Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

Zhang,Ruixian; Li,Ya; Pan,Bangpin; Li,Yi; Liu,Aimin; Li,Xiaolan

doi:10.3892/etm.2019.8013

Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

Authors:
- Ruixian Zhang
- Ya Li
- Bangpin Pan
- Yi Li
- Aimin Liu
- Xiaolan Li
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Affiliations: Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China, Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650031, P.R. China, Basic Nursing Teaching Department of Kunming Medical University, Kunming, Yunnan 650500, P.R. China
Published online on: September 17, 2019 https://doi.org/10.3892/etm.2019.8013
Pages: 4067-4075
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by overactive inflammation and aberrant activation of lymphocytes. Chemokine C‑X‑C motif ligand 10 (CXCL10) has an important role in the initiation and deterioration of SLE. However, the expression levels of CXCL10 mRNA in T‑helper (Th) cells and B lymphocytes from SLE patients have remained elusive. In the present study, a Bioinformatics analysis of differentially expressed gene (DEG) profiles obtained from RNA sequencing data for three matched samples was performed to explore the hub genes, mainly through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes and protein‑protein interaction analysis. Furthermore, the expression of CXCL10 in peripheral blood mononuclear cells (PBMCs), CD4+ Th cells and CD19+ B cells of 108 subjects, including 66 SLE patients and 42 healthy controls, was confirmed by reverse transcription‑quantitative PCR. In addition, 4 single‑nucleotide polymorphism (SNP) loci in the 3'‑untranslated region of CXCL10 were assessed using the Snapshot SNP genotyping assay. A total of 152 clustered DEGs mainly accumulated in immune‑associated GO terms and interferon‑associated pathways were identified. The expression of CXCL10, one of the central genes in the interaction network cluster (the degree of interaction, MCODE score=28.414), was 6.27‑fold higher in SLE patients compared with control patients. Furthermore, CXCL10 mRNA was confirmed to be elevated in PBMCs and CD19+ B cells of patients with SLE (P<0.001 for the two cell types). However, no significant difference in CD4+ T lymphocytes was present (P=0.881). In addition, no polymorphism was identified in four selected loci from the samples. Taken together, the present results demonstrated that CXCL10, one of the hub genes in the pathogenesis of SLE, is upregulated in PBMCs and B lymphocytes of patients with SLE, although none of the SNPs selected for analysis in the present study were identified to have any potential associations with SLE.

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1	Stojan G and Petri M: Epidemiology of systemic lupus erythematosus: An update. Curr Opin Rheumatol. 30:144–150. 2018. View Article : Google Scholar : PubMed/NCBI
2	Ghodke-Puranik Y and Niewold TB: Immunogenetics of systemic lupus erythematosus: A comprehensive review. J Autoimmun. 64:125–136. 2015. View Article : Google Scholar : PubMed/NCBI
3	Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A and Anaya JM: Autoimmune disease and gender: Plausible mechanisms for the female predominance of autoimmunity. J Autoimmun. 38:J109–J119. 2012. View Article : Google Scholar : PubMed/NCBI
4	Barbhaiya M and Costenbader KH: Environmental exposures and the development of systemic lupus erythematosus. Curr Opin Rheumatol. 28:497–505. 2016. View Article : Google Scholar : PubMed/NCBI
5	Barbhaiya M and Costenbader KH: Ultraviolet radiation and systemic lupus erythematosus. Lupus. 23:588–595. 2014. View Article : Google Scholar : PubMed/NCBI
6	Bernatsky S, Fournier M, Pineau CA, Clarke AE, Vinet E and Smargiassi A: Associations between ambient fine particulate levels and disease activity in patients with systemic lupus erythematosus (SLE). Environ Health Perspect. 119:45–49. 2010. View Article : Google Scholar : PubMed/NCBI
7	Zandman-Goddard G and Shoenfeld Y: Infections and SLE. Autoimmunity. 38:473–485. 2005. View Article : Google Scholar : PubMed/NCBI
8	Zhang Y, Yin Y, Zhang E, Zhu G, Liu M, Feng L, Qin B and Liu X: Spectral attenuation of ultraviolet and visible radiation in lakes in the Yunnan Plateau, and the middle and lower reaches of the Yangtze River, China. Photochem Photobiol Sci. 10:469–482. 2011. View Article : Google Scholar : PubMed/NCBI
9	Zhong H, Li XL, Li M, Hao LX, Chen RW, Xiang K, Qi XB, Ma RZ and Su B: Replicated associations of TNFAIP3, TNIP1 and ETS1 with systemic lupus erythematosus in a southwestern Chinese population. Arthritis Res Ther. 13:R1862011. View Article : Google Scholar : PubMed/NCBI
10	Qian G, Ran X, Zhou CX, Deng DQ, Zhang PL, Guo Y, Luo JH, Zhou XH, Xie H and Cai M: Systemic lupus erythematosus patients in the low-latitude plateau of China: Altitudinal influences. Lupus. 23:1537–1545. 2014. View Article : Google Scholar : PubMed/NCBI
11	Dominguez-Gutierrez PR, Ceribelli A, Satoh M, Sobel ES, Reeves WH and Chan EK: Reduced levels of CCL2 and CXCL10 in systemic lupus erythematosus patients under treatment with prednisone, mycophenolate mofetil, or hydroxychloroquine, except in a high STAT1 subset. Arthritis Res Ther. 16:R232014. View Article : Google Scholar : PubMed/NCBI
12	Crow MK: Type I interferon in the pathogenesis of lupus. J Immunol. 192:5459–5468. 2014. View Article : Google Scholar : PubMed/NCBI
13	Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C and Fallahi P: Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev. 13:272–280. 2014. View Article : Google Scholar : PubMed/NCBI
14	Bruck P, Bartsch W, Penna-Martinez M, Kahles H, Seidl C, Böhme A, Badenhoop K and Ramos-Lopez E: Polymorphisms of CXCR3-binding chemokines in type 1 diabetes. Hum Immunol. 70:552–555. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ruffilli I, Ferrari SM, Colaci M, Ferri C, Fallahi P and Antonelli A: IP-10 in autoimmune thyroiditis. Horm Metab Res. 46:597–602. 2014. View Article : Google Scholar : PubMed/NCBI
16	Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, Panoskaltsis-Mortari A, Gregersen PK, Behrens TW and Baechler EC: Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: A validation study. Arthritis Rheum. 60:3098–3107. 2009. View Article : Google Scholar : PubMed/NCBI
17	Reynolds JA, McCarthy EM, Haque S, Ngamjanyaporn P, Sergeant JC, Lee E, Lee E, Kilfeather SA, Parker B and Bruce IN: Cytokine profiling in active and quiescent SLE reveals distinct patient subpopulations. Arthritis Res Ther. 20:1732018. View Article : Google Scholar : PubMed/NCBI
18	Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40:17251997. View Article : Google Scholar : PubMed/NCBI
19	O'Leary NA, Wright MW, Brister JR, Ciufo S, Haddad D, McVeigh R, Rajput B, Robbertse B, Smith-White B, Ako-Adjei D, et al: Reference sequence (RefSeq) database at NCBI: Current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 44:D733–D745. 2016. View Article : Google Scholar : PubMed/NCBI
20	Hinrichs AS, Raney BJ, Speir ML, Rhead B, Casper J, Karolchik D, Kuhn RM, Rosenbloom KR, Zweig AS, Haussler D and Kent WJ: UCSC data integrator and variant annotation integrator. Bioinformatics. 32:1430–1432. 2016. View Article : Google Scholar : PubMed/NCBI
21	Aken BL, Ayling S, Barrell D, Clarke L, Curwen V, Fairley S, Fernandez Banet J, Billis K, García Girón C, Hourlier T, et al: The Ensembl gene annotation system. Database (Oxford). 2016(pii): baw0932016. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Huang da W, Sherman BT and Lempicki RA: Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37:1–13. 2009. View Article : Google Scholar : PubMed/NCBI
24	Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, et al: The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45:D362–D368. 2017. View Article : Google Scholar : PubMed/NCBI
25	Díaz-Montaña JJ, Gómez-Vela F and Díaz-Díaz N: GNC-app: A new Cytoscape app to rate gene networks biological coherence using gene-gene indirect relationships. Biosystems. 166:61–65. 2018. View Article : Google Scholar : PubMed/NCBI
26	Foster MH: T cells and B cells in lupus nephritis. Semin Nephrol. 27:47–58. 2007. View Article : Google Scholar : PubMed/NCBI
27	Bruck P, Bartsch W, Sadet D, Penna-Martinez M, Kurylowicz A, Bednarczuk T, Robbers I, Paunkovic J, Böhme A, Badenhoop K and Ramos-Lopez E: A CXC motif ligand 10 polymorphism as a marker to predict severity of Graves' disease. Thyroid. 20:343–345. 2010. View Article : Google Scholar : PubMed/NCBI
28	Wang Z, Li M, Wang Y, Xu D, Wang Q, Zhang S, Zhao J, Su J, Wu Q, Shi Q, et al: Long-term mortality and morbidity of patients with systemic lupus erythematosus: A single-center cohort study in China. Lupus. 27:864–869. 2018. View Article : Google Scholar : PubMed/NCBI
29	Kemp MG, Lindsey-Boltz LA and Sancar A: UV light potentiates STING (Stimulator of Interferon Genes)-dependent innate immune signaling through deregulation of ULK1 (Unc51-like Kinase 1). J Biol Chem. 290:12184–12194. 2015. View Article : Google Scholar : PubMed/NCBI
30	Olson JK, Croxford JL and Miller SD: Virus-induced autoimmunity: Potential role of viruses in initiation, perpetuation and progression of T-cell-mediated autoimmune disease. Viral immunol. 14:227–250. 2001. View Article : Google Scholar : PubMed/NCBI
31	Feng D and Barnes BJ: Bioinformatics analysis of the factors controlling type I IFN gene expression in autoimmune disease and virus-induced immunity. Front Immunol. 4:2912013. View Article : Google Scholar : PubMed/NCBI
32	Becker AM, Dao KH, Han BK, Kornu R, Lakhanpal S, Mobley AB, Li QZ, Lian Y, Wu T, Reimold AM, et al: SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One. 8:e670032013. View Article : Google Scholar : PubMed/NCBI
33	Ronnblom L and Alm GV: Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther. 5:68–75. 2003. View Article : Google Scholar : PubMed/NCBI
34	Garcia-Sastre A and Biron CA: Type 1 interferons and the virus-host relationship: A lesson in detente. Science. 312:879–882. 2006. View Article : Google Scholar : PubMed/NCBI
35	Kawai T and Akira S: Innate immune recognition of viral infection. Nat Immunol. 7:131–137. 2006. View Article : Google Scholar : PubMed/NCBI
36	Liu J, Ni J, Li LJ, Leng RX, Pan HF and Ye DQ: Decreased UBASH3A mRNA expression levels in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Inflammation. 38:1903–1910. 2015. View Article : Google Scholar : PubMed/NCBI
37	Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, Panoskaltsis-Mortari A, Gregersen PK, Behrens TW and Baechler EC: Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: A validation study. Arthritis Rheum. 60:3098–3107. 2009. View Article : Google Scholar : PubMed/NCBI
38	Rose T, Grutzkau A, Hirseland H, Huscher D, Dähnrich C, Dzionek A, Ozimkowski T, Schlumberger W, Enghard P, Radbruch A, et al: IFNα and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis. 72:1639–1645. 2013. View Article : Google Scholar : PubMed/NCBI
39	Oke V, Brauner S, Larsson A, Gustafsson J, Zickert A, Gunnarsson I and Svenungsson E: IFN-λ1 with Th17 axis cytokines and IFN-α define different subsets in systemic lupus erythematosus (SLE). Arthritis Res Ther. 19:1392017. View Article : Google Scholar : PubMed/NCBI
40	Lee HT, Wu TH, Lin CS, Lee CS, Pan SC, Chang DM, Wei YH and Tsai CY: Oxidative DNA and mitochondrial DNA change in patients with SLE. Front Biosci (Landmark Ed). 22:493–503. 2017. View Article : Google Scholar : PubMed/NCBI
41	Narumi S, Takeuchi T, Kobayashi Y and Konishi K: Serum levels of IFN-inducible protein-10 relating to the activity of systemic lupus erythematosus. Cytokine. 12:1561–1565. 2000. View Article : Google Scholar : PubMed/NCBI
42	Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO and Stiles JK: CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. 22:121–130. 2011.PubMed/NCBI
43	Touzot M, Cacoub P, Bodaghi B, Soumelis V and Saadoun D: IFN-α induces IL-10 production and tilt the balance between Th1 and Th17 in Behçet disease. Autoimmun Rev. 14:370–375. 2015. View Article : Google Scholar : PubMed/NCBI
44	Mezger M, Steffens M, Beyer M, Manger C, Eberle J, Toliat MR, Wienker TF, Ljungman P, Hebart H, Dornbusch HJ, et al: Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood. 111:534–536. 2008. View Article : Google Scholar : PubMed/NCBI
45	Deng GM and Tsokos GC: Pathogenesis and targeted treatment of skin injury in SLE. Nat Rev Rheumatol. 11:663–669. 2015. View Article : Google Scholar : PubMed/NCBI
46	Wahren-Herlenius M and Dörner T: Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 382:819–831. 2013. View Article : Google Scholar : PubMed/NCBI
47	Holder A, Jones G, Soutter F, Palmer DB, Aspinall R and Catchpole B: Polymorphisms in the canine IL7R 3′UTR are associated with thymic output in Labrador retriever dogs and influence post-transcriptional regulation by microRNA 185. Dev Comp Immunol. 81:244–251. 2018. View Article : Google Scholar : PubMed/NCBI
48	Liu X, Wang L, Chi H, Wang J, Zheng Q, Li J, Li Y and Yang D: The SNP Rs915014 in MTHFR regulated by MiRNA associates with atherosclerosis. Cell Physiol Biochem. 45:1149–1155. 2018. View Article : Google Scholar : PubMed/NCBI
49	Wilson N, Driss A, Solomon W, Dickinson-Copeland C, Salifu H, Jain V, Singh N and Stiles J: CXCL10 gene promoter polymorphism-1447A>G correlates with plasma CXCL10 levels and is associated with male susceptibility to cerebral malaria. PLoS One. 8:e813292013. View Article : Google Scholar : PubMed/NCBI
50	Deng G, Zhou G, Zhang R, Zhai Y, Zhao W, Yan Z, Deng C, Yuan X, Xu B, Dong X, et al: Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers. Gastroenterology. 134:716–726. 2008. View Article : Google Scholar : PubMed/NCBI