• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

在异种移植的银屑病皮肤中，小发夹RNA对人白细胞介素-12B的靶向作用。

Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin.

作者信息

Bak Rasmus O, Stenderup Karin, Rosada Cecilia, Petersen Line B, Moldt Brian, Dagnæs-Hansen Frederik, Jakobsen Maria, Kamp Søren, Jensen Thomas G, Dam Tomas N, Mikkelsen Jacob Giehm

机构信息

Department of Human Genetics, University of Aarhus, Aarhus, Denmark.

出版信息

BMC Dermatol. 2011 Feb 27;11:5. doi: 10.1186/1471-5945-11-5.

DOI:10.1186/1471-5945-11-5
PMID:21352568
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3058081/
Abstract

BACKGROUND

Psoriasis is a chronic inflammatory skin disorder that shows as erythematous and scaly lesions. The pathogenesis of psoriasis is driven by a dysregulation of the immune system which leads to an altered cytokine production. Proinflammatory cytokines that are up-regulated in psoriasis include tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), and IL-23 for which monoclonal antibodies have already been approved for clinical use. We have previously documented the therapeutic applicability of targeting TNFα mRNA for RNA interference-mediated down-regulation by anti-TNFα small hairpin RNAs (shRNAs) delivered by lentiviral vectors to xenografted psoriatic skin. The present report aims at targeting mRNA encoding the shared p40 subunit (IL-12B) of IL-12 and IL-23 by cellular transduction with lentiviral vectors encoding anti-IL12B shRNAs.

METHODS

Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in cultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated by bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing lentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated by clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels.

RESULTS

Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in xenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are achieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs. These findings mimic the results obtained with anti-TNFα shRNAs but, in contrast to anti-TNFα treatment, anti-IL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by immunohistological examination.

CONCLUSIONS

Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for evaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFα treatment, the therapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.

摘要

背景

银屑病是一种慢性炎症性皮肤病，表现为红斑和鳞屑性皮损。银屑病的发病机制是由免疫系统失调导致细胞因子产生改变所驱动。在银屑病中上调的促炎细胞因子包括肿瘤坏死因子α（TNFα）、白细胞介素12（IL-12）和IL-23，针对这些细胞因子的单克隆抗体已被批准用于临床。我们之前已经记录了通过慢病毒载体递送抗TNFα小发夹RNA（shRNAs）靶向TNFα mRNA进行RNA干扰介导的下调在异种移植银屑病皮肤中的治疗适用性。本报告旨在通过用编码抗IL12B shRNAs的慢病毒载体进行细胞转导来靶向编码IL-12和IL-23共享p40亚基（IL-12B）的mRNA。

方法

通过在培养细胞中的效力测量，从一组shRNAs中鉴定出有效的抗IL12B shRNAs。通过对用编码荧光素酶基因的慢病毒载体处理的皮肤进行生物发光分析，研究慢病毒基因递送至异种移植人皮肤的效率和持久性。将表达shRNA的慢病毒载体皮内注射到异种移植的银屑病皮肤中，并通过临床银屑病评分、表皮厚度测量和IL-12B mRNA水平评估治疗效果。

结果

报告了在异种移植人皮肤中单次皮内注射慢病毒载体后强大且持久的转基因表达。在用慢病毒编码的抗IL12B shRNAs处理异种移植的银屑病皮肤三周后，实现了稳定的IL-12B mRNA敲低和表皮厚度降低。这些发现与用抗TNFα shRNAs获得的结果相似，但与抗TNFα治疗相反，通过半定量临床评分和免疫组织学检查评估，抗IL12B shRNAs并未改善银屑病表型。

结论

我们的研究巩固了慢病毒载体作为有效基因递送工具和抗炎治疗mRNA靶点评估工具的特性。然而，与局部抗TNFα治疗相反，在银屑病中RNA水平靶向IL-12B的治疗潜力受到质疑。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/1131c964e763/1471-5945-11-5-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/e423223d6651/1471-5945-11-5-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/57af0e799877/1471-5945-11-5-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/4bbe0a5b8d60/1471-5945-11-5-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/9aa3c5ce671f/1471-5945-11-5-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/81f4064dde43/1471-5945-11-5-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/1131c964e763/1471-5945-11-5-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/e423223d6651/1471-5945-11-5-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/57af0e799877/1471-5945-11-5-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/4bbe0a5b8d60/1471-5945-11-5-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/9aa3c5ce671f/1471-5945-11-5-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/81f4064dde43/1471-5945-11-5-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f327/3058081/1131c964e763/1471-5945-11-5-6.jpg

相似文献

1
Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin.在异种移植的银屑病皮肤中，小发夹RNA对人白细胞介素-12B的靶向作用。
BMC Dermatol. 2011 Feb 27;11:5. doi: 10.1186/1471-5945-11-5.
2
Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model.在异种移植移植模型中通过抗 TNF-α RNAi 改善银屑病。
Mol Ther. 2009 Oct;17(10):1743-53. doi: 10.1038/mt.2009.141. Epub 2009 Jun 30.
3
Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones.慢病毒载体编码短发夹 RNA 可有效转导和敲低 LINGO-1，但会在中枢神经系统神经元中诱导干扰素反应和细胞毒性。
J Gene Med. 2012 May;14(5):299-315. doi: 10.1002/jgm.2626.
4
Lentiviral vectors that carry anti-HIV shRNAs: problems and solutions.携带抗HIV短发夹RNA的慢病毒载体：问题与解决方案
J Gene Med. 2007 Sep;9(9):743-50. doi: 10.1002/jgm.1078.
5
Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors.使用慢病毒载体递送RNAi的短期细胞毒性作用和长期不稳定性。
BMC Mol Biol. 2004 Aug 3;5:9. doi: 10.1186/1471-2199-5-9.
6
RNA Interference Therapy for Machado-Joseph Disease: Long-Term Safety Profile of Lentiviral Vectors Encoding Short Hairpin RNAs Targeting Mutant Ataxin-3.肌萎缩性脊髓侧索硬化症的 RNA 干扰治疗：靶向突变 Ataxin-3 的短发夹 RNA 的慢病毒载体的长期安全性特征。
Hum Gene Ther. 2019 Jul;30(7):841-854. doi: 10.1089/hum.2018.157. Epub 2019 May 28.
7
Inhibition of GM-CSF receptor function by stable RNA interference in a NOD/SCID mouse hematopoietic stem cell transplantation model.在NOD/SCID小鼠造血干细胞移植模型中通过稳定RNA干扰抑制GM-CSF受体功能
Oligonucleotides. 2003;13(5):353-63. doi: 10.1089/154545703322617032.
8
Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFα therapy.抗 TNF-α 治疗可优先抑制银屑病皮肤中 p38 丝裂原活化蛋白激酶调节细胞因子的 mRNA 表达。
Br J Dermatol. 2010 Dec;163(6):1194-204. doi: 10.1111/j.1365-2133.2010.10036.x.
9
Lentiviral miR30-based RNA interference against heparanase suppresses melanoma metastasis with lower liver and lung toxicity.基于慢病毒 miR30 的 RNA 干扰对乙酰肝素酶抑制可降低肝肺毒性的黑色素瘤转移。
Int J Biol Sci. 2013 Jun 12;9(6):564-77. doi: 10.7150/ijbs.5425. Print 2013.
10
Transduction with Lentiviral Vectors Altered the Expression Profile of Host MicroRNAs.慢病毒载体转导改变了宿主 microRNAs 的表达谱。
J Virol. 2018 Aug 29;92(18). doi: 10.1128/JVI.00503-18. Print 2018 Sep 15.

引用本文的文献

1
Blank Spots in the Map of Human Skin: The Challenge for Xenotransplantation.人体皮肤图谱中的空白：异种移植面临的挑战。
Int J Mol Sci. 2023 Aug 14;24(16):12769. doi: 10.3390/ijms241612769.
2
Sustaining the T-cell activity in xenografted psoriasis skin.维持异种移植银屑病皮肤中的 T 细胞活性。
PLoS One. 2023 Jan 17;18(1):e0278390. doi: 10.1371/journal.pone.0278390. eCollection 2023.
3
Improved Lentiviral Gene Delivery to Mouse Liver by Hydrodynamic Vector Injection through Tail Vein.通过尾静脉水动力载体注射改善慢病毒基因向小鼠肝脏的递送。

本文引用的文献

1
Cutting edge: A critical functional role for IL-23 in psoriasis.前沿：IL-23 在银屑病中的关键功能作用。
J Immunol. 2010 Nov 15;185(10):5688-91. doi: 10.4049/jimmunol.1001538. Epub 2010 Oct 18.
2
Novel biologic therapies in development targeting IL-12/IL-23.开发中的靶向 IL-12/IL-23 的新型生物疗法。
J Eur Acad Dermatol Venereol. 2010 Oct;24 Suppl 6:5-9. doi: 10.1111/j.1468-3083.2010.03830.x.
3
Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis.白细胞介素-21参与银屑病的表皮增生。
Mol Ther Nucleic Acids. 2018 Sep 7;12:672-683. doi: 10.1016/j.omtn.2018.07.005. Epub 2018 Aug 6.
4
Robust Lentiviral Gene Delivery But Limited Transduction Capacity of Commonly Used Adeno-Associated Viral Serotypes in Xenotransplanted Human Skin.在异种移植的人皮肤中，强大的慢病毒基因传递，但常用腺相关病毒血清型的转导能力有限。
Hum Gene Ther Methods. 2015 Aug;26(4):123-33. doi: 10.1089/hgtb.2014.135.
5
Driving DNA transposition by lentiviral protein transduction.通过慢病毒蛋白转导驱动DNA转座。
Mob Genet Elements. 2014 Jun 23;4:e29591. doi: 10.4161/mge.29591. eCollection 2014.
6
Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases.通过锌指核酸酶和转录激活因子样效应物核酸酶的慢病毒蛋白转导进行靶向基因组编辑。
Elife. 2014 Apr 24;3:e01911. doi: 10.7554/eLife.01911.
7
DNA transposition by protein transduction of the piggyBac transposase from lentiviral Gag precursors.通过慢病毒 Gag 前体中的 piggyBac 转座酶的蛋白转导实现 DNA 转座。
Nucleic Acids Res. 2014 Feb;42(4):e28. doi: 10.1093/nar/gkt1163. Epub 2013 Nov 21.
8
Suppression of microRNAs by dual-targeting and clustered Tough Decoy inhibitors.双靶点和聚集 Tough Decoy 抑制剂对 microRNAs 的抑制作用。
RNA Biol. 2013 Mar;10(3):406-14. doi: 10.4161/rna.23543. Epub 2013 Jan 16.
9
Potent microRNA suppression by RNA Pol II-transcribed 'Tough Decoy' inhibitors.RNA Pol II 转录的“坚韧诱饵”抑制剂对 microRNA 的强效抑制作用。
RNA. 2013 Feb;19(2):280-93. doi: 10.1261/rna.034850.112. Epub 2012 Dec 18.
10
Mobilization of DNA transposable elements from lentiviral vectors.慢病毒载体中DNA转座元件的激活
Mob Genet Elements. 2011 Jul;1(2):139-144. doi: 10.4161/mge.1.2.17062. Epub 2011 Jul 1.
Nat Med. 2009 Sep;15(9):1013-5. doi: 10.1038/nm.1995. Epub 2009 Aug 16.
4
Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model.在异种移植移植模型中通过抗 TNF-α RNAi 改善银屑病。
Mol Ther. 2009 Oct;17(10):1743-53. doi: 10.1038/mt.2009.141. Epub 2009 Jun 30.
5
Therapeutic silencing of an endogenous gene by siRNA cream in an arthritis model mouse.利用 siRNA 乳膏在关节炎模型小鼠中对内源性基因进行治疗性沉默。
Gene Ther. 2009 Aug;16(8):982-9. doi: 10.1038/gt.2009.66. Epub 2009 May 28.
6
Increased expression of IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque psoriasis.斑块状银屑病中多个树突状细胞和巨噬细胞亚群的IL-12p70和IL-23表达增加。
J Dermatol Sci. 2009 May;54(2):99-105. doi: 10.1016/j.jdermsci.2009.01.003. Epub 2009 Mar 4.
7
The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004.美国成年人中既往诊断和未诊断的银屑病患病率：2003 - 2004年美国国家健康和营养检查调查结果
J Am Acad Dermatol. 2009 Feb;60(2):218-24. doi: 10.1016/j.jaad.2008.09.022. Epub 2008 Nov 20.
8
Trial watch: novel biologic for psoriasis shows superiority over current best-seller.试验观察：用于治疗银屑病的新型生物制剂显示出优于当前畅销药的效果。
Nat Rev Drug Discov. 2008 Nov;7(11):880-1. doi: 10.1038/nrd2753.
9
Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model.白细胞介素-20在人异种移植模型中银屑病的维持和发展中起关键作用。
Br J Dermatol. 2009 Feb;160(2):284-96. doi: 10.1111/j.1365-2133.2008.08890.x. Epub 2008 Oct 20.
10
Genomic insertion of lentiviral DNA circles directed by the yeast Flp recombinase.由酵母Flp重组酶介导的慢病毒DNA环的基因组插入。
BMC Biotechnol. 2008 Aug 9;8:60. doi: 10.1186/1472-6750-8-60.