北京大学学报(医学版) ›› 2019, Vol. 51 ›› Issue (4): 716-722. doi: 10.19723/j.issn.1671-167X.2019.04.021

• 论著 • 上一篇    下一篇

系统性硬化症血清细胞因子表达谱变化及调控机制

朱红林,杜倩,谌威霖,左晓霞,李全贞,刘思佳()   

  1. 中南大学湘雅医院风湿免疫科,长沙 410008
  • 收稿日期:2019-01-11 出版日期:2019-08-18 发布日期:2019-09-03
  • 通讯作者: 刘思佳 E-mail:celialiu@csu.edu.cn
  • 基金资助:
    国家自然科学基金(81671622);国家自然科学基金(81771765);湖南省自然科学基金(2018JJ3823)

Altered serum cytokine expression profile in systemic sclerosis and its regulatory mechanisms

Hong-lin ZHU,Qian DU,Wei-lin CHEN,Xiao-xia ZUO,Quan-zhen LI,Si-jia LIU()   

  1. Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha 410008, China
  • Received:2019-01-11 Online:2019-08-18 Published:2019-09-03
  • Contact: Si-jia LIU E-mail:celialiu@csu.edu.cn
  • Supported by:
    Supported by the National Natural Science Foundation of China(81671622);Supported by the National Natural Science Foundation of China(81771765);Hunan Provincial Natural Science Fundation(2018JJ3823)

摘要:

目的:分析系统性硬化症(systemic sclerosis,SSc)血清细胞因子表达谱,探讨其可能的调控机制。方法:收集30例SSc 患者及80例正常对照组血清和外周血单个核细胞DNA,按照SSc有无合并肺间质病变(interstitial lung disease, ILD)分为SSc合并ILD组及SSc不合并ILD组,根据皮肤受累程度,分为弥漫性系统性硬化症(diffuse cutaneous scleroderma,dcSSc)组和局限性系统性硬化症(limited cutaneous scleroderma,lcSSc)组,根据SSc患者血清中是否存在抗拓扑异构酶-1抗体(即抗Scl-70抗体), 分为SSc Scl-70(+)组及SSc Scl-70(-)组。使用Luminex MAGPIX检测系统和Bio-Plex Pro Human Cytokine 27-plex Assay试剂盒检测血清中的27种细胞因子:白细胞介素(interleukin,IL)1β(IL-1β)、IL-1受体拮抗剂(interleukin-1 receptor antagonist,IL-1ra)、IL-2、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12P70、IL-13、IL-15、IL-17、碱性纤维生长因子(basic fiber growth factor,BASIC FGF)、嗜酸性粒细胞趋化因子(eotaxin)、粒细胞集落刺激因子(granulocyte colony stimulating factor,G-CSF)、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony stimulating factor,GM-CSF)、干扰素γ(interferon-γ,IFN-γ)、人干扰素诱导蛋白10(interferon-gamma induced protein 10,IP-10)、单核细胞趋化蛋白-1(monocyte chemotactic protein 1, MCP-1)、人巨噬细胞炎性蛋白1α(macrophage inflammatory protein-1α,MIP-1α)、人巨噬细胞炎性蛋白1β(macrophage inflammatory protein 1β,MIP-1β)、人血小板衍生生长因子BB (platelet-derived growth factor BB,PDGF-BB)、调节激活正常T细胞表达和分泌细胞因子(regulated on activation in normal T-cell expressed and secreted,RANTES)、肿瘤坏死因子-α(tumor necrosis factorα,TNF-α)和血管内皮生长因子(vascular endothelial growth factor,VEGF)。利用Illumina 450K甲基化芯片检测单个核细胞DNA全基因组甲基化位点变化。结果:与正常对照组相比较,12种细胞因子(BASIC FGF、eotaxin、G-CSF、GM-CSF、IFN-γ、IL-1β、IL-1RA、IL-6、IP-10、MCP-1、TNF-α和RANTES)在SSc中表达明显升高(P<0.05), IL-5在SSc中表达降低(P<0.05),其余细胞因子表达差异无统计学意义。与lcSSc组比较, 9种细胞因子(eotaxin、IL-5、MCP-1、IL-2、RANTES、IL17A、IL-8、MIP-1β和PDGF-BB)在dcSSc组增高,但差异无统计学意义。与SSc不合并ILD组相比较,IL-15 在SSc合并ILD组增高[18.2(172.97) ng/L vs. 2.03(0.05) ng/L,P<0.05];与SSc Scl-70(-)组相比较,IP-10在SSc Scl-70(+)组表达降低[1 030(2 196.6) ng/L vs. 1 878(2 964) ng/L,P<0.05]。分析血清细胞因子与红细胞沉降率(erythrocyte sedimentation rate,ESR)、C反应蛋白(C-reactive protein,CRP)的相关性发现,IL-6与ESR正相关(r= 0.04, P= 0.017);MCP-1(r =0.49, P =0.043)和MIP-1β(r =0.41, P =0.007)与CRP正相关。分析细胞因子甲基化位点变化,发现IL-10 TSS1500区的cg17744604、IL-12P70TSS200区的cg06111286、IL-1β TSS200区的cg07935264、IL-1 ra TSS1500区的cg01467417、IL-1 ra 5'非翻译区的cg03989987和VEGF TSS200区的cg21099624 均呈低甲基化。结论:SSc患者血清存在多种细胞因子变化,且细胞因子变化与皮肤受损程度、肺纤维化有关,多种细胞因子表达受甲基化调控。

关键词: 系统性硬化症, 细胞因子, 全基因组甲基化

Abstract:

Objective: To analyze the expression profile of serum cytokines in patients with systemic sclerosis (SSc) and explore its possible regulatory mechanisms.Methods: Serum and DNA of peripheral blood mononuclear cells were collected from 30 SSc patients and 80 normal controls (NCs). According to the presence or absence of interstitial lung disease (ILD) in SSc, the patients were divided into SSc with ILD group and SSc without ILD group. According to the degree of skin involvement, the patients were divided into diffuse systemic scleroderma (dcSSc) group and limited systemic scleroderma (lcSSc) group. According to the presence of anti-topoisomerase-1 antibody (anti-Scl-70 antibody) in the serum of patients with SSc, they were divided into SSc Scl-70 (+) group and SSc Scl-70 (-) group. 27 cytokines in serum were detected by Luminex MAGPIX detection system and Bio-Plex Pro Human Cytokine 27-plex Assay kit: interleukin-1β (IL-1β), interleukin-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12P70, IL-13, IL-15, IL-17, basic fiber growth factor (BASIC FGF), eotaxin, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-γ (IFN-γ), interferon-gamma induced protein 10(IP-10), monocyte chemotactic protein 1(MCP-1), macrophage inflammatory protein-1α(MIP-1α), macrophage inflammatory protein 1β(MIP-1β), platelet-derived growth factor BB (PDGF-BB), regulated on activation in normal T-cell expressed and secreted (RANTES), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor(VEGF). Methylation sites were detected by Illumina 450K methylation chip.Results: Compared with NCs group, the expression of 12 cytokines (BASIC FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IL-1β, IL-1ra, IL-6, IP-10, MCP-1, TNF-α and RANTES) in the SSc group significantly increased (P<0.05), IL-5 was decreased expression in the SSc group (P<0.05), there was no signi-ficant difference in the expressions of the other 14 cytokines. Compared with lcSSc group, 9 cytokines (eotaxin, IL-5, MCP-1, IL-2, RANTES, IL17A, IL-8, MIP-1β and PDGF-BB) increased in dcSSc group, but there was no significant difference. Compared with SSc without ILD group, IL-15 increased in SSC with ILD group [18.2(172.97) ng/L vs. 2.03(0.05) ng/L, P<0.05]. Compared with SSc Scl-70 (-) group, the expression of IP-10 decreased in SSc Scl-70 (+) group [1 030 (2 196.6) ng/L vs. 1 878 (2 964) ng/L, P<0.05]. The correlation analysis of serum cytokines with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) showed that IL-6 was positively correlated with ESR (r =0.04, P= 0.017), MCP-1 (r= 0.49, P= 0.043) and MIP-1β (r= 0.41, P= 0.007) positively correlated with CRP. By analyzing the changes of methylation sites of cytokines, it was found that cg17744604 in IL-10 TSS1500 region, cg06111286 in IL-12P70 TSS200 region, cg07935264 in IL-1 β TSS200 region, cg01467417 in IL-1ra TSS1500 region, cg03989987 in IL-1ra 5'UTR region and cg21099624 in VEGF TSS200 region were all hypomethylated.Conclusion: There were different cytokines expression profiles in the serum of SSc patients, and the altered cytokines were correlected with the degree of skin damage and pulmonary fibrosis. Many cytokines were regulated by methylation.

Key words: Systemic sclerosis, Cytokine, Genome-wide methylation

中图分类号: 

  • R593.25

表1

血清细胞因子表达谱在SSc、dcSSc和lcSSc组中的变化/(ng/L), 中位数(四分位距)"

Cytokine NCs (n=80) SSc (n=30) P value
(NC vs. SSc)
lcSSc (n=10) dcSSc (n=20) P value
(lcSSc vs. dcSSc)
BASIC FGF 64.27 (42.37) 88.51 (46.58) 0.002 94.07 (49.47) 86.70 (48.08) >0.05
Eotaxin 145.90 (89.30) 178.80 (155.70) 0.039 139.40 (127.30) 188.60 (156.60) >0.05
G-CSF 75.87 (58.45) 113.90 (104.84) <0.001 122.40 (149.89) 108.00 (82.50) >0.05
GM-CSF 30.75 (57.51) 53.17 (124.65) 0.039 106.50 (96.09) 42.76 (134.16) >0.05
IFN-γ 65.50 (75.52) 198.60 (149.60) <0.001 259.20 (224.60) 194.90 (116.90) >0.05
IL-5 8.76 (23.13) 3.28 (4.27) 0.001 3.28 (10.23) 4.63 (4.57) >0.05
IL-1β 1.62 (27.08) 6.58 (6.64) <0.001 7.69 (5.82) 5.46 (10.36) >0.05
IL-1ra 143.70 (177.36) 481.60 (613.10) <0.001 541.40 (514.60) 359.50 (399.10) >0.05
IL-6 21.58 (32.72) 35.92 (31.39) 0.002 34.49 (40.10) 33.86 (21.01) >0.05
IP-10 766.00 (523.40) 1 307.00 (2 506.40) 0.002 2 096.00 (2 885.00) 1 094.00 (2 081.60) >0.05
MCP-1 118.30 (73.10) 229.60 (319.40) <0.001 180.30 (284.18) 261.00 (548.40) >0.05
TNF-α 43.17 (33.35) 62.64 (43.74) <0.001 63.43 (61.72) 55.81 (39.60) >0.05
RANTES 23 404.00 (27 482.00) 52 632.00 (75 694.00) 0.019 42 802.00 (80 383.00) 71 752.00 (75 270.00) >0.05
IL-2 37.29 (54.92) 5.04 (30.77) 0.053 4.48 (36.44) 5.04 (29.21) >0.05
VEGF 153.10 (139.00) 204.00 (278.90) 0.052 304.80 (338.20) 150.30 (285.10) >0.05
IL-10 19.43 (30.78) 19.84 (15.76) >0.05 23.91 (36.54) 18.92 (12.44) >0.05
IL-15 13.88 (46.35) 2.03 (20.51) >0.05 2.03 (7.33) 2.03 (42.40) >0.05
IL-17A 92.95 (108.01) 127.20 (64.19) >0.05 119.00 (76.45) 143.50 (97.83) >0.05
MIP-1α 7.46 (23.51) 6.76 (4.90) >0.05 7.56 (5.43) 6.66 (4.48) >0.05
IL-4 7.30 (17.02) 5.92 (3.51) >0.05 6.39 (6.85) 5.98 (4.23) >0.05
IL-7 23.91 (19.28) 19.26 (15.27) >0.05 20.67 (29.32) 19.79 (13.86) >0.05
IL-8 48.05 (55.05) 41.05 (32.61) >0.05 36.59 (54.53) 42.06 (31.75) >0.05
IL-9 35.19 (71.11) 36.04 (32.79) >0.05 43.78 (52.64) 35.57 (26.95) >0.05
IL-13 21.49 (23.94) 17.51 (43.08) >0.05 21.25 (88.46) 16.15 (15.30) >0.05
MIP-1β 317.80 (280.30) 290.60 (260.70) >0.05 254.30 (273.70) 324.60 (231.60) >0.05
IL-12P70 45.26 (25.25) 45.89 (45.64) >0.05 57.69 (43.41) 41.08 (43.54) >0.05
PDGF-BB 4 623.00 (2 680.00) 4 701.00 (2 770.00) >0.05 3 911.00 (2 521.00) 5 598.00 (3 036.00) >0.05

表2

血清细胞因子表达谱在SSc ILD(+)、SSc Scl-70(+)组中的变化/(ng/L), 中位数(四分位距)"

Cytokine SSc ILD(-)
(n=15)
SSc ILD(+)
(n=15)
P value
[ILD(-) vs.
ILD(+)]
SSc Scl-70(-)
(n=10)
SSc Scl-70(+)
(n=20)
P value
[Scl-70(-) vs.
Scl-70(+)]
BASIC FGF 88.51 (42.70) 99.08 (51.46) >0.05 77.49 (40.47) 89.70 (50.58) >0.05
Eotaxin 172.10 (140.60) 185.40 (195.20) >0.05 158.40 (402.00) 188.60 (179.00) >0.05
G-CSF 122.40 (128.54) 112.00 (97.04) >0.05 105.40 (230.59) 115.90 (89.78) >0.05
GM-CSF 52.97 (86.94) 121.60 (136.55) >0.05 49.65 (143.35) 53.17 (122.49) >0.05
IFN-γ 205.90 (131.00) 184.00 (188.80) >0.05 238.10 (943.10) 187.70 (114.80) >0.05
IL-12P70 36.59 (44.73) 47.48 (34.56) >0.05 50.77 (186.11) 45.89 (46.69) >0.05
IL-1β 6.30 (5.34) 9.23 (23.73) >0.05 6.58 (40.19) 7.05 (6.57) >0.05
IL-1ra 460.40 (508.50) 502.90 (792.10) >0.05 500.90 (6421.90) 456.30 (524.80) >0.05
IL-6 35.74 (16.38) 36.27 (119.28) >0.05 27.34 (170.27) 36.36 (33.49) >0.05
IP-10 1 418.00 (2 969.90) 1 182.00 (2 306.60) >0.05 1 878.00 (2 964.00) 1 030.00 (2 196.60) 0.039
MCP-1 180.40 (179.90) 323.10 (571.20) >0.05 175.00 (216.12) 296.90 (499.10) >0.05
TNF-α 71.00 (39.17) 52.80 (118.41) >0.05 51.18 (315.81) 69.48 (41.94) >0.05
VEGF 193.70 (210.20) 298.10 (388.80) >0.05 275.20 (428.40) 176.30 (232.30) >0.05
IL-13 24.73 (83.62) 15.12 (36.66) >0.05 18.94 (76.56) 17.51 (55.58) >0.05
IL-7 18.19 (18.71) 19.61 (12.01) >0.05 18.02 (57.74) 21.20 (15.01) >0.05
RANTES 45 504.00 (74 609.00) 59 759.00 (77 217.00) >0.05 78 450.00 (76 739.00) 38 953.00 (75 650.00) >0.05
IL-10 18.28 (11.81) 23.40 (13.45) >0.05 14.85 (156.50) 21.64 (14.77) >0.05
IL-15 2.03 (0.05) 18.20 (172.97) 0.024 2.03 (63.31) 2.03 (25.19) >0.05
IL-17A 122.30 (66.79) 145.20 (112.53) >0.05 123.90 (43.10) 134.50 (73.82) >0.05
IL-2 2.84 (16.57) 5.95 (34.50) >0.05 4.36 (180.43) 5.08 (29.21) >0.05
MIP-1α 6.76 (3.18) 6.46 (20.36) >0.05 6.51 (6.51) 7.74 (4.39) >0.05
IL-4 6.23 (4.63) 5.72 (3.04) >0.05 6.05 (10.81) 5.85 (3.51) >0.05
IL-5 3.21 (3.90) 3.34 (4.84) >0.05 4.09 (10.88) 3.21 (3.21) >0.05
IL-8 37.45 (21.89) 49.71 (47.20) >0.05 40.31 (58.24) 41.05 (28.72) >0.05
IL-9 36.22 (35.10) 35.86 (30.29) >0.05 33.01 (30.67) 38.56 (29.77) >0.05
MIP-1β 260.70 (285.40) 310.60 (420.10) >0.05 312.30 (293.10) 290.60 (243.80) >0.05
PDGF-BB 4 359.00 (3 072.00) 5 043.00 (3 128.00) >0.05 4 827.00 (3 340.00) 4 701.00 (2 958.00) >0.05

表3

SSc血清细胞因子表达谱与ESR、CRP的相关性"

Cytokine ESR CRP
r P r P
BASIC FGF -0.09 0.009 0.12 >0.05
Eotaxin -0.12 0.013 0.15 >0.05
G-CSF -0.11 0.004 0.19 >0.05
GM-CSF -0.04 0.012 0.05 >0.05
IFN-γ -0.07 0.010 0.10 >0.05
IL-10 -0.09 0.002 0.25 >0.05
IL-12P70 -0.19 <0.001 0.16 >0.05
IL-15 0.09 >0.05 0.08 >0.05
IL-17A 0.05 >0.05 0.14 >0.05
IL-1β -0.06 0.008 0.23 >0.05
IL-1ra -0.02 0.011 0.10 >0.05
IL-2 -0.31 <0.001 0.07 >0.05
IL-6 0.04 0.017 0.30 >0.05
IP-10 -0.02 >0.05 0.09 >0.05
MCP-1 0.09 >0.05 0.49 0.043
MIP-1α -0.05 >0.05 0.38 >0.05
TNF-α -0.06 0.011 0.16 >0.05
VEGF -0.13 0.024 0.17 >0.05
IL-13 -0.35 <0.001 -0.07 0.050
IL-4 -0.2 0.005 0.04 >0.05
IL-5 -0.07 0.034 0.06 >0.05
IL-7 -0.04 0.006 0.17 >0.05
IL-8 0.09 >0.05 0.32 >0.05
IL-9 -0.21 0.001 0.30 >0.05
MIP-1β -0.02 >0.05 0.41 0.007
PDGF-BB -0.04 >0.05 -0.01 0.042
RANTES 0.17 >0.05 0.02 >0.05

表4

细胞因子甲基化表达的改变"

Cytokine Gene Methylation sites NCs β (Mean) SSc β (Mean) Δβ P value Gene locus Chromosomal location
IL-10 IL10 cg17744604 0.403 0.297 -0.106 <0.001 TSS1500 1
IL-12P70 IL12B cg06111286 0.316 0.250 -0.066 0.001 TSS200 5
IL-1β IL1B cg07935264 0.195 0.150 -0.045 <0.001 TSS200 2
IL-1ra IL1RN cg01467417 0.127 0.108 -0.019 0.014 TSS1500 2
IL-1ra IL1RN cg03989987 0.301 0.238 -0.063 0.006 5'UTR 2
VEGF VEGFA cg21099624 0.097 0.089 -0.008 0.011 TSS200 6
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