Fra2通过调节白细胞介素23受体参与银屑病发病的研究

doi:10.16150/j.1671-2870.2018.03.005

诊断学理论与实践 ›› 2018, Vol. 17 ›› Issue (03): 254-259.doi: 10.16150/j.1671-2870.2018.03.005

Fra2通过调节白细胞介素23受体参与银屑病发病的研究

林镇, 郭茹茹, 吕良敬, 陈晓翔

上海交通大学医学院附属仁济医院风湿科,上海 200001

收稿日期:2018-05-07 出版日期:2018-06-25 发布日期:2018-06-25
通讯作者: 陈晓翔 E-mail: xiaoxiang0721@126.com
基金资助:
国家自然科学基金（81273306; 81771729）; 国家重点研发计划（2017YFC0909002）

Study on the involving of Fra2 via regulating IL23 receptor in the pathogenesis of psoriasis

LIN Zhen, GUO Ruru, LÜ Liangjing, CHEN Xiaoxiang

Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China

Received:2018-05-07 Online:2018-06-25 Published:2018-06-25

摘要/Abstract

摘要： 目的：研究银屑病患者外周血单个核细胞（peripheral blood mononuclear cell,PBMC）内转录因子AP1家族中Fos家族中Fra2的表达情况,通过生物信息学分析银屑病中Fra2可能参与调节的下游基因,并通过双荧光素酶报告实验验证,初步探讨其在疾病中的发病机制。方法：采用实时定量PCR检测21例银屑病患者及30名健康者对照外周血中Fra2的表达水平;在基因转录调节数据库上预测Fra2的靶基因,并与GeneCards上银屑病相关基因交集分析,采用DAVID（The Database for Annotation, Visualization and Integrated Discovery）数据库查找靶基因本体功能分类和KEGG富集分析;用实时定量PCR验证Fra2可能参与调控的基因;R语言调用JASPAR 2018软件包预测Fra2结合位点;双荧光素酶报告实验验证Fra2对白细胞介素23受体（interleukin 23receptor, IL-23R）的调控关系。结果： 21例银屑病患者PBMC中Fra2的mRNA表达水平（0.711±0.072）显著低于健康人群（1.070±0.086）（P=0.004 2）;生物信息学分析显示,炎症反应和细胞因子-细胞因子受体互作是富集程度最为显著的条目（P=5.2×10^-71;P=7.0×10^-45）;实时定量PCR检测显示,IL-23R的mRNA表达水平显著高于健康人群（P=0.000 1）,且与Fra2表达水平呈显著负相关（r=-0.509 5,P=0.018 3）;用R语言调用JASPAR在启动子区域预测了Fra2的结合位点,双荧光素酶报告实验发现,Fra2调控了IL-23R的表达。结论：Fra2/AP1作为重要的转录因子,可能通过调节IL-23R的表达参与了银屑病的发生和发展。

关键词: 银屑病, Fra2, 白细胞介素23受体机制

Abstract: Objective: To study the expression of Fra2, a member of Fos family of transcription factor AP1 family, in peripheral blood mononuclear cells (PBMC) of psoriatic patients, and to analyze the potential genes regulated by Fra2 via bioinformatics and confirmed by dual-luciferase reporter assay for investigating the role of Fra2 in the pathogenesis of psoriasis. Methods: The expression of Fra2 in 21 patients with psoriasis and 30 healthy controls were detected by quantitative real-time-PCR（qrt-RCR）. The target genes of Fra2 were predicted by gene transcription regulation Database (GTRD), and were intersected with psoriasis-related gene in GeneCards. The function classification of Gene Ontology (GO)and KEGG enrichment analysis were adopted by DAVID (The Database for Annotation, Visualization and Integrated Discovery); the potential genes regulated by Fra2 were verified by qrt -PCR; the binding sites of Fra2 were predicted by JASPAR package in R Programming Language;the relationship between Fra2 and IL23 receptor(IL23R) was verified by Dual-luciferase report assay. Results: The expression of Fra2 mRNA in PBMC of 21 patients with psoriasis (0.711±0.072) was significantly lower than that in healthy controls (1.070±0.086) (P=0.004 2). Bioinformatics analysis showed that inflammatory response and cytokine-cytokine receptor interaction was the most significant items(P=5.2×10^-71; P=7.0×10^-45). qrt-PCR found that the mRNA expression level of IL23R was significantly higher than healthy controls (P=0.000 1), and was correlated with Fra2 expression level(r=-0.509 5, P=0.018 3); the regulating effect of Fra2 on IL23R was verified by Dual-luciferase report assay. Conclusions: Fra2 is an important transcription factor involved in the development and progress of psoriasis by regulating the expression of IL23R.

Key words: Psoriasis, Fra2, IL23R

中图分类号:

R758.63

林镇, 郭茹茹, 吕良敬, 陈晓翔. Fra2通过调节白细胞介素23受体参与银屑病发病的研究[J]. 诊断学理论与实践, 2018, 17(03): 254-259.

LIN Zhen, GUO Ruru, LÜ Liangjing, CHEN Xiaoxiang. Study on the involving of Fra2 via regulating IL23 receptor in the pathogenesis of psoriasis[J]. Journal of Diagnostics Concepts & Practice, 2018, 17(03): 254-259.

参考文献

[1] Gupta R, Debbaneh MG, Liao W.Genetic Epidemiology of Psoriasis[J]. Curr Dermatol Rep,2014,3(1):61-78.
[2] Kim J, Krueger JG.The immunopathogenesis of psoriasis[J]. Dermatol Clin,2015,33(1):13-23.
[3] Davies JS, Klein DC, Carter DA.Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism[J]. J Biol Chem,2011,286(17):15227-15239.
[4] Foletta VC, Sonobe MH, Suzuki T, et al.Cloning and characterisation of the mouse fra-2 gene[J]. Oncogene,1994,9(11):3305-3311.
[5] Uluçkan Ö, Guinea-Viniegra J, Jimenez M, et al.Signalling in inflammatory skin disease by AP-1 (Fos/Jun)[J]. Clin Exp Rheumatol,2015,33(4 Suppl 92):S44-S49.
[6] Zenz R, Eferl R, Kenner L, et al.Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins[J]. Nature,2005,437(7057):369-375.
[7] Kouzarides T, Ziff E.The role of the leucine zipper in the fos-jun interaction[J]. Nature,1988,336(6200):646-651.
[8] Wurm S, Zhang J, Guinea-Viniegra J, et al.Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2[J]. Genes Dev,2015, 29(2):144-156.
[9] Briso EM, Guinea-Viniegra J, Bakiri L, et al.Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos[J]. Genes Dev,2013,27(18):1959-1973.
[10] Nakayama T, Higuchi T, Oiso N, et al.Expression and function of FRA2/JUND in cutaneous T-cell lymphomas[J]. Anticancer Res,2012,32(4):1367-1373.
[11] Nestle FO, Kaplan DH, Barker J.Psoriasis[J]. N Engl J Med,2009,361(5):496-509.
[12] Beranger GE, Momier D, Guigonis JM, et al.Differential binding of poly(ADP-Ribose) polymerase-1 and JunD/Fra2 accounts for RANKL-induced Tcirg1 gene expression during osteoclastogenesis[J]. J Bone Miner Res,2007,22(7):975-983.
[13] Wagner EF.Bone development and inflammatory disease is regulated by AP-1(Fos/Jun)[J]. Ann Rheum Dis,2010,69(Suppl 1):i86-i88.
[14] Uluçkan Ö, Guinea-Viniegra J, Jimenez M, et al.Signalling in inflammatory skin disease by AP-1 (Fos/Jun)[J]. Clin Exp Rheumatol,2015,33(4 Suppl 92):S44-S49.
[15] Bozec A, Bakiri L, Jimenez M, et al.Osteoblast-specific expression of Fra-2/AP-1 controls adiponectin and osteocalcin expression and affects metabolism[J]. J Cell Sci,2013,126(Pt 23):5432-5440.
[16] Bozec A, Bakiri L, Jimenez M, et al.Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production[J]. J Cell Biol,2010,190(6):1093-1106.
[17] Wagner EF, Eferl R.Fos/AP-1 proteins in bone and the immune system[J]. Immunol Rev,2005,208:126-140.
[18] Beranger GE, Momier D, Guigonis JM, et al.Differential binding of poly(ADP-Ribose) polymerase-1 and JunD/Fra2 accounts for RANKL-induced Tcirg1 gene expression during osteoclastogenesis[J]. J Bone Miner Res,2007,22(7):975-983.
[19] Alli NS, Yang EC, Miyake T, et al.Signal-dependent fra-2 regulation in skeletal muscle reserve and satellite cells[J]. Cell Death Dis,2013,4:e692.
[20] Lew W, Bowcock AM, Krueger JG.Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and "Type 1" inflammatory gene expression[J]. Trends Immunol,2004,25(6):295-305.
[21] Bettelli E, Oukka M, Kuchroo VK.T(H)-17 cells in the circle of immunity and autoimmunity[J]. Nat Immunol,2007,8(4):345-350.
[22] Oka A, Mabuchi T, Ikeda S, et al.IL12B and IL23R gene SNPs in Japanese psoriasis[J]. Immunogenetics,2013,65(11):823-828.

Fra2通过调节白细胞介素23受体参与银屑病发病的研究

Study on the involving of Fra2 via regulating IL23 receptor in the pathogenesis of psoriasis

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 8

编辑推荐

Metrics

本文评价

[1]	史玉玲. 英国《皮肤科医师协会银屑病生物制剂治疗指南》（2020版）解读[J]. 诊断学理论与实践, 2021, 20(01): 37-42.
[2]	黄丹, 陈崑. 银屑病相关流行病学调查进展[J]. 诊断学理论与实践, 2021, 20(01): 48-52.
[3]	戴生明. 银屑病关节炎的危害、诊治现状[J]. 诊断学理论与实践, 2018, 17(03): 238-243.
[4]	鲁智勇, 郑捷,. 银屑病病情严重程度的评价方法[J]. 诊断学理论与实践, 2009, 8(03): 360-362.
[5]	陈颖炜, 陈小英, 邬玉美, 鲁智勇, 薛峰, 潘萌, 施若非, 郑捷,. 银屑病患者白介素-20基因多态性和临床表型研究[J]. 诊断学理论与实践, 2008, 7(05): 521-525.
[6]	陈华, 张华, 项明洁, 张志伟, 周文龙, 沈周俊, 黄海峰,. 尿膀胱癌抗原、CYFRA21-1和透明质酸在膀胱癌诊断中的价值[J]. 诊断学理论与实践, 2008, 7(01): 73-76.
[7]	宋珺, 郑捷,. 银屑病与白细胞介素-10关系的研究进展[J]. 诊断学理论与实践, 2007, 6(01): 71-73.
[8]	陈珏, 曹华, 潘萌, 郑捷,. 寻常型银屑病伴大疱性皮肤病的诊断和临床分析[J]. 诊断学理论与实践, 2006, 5(04): 306-307.