Notch信号通路调控CD4~+T细胞分泌IL-22在Vogt-小柳原田综合征中的作用
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摘要
目的:观察Notch受体和IL-22在Vogt-小柳原田(VKH)综合征患者中的表达变化,探讨Notch信号通路对VKH综合征患者CD4~+T细胞分泌IL-22的调控作用。方法:选取VKH综合征患者35例(活动期15例和静止期20例)和健康对照者12例,分选血浆和CD4~+T细胞,qRT-PCR和Western blot法检测Notch受体,ELISA法检测血浆IL-22表达,流式细胞术检测Th17和Th22的比例。观察抑制Notch信号通路对VKH综合征患者CD4~+T细胞转录因子相对表达量和IL-22分泌水平的变化。结果:活动期VKH综合征患者CD4~+T细胞中Notch1～3较静止期和健康对照者显著升高。活动期VKH综合征患者血浆IL-22及Th17、Th22水平高于静止期和健康对照者。抑制Notch信号通路可导致活动性VKH综合征患者CD4~+T细胞中AhR mRNA降低,分泌IL-22水平降低。结论:Notch-AhR-IL-22信号通路可能参与了VKH综合征的发病。
AIM:To investigate the changes of Notch receptors and interleukin(IL)-22 expression in patients with Vogt-Koyanagi-Harada(VKH) syndrome, and to assess the regulatory activity of Notch signaling to IL-22 production by CD4~+ T cells in patients with VKH syndrome.METHODS: Thirty-five patients with VKH syndrome(including fifteen active VKH and twenty inactive VKH) and twelve healthy controls were enrolled.Plasma was isolated, and CD4~+T cells were purified.Notch receptors were investigated by qRT-PCR and Western blot.Plasma IL-22 expression was measured by ELISA.The percentage of Th17 and Th22 cells was investigated by flow cytometry.CD4~+T cells, which were purified from active VKH patients, were stimulated with Notch signaling inhibitor DAPT.mRNA expression of transcription factor in CD4~+T cells as well as IL-22 secretion by CD4~+T cells was investigated.RESULTS: Notch1-Notch3 in CD4~+T cells from active VKH syndrome patients was significantly elevated in comparison with inactive VKH and healthy controls.Plasma IL-22 expression and percentage of Th17 and Th22 was notably increased in active VKH syndrome in comparison with inactive VKH and controls.DAPT stimulation inhibited Notch signaling pathway in CD4~+T cells, leading to the down-regulation of AhR mRNA and IL-22 secretion.CONCLUSION:Notch-AhR-IL-22 signaling pathway might take part in the pathogenesis of VKH syndrome.
AIM:To investigate the changes of Notch receptors and interleukin(IL)-22 expression in patients with Vogt-Koyanagi-Harada(VKH) syndrome, and to assess the regulatory activity of Notch signaling to IL-22 production by CD4~+ T cells in patients with VKH syndrome.METHODS: Thirty-five patients with VKH syndrome(including fifteen active VKH and twenty inactive VKH) and twelve healthy controls were enrolled.Plasma was isolated, and CD4~+T cells were purified.Notch receptors were investigated by qRT-PCR and Western blot.Plasma IL-22 expression was measured by ELISA.The percentage of Th17 and Th22 cells was investigated by flow cytometry.CD4~+T cells, which were purified from active VKH patients, were stimulated with Notch signaling inhibitor DAPT.mRNA expression of transcription factor in CD4~+T cells as well as IL-22 secretion by CD4~+T cells was investigated.RESULTS: Notch1-Notch3 in CD4~+T cells from active VKH syndrome patients was significantly elevated in comparison with inactive VKH and healthy controls.Plasma IL-22 expression and percentage of Th17 and Th22 was notably increased in active VKH syndrome in comparison with inactive VKH and controls.DAPT stimulation inhibited Notch signaling pathway in CD4~+T cells, leading to the down-regulation of AhR mRNA and IL-22 secretion.CONCLUSION:Notch-AhR-IL-22 signaling pathway might take part in the pathogenesis of VKH syndrome.
引文
1黄果,杨培增.Vogt-小柳原田综合征的治疗进展.国际眼科杂志2017;17(6):1082-1086
2 Perusina Lanfranca M,Lin Y,Fang J,et al.Biological and pathological activities of interleukin-22.J Mol Med (Berl) 2016;94(5):523-534
3 Eyerich K,Dimartino V,Cavani A.IL-17 and IL-22 in immunity:Driving protection and pathology.Eur J Immunol 2017;47(4):607-614
4 Alam MS,Maekawa Y,Kitamura A,et al.Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.Proc Natl Acad Sci U S A 2010;107(13):5943-5948
5 Jiang BC,Liu X,Liu XH,et al.Notch Signaling Regulates Circulating T Helper 22 Cells in Patients with Chronic Hepatitis C.Viral Immunol 2017;30(7):522-532
6王伟,赵荣荣,杨晓飞,等.Notch信号通路对乙型肝炎患者CD4+T淋巴细胞分泌白细胞介素22的影响.临床肝胆病杂志 2016;32(7):1315-1318
7 Read RW,Holland GN,Rao NA,et al.Revised diagnostic criteria for Vogt-Koyanagi-Harada disease:report of an international committee on nomenclature.Am J Ophthalmol 2001;131(5):647-652
8 Wei X,Wang JP,Hao CQ,et al.Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection.Front Cell Infect Microbiol 2016;6:132
9 Du L,Kijlstra A,Yang P.Vogt-Koyanagi-Harada disease:Novel insights into pathophysiology,diagnosis and treatment.Prog Retin Eye Res 2016;52:84-111
10 Liu B,Deng T,Zhu L,et al.Association of human leukocyte antigen (HLA)-DQ and HLA-DQA1/DQB1 alleles with Vogt-Koyanagi-Harada disease:A systematic review and meta-analysis.Medicine (Baltimore) 2018;97(7):e9914
11 Wang C,Wang L,Hu J,et al.Increased Expression of IL-23 Receptor (IL-23R) in Vogt-Koyanagi-Harada (VKH) Disease.Curr Eye Res 2018;43(11):1369-1373
12 Siebel C,Lendahl U.Notch Signaling in Development,Tissue Homeostasis,and Disease.Physiol Rev 2017;97(4):1235-1294
13 Dou GR,Wang L,Wang YS,et al.Notch signaling in ocular vasculature development and diseases.Mol Med 2012;18:47-55
14 Zhu G,Lin Y,Liu H,et al.Dll4-Notch1 signaling but not VEGF-A is essential for hyperoxia induced vessel regression in retina.Biochem Biophys Res Commun 2018;507(1-4):400-406
15 Weinstein JE,Pepple KL.Cytokines in uveitis.Curr Opin Ophthalmol 2018;29(3):267-274
16 Sainz-de-la-Maza M,Molins B,Mesquida M,et al.Interleukin-22 serum levels are elevated in active scleritis.Acta Ophthalmol 2016;94(6):e395-e399
17 Li Z,Liu B,Maminishkis A,et al.Gene expression profiling in autoimmune noninfectious uveitis disease.J Immunol 2008;181(7):5147-5157
18 Tan X,Sun S,Liu Y,et al.Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome.Eye (Lond) 2014;28(5):608-613
19 Takeuchi M,Sato T,Sakurai Y,et al.Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy.PLoS One 2017;12(5):e0178230
20 Pang B,Hu C,Xing N,et al.Elevated Notch1 enhances interleukin-22 production by CD4+ T cells via aryl hydrocarbon receptor in patients with lung adenocarcinoma.Biosci Rep 2018;38(6):BSR20181922
21 Wang C,Tian Y,Lei B,et al.Decreased IL-27 expression in association with an increased Th17 response in Vogt-Koyanagi-Harada disease.Invest Ophthalmol Vis Sci 2012;53(8):4668-4675
2 Perusina Lanfranca M,Lin Y,Fang J,et al.Biological and pathological activities of interleukin-22.J Mol Med (Berl) 2016;94(5):523-534
3 Eyerich K,Dimartino V,Cavani A.IL-17 and IL-22 in immunity:Driving protection and pathology.Eur J Immunol 2017;47(4):607-614
4 Alam MS,Maekawa Y,Kitamura A,et al.Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.Proc Natl Acad Sci U S A 2010;107(13):5943-5948
5 Jiang BC,Liu X,Liu XH,et al.Notch Signaling Regulates Circulating T Helper 22 Cells in Patients with Chronic Hepatitis C.Viral Immunol 2017;30(7):522-532
6王伟,赵荣荣,杨晓飞,等.Notch信号通路对乙型肝炎患者CD4+T淋巴细胞分泌白细胞介素22的影响.临床肝胆病杂志 2016;32(7):1315-1318
7 Read RW,Holland GN,Rao NA,et al.Revised diagnostic criteria for Vogt-Koyanagi-Harada disease:report of an international committee on nomenclature.Am J Ophthalmol 2001;131(5):647-652
8 Wei X,Wang JP,Hao CQ,et al.Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection.Front Cell Infect Microbiol 2016;6:132
9 Du L,Kijlstra A,Yang P.Vogt-Koyanagi-Harada disease:Novel insights into pathophysiology,diagnosis and treatment.Prog Retin Eye Res 2016;52:84-111
10 Liu B,Deng T,Zhu L,et al.Association of human leukocyte antigen (HLA)-DQ and HLA-DQA1/DQB1 alleles with Vogt-Koyanagi-Harada disease:A systematic review and meta-analysis.Medicine (Baltimore) 2018;97(7):e9914
11 Wang C,Wang L,Hu J,et al.Increased Expression of IL-23 Receptor (IL-23R) in Vogt-Koyanagi-Harada (VKH) Disease.Curr Eye Res 2018;43(11):1369-1373
12 Siebel C,Lendahl U.Notch Signaling in Development,Tissue Homeostasis,and Disease.Physiol Rev 2017;97(4):1235-1294
13 Dou GR,Wang L,Wang YS,et al.Notch signaling in ocular vasculature development and diseases.Mol Med 2012;18:47-55
14 Zhu G,Lin Y,Liu H,et al.Dll4-Notch1 signaling but not VEGF-A is essential for hyperoxia induced vessel regression in retina.Biochem Biophys Res Commun 2018;507(1-4):400-406
15 Weinstein JE,Pepple KL.Cytokines in uveitis.Curr Opin Ophthalmol 2018;29(3):267-274
16 Sainz-de-la-Maza M,Molins B,Mesquida M,et al.Interleukin-22 serum levels are elevated in active scleritis.Acta Ophthalmol 2016;94(6):e395-e399
17 Li Z,Liu B,Maminishkis A,et al.Gene expression profiling in autoimmune noninfectious uveitis disease.J Immunol 2008;181(7):5147-5157
18 Tan X,Sun S,Liu Y,et al.Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome.Eye (Lond) 2014;28(5):608-613
19 Takeuchi M,Sato T,Sakurai Y,et al.Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy.PLoS One 2017;12(5):e0178230
20 Pang B,Hu C,Xing N,et al.Elevated Notch1 enhances interleukin-22 production by CD4+ T cells via aryl hydrocarbon receptor in patients with lung adenocarcinoma.Biosci Rep 2018;38(6):BSR20181922
21 Wang C,Tian Y,Lei B,et al.Decreased IL-27 expression in association with an increased Th17 response in Vogt-Koyanagi-Harada disease.Invest Ophthalmol Vis Sci 2012;53(8):4668-4675