164-172
172 Goldammer T, Zerbe H, Molenaar A, et al. Mastitis Increases Mammary mRNA Abundance of β-Defensin 5, Toll-Like-Receptor 2 (TLR2), and TLR4 but Not TLR9 in Cattle[J]. Clinical and Diagnostic Laboratory Immunology,2004,11(1):174-185
173 Yang W, Molenaar A, Kurts-Ebert B, et al. NF-kappaB factors are essential, but not the switch, for pathogen-related induction of the bovine beta-defensin 5-encoding gene in mammary epithelial cells [J]. Mol Immunol.,2006,43(3):210-225
174曹随忠,李宏滨,姚学萍,等.奶牛乳房炎抗性基因的反向Northern斑点杂交差异筛选[J].家畜生态学报,2007,28(3)：57-61
175Weichen, Ulrike Syldath, Kerstin Bellmann, et al. Human 60-kDa heat-shock protein: A danger signal to the innate immune system [J]. J. Immunology.1999,162:3212
176 Riollet C, Rainard P, Poutrela B. Cell subpopulations and cytokine expression in cow milk in response to chronic Staphylococcus aureus infection [J]. J Dairy SCI, 2001,84(5):1077-1084
177杨雷,漆世华,刘汉平.猪繁殖与呼吸综合征活疫苗耐热冻干保护剂的试验[J].中国兽医杂志,2011,47(10)：35-37
178刘学进,陈垦,龙友明等,不同浓度脂多糖刺激AR42J细胞对NF-κB及ICAM-1表达的影响[J].广东药学院学报,2007,23(1)：71-75
179顾建车,孙华.脂多糖诱导大鼠心肌细胞NF-κB、IκB-α的表达及意义[J]. J. o f ChineseM icroc irculation Aug 2006,10 (4):266-268
180徐静,张鑫,刘艳杰等.LPS对PC12细胞NF-κB的激活时程[J].大连医科大学学报,2010,32(2)：156-159
181祈春梅.猪CREB家族基因的克隆及表达研究的初步探讨[C].华中农业大学,2009
182查道德.TLR4与NF-κB在非小细胞肺癌组织中的表达及临床意义[C].安徽医科大学,2007
183 Bohnhorst J, Rasmussen T, Moen SH, et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells[J]. Leukemia,2006,20(6):1138-1144
184 Akihiro Sakai, Jiahuai Han, Andrew CB Cato, Shizuo Akira and Jian-Dong Li. Glucocorticoids synergize with IL-1 β to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells [J]. BMC Molecular Biology,2004,5:2
185 Min Yu, Danbing Shao, Jianjun Yang, Shangwu Feng, Jianguo Xu. Ketamine Suppresses Intestinal TLR4 Expression and NF-κB Activity in Lipopolysaccharide-treated Rats[J]. Croat Med J.,2006,47:825-31
186 H. D. BRIGHTBILL, R. L. MODLIN. Toll-like receptors:molecular mechanisms of the mammalian immune response[J]. Immunology 2000,101:1-10
187 Jeongmin Song, and Soman N. Abraham. TLR Mediated Immune Responses in the Urinary Tract [J]. Curr Opin Microbiol.2008,11(1):66-73. doi:10.1016/j. mib.2007.12.001.
188 Manjunatha R. Benakanakere, Jiawei Zhao, Johnah C. Galicia, Michael Martin, Denis F. Kinane Sphingosine Kinase-1 Is Required for Toll Mediated β-Defensin 2 Induction in Human Oral Keratinocytes [J]. PLoS ONE | www.plosone.org July 2010, 5:1-12
189 Diana Legarda, Marcia E. Klein-Patel, Sunghan Yim, Ming H. Yuk, and Gill Diamond. Suppression of NF-κ B-mediated β-defensin gene expression in the mammal ian airway by the Bordetella type Ⅲ secretion system[J]. Cell Microbiol.2005,7(4):489-497
190 Ju SM, Goh AR, Kwon DJ, et al. Extracellular HIV-1 tat induces human beta-defens in-2 production via NF-kappaB/AP-1 dependent pathways in human B cells [J]. Mol Cells, 2012 Mar 23. [Epub ahead of print] PMID:22450687 [PubMed-as supplied by publ isher]
191 Aul R, Armstrong J, Duvoix A, et al. Inhaled LPS challenges in smokers:a study of pulmonary and systemic effects [J]. Br J Clin Pharmacol.2012 Mar 30. doi: 10.1111/j.1365-2125.2012.04287. x. [Epub ahead of print]
192 Yamakawa, M., and Tanaka, H., Immune proteins and their gene expression in the silkworm, Bombyx mori. Dev. Comp. Immunol.,1999,23:281-289
193Pace E, Ferraro M, Minervini MI, et al. Beta Defensin-2 Is Reduced in Central but Not in Distal Airways of Smoker COPD Patients [J]. PLoS One.2012,7(3):e33601. Epub 2012 Mar 16
194 Nadine Steubesand, Karlheinz Kiehne, Gabriele Brunke, et al.The expression of the p-defensins hBD-2 and hBD-3 is differentially regulated by NF-κB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis [J]. BMC Immunology,2009:1-16
195张方,李子玲等.LPS致大鼠肺巨噬细胞NF-κB促进TNF-α分泌[J].中国病理生理杂志,2007,23(2)：1412-1414
196 Gankovskaia OA, Gankovskaia LV, Koval'chuk LV, et al. [Changes in expression level of TLR9 and BD-2 genes in cornea of mice with viral keratitis] [J]. Zh Mikrobiol Epidemiol Immunobiol.,2012 Jan-Feb, (1):80-3. [Article in Russian]
197 Susumu MATSUO, Soh YAMAZAKI, Koichiro TAKESHIGE and Tatsushi MUTA. Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation [J]. Biochem. J.,2007,40(5):605-615
198 Matsusaka, T., Fujikawa, K., Nishio, Y., Mukaida, N., Matsushima, K., Kishimoto, T. and Akira, S. Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl. Acad. Sci. U.S.A.1993,90:10193-10197
199 Zhang, Y. and Rom, W. N. Regulation of the interleukin-1β (IL-1β) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs. Mol. Cell. Biol.1993,13:3831-3837
200 Natsuka, S., Akira, S., Nishio, Y., Hashimoto, S., Sugita, T., Isshiki, H. and Kishimoto, T. Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood,1992,79,460-466
201 Ruddy, M. J., Wong, G. C., Liu, X. L, Yamamoto, H., Kasayama, S., Kirkwood, K. L. and Gaffen, S. L. Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer-binding protein family members. J. Biol. Chem.2004,279,2559-2567
202 Shen, F., Hu, Z., Goswami, J. and'Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 2006,281:24138-241.48
203 Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos.M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beuter.1998. Defective LPS signaling in C3H/HeL and C57BL/10ScCr mice:mutations in Tlr4 gene. Science 282:2085-2088
204 Hoshino, K.,0. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Takeda, and S. Akira.1999. Cutting edge:Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product. J. Immunol.162:3749-3752
205 Shimazu, R., S. Akashi, H. Ogata, Y. Nagai, K. Fukudome, K. Miyake, and M. Kimoto. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med.189:1777-1782
206 Yang, H., D. W. Young, F. Gusovsky, and J. C. Chow.2000. Cel lular events mediated by lipopolysaccharide-stimulated toll-like receptor 4. MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. J. Biol. Chem.275:20861-20866
207 Nagai, Y., S. Akashi, M. Nagafuku, M. Ogata, Y. Iwakura, S. Akira, T. Kitamura, A. Kosugi, M. Kimoto, and K. Miyake.2002. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat. Immunol.3:667-672
208 Weicheng Wu, Raymond D. Mosteller, and Daniel Broek Sphingosine Kinase Protects Lipopolysaccharide-Activated Macrophages from Apoptosis[J]. MOLECULAR AND CELLULAR BIOLOGY, Sept.2004, Vol.24, No.17p.7359-7369
209 T. Goldammer, H. Zerbe, A. Melenaar, et al. Mastitis Increases Mammary mRNA Abundance of beta-Defensin 5, Toll-Like-Receptor 2 (TLR2), and TLR4 but Not TLR9 in Cattle[J]. CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY,2004:174-185
210宋祖军,王少波,王琦等.NF-kB的研究进展[J].世界急危重病医学杂志[J].2007,4(1)：1693-1696
211 Ulich TR, Yin S, Guo K, et a.1 Intratracheal injection of endotoxin and cytokines II, Interleukin-6 and transforming growth factor beta inhibit acute inflammation [J]. Am J Patho,11991,138(5):1097-110
212韦安猛,夏熙郑NF-κB, TNF-α在大鼠慢性阻塞性肺疾病中的作用[J].医药论坛杂志,2006.27(24)：62-63
213 Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences [J]. Cell 1986; 46 (5):705-716
214 Laurence Hoareau, Karima Bencharif, Philippe Rondeau, Ravi Murumalla, Palaniyandi Ravanan, Frank Tallet, Pierre Delarue, Maya Cesari, Regis Rochel, Franck Festy. Signaling pathways involved in LPS induced TNFalpha production in human adipocytes [J]. Iloareau et al. Journal of Inflammation,2010',7:1
215 Pomerantz JL, Baltimore D. Two pathways for NFkB. Mol Cell 2002,10:693-701. [PubMed:12419209
216 Li, Q. and Verma, I. M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2002,2,725-734
217 Hayden, M. S. and Ghosh, S. Signaling to NF-κB. Genes Dev.2004,18,2195-2224
218 Chen, L. F. and Greene, W. C. Shaping the nuclear action of NF-κB. Nat. Rev. Mol. Cell Biol.2004,5,392-401