Skip to main content
SpringerLink
Log in

Expression profile of PU.1 in CD4+T cells from patients with systemic lupus erythematosus

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

A Correction to this article was published on 05 June 2021

This article has been updated

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with complex genetic predisposing factors involved. PU.1 is an important member of the ETS transcription factors family which has diverse functions such as regulating the proliferation, differentiation of immune cells and multiple inflammatory cytokines. Previous studies preliminary explored the relation between PU.1 and SLE. To further explain the potential role of PU.1 in the pathogenesis of SLE, 40 SLE patients and 20 age-sex matched healthy controls (HC) were recruited in this study. Flow cytometry was used to test the percentages of CD4+PU.1+T cells in peripheral blood mononuclear cells (PBMCs) from patients with SLE and HC. Expression levels of PU.1 mRNA in CD4+T cells from SLE patients and HC were analyzed by real-time transcription-polymerase chain reaction. Expression levels of plasma IL-1β, IL-9, IL-18, IL-6, IFN-α, TNF-α, IL-10 and TGF-β1 were measured by enzyme-linked immunosorbent assay. The percentage of CD4+PU.1+T cells in PBMCs from patients with SLE was significantly higher than that from HC (P < 0.001). In addition, the PU.1 mRNA expression in CD4+T cells from SLE patients was increased than that from HC (P = 0.002). In SLE patients, no significant correlation was found between the percentage of CD4+PU.1+T cells and the expression of PU.1 mRNA in CD4+T cells (P > 0.05). Associations of PU.1 mRNA expression in CD4+T cells with major clinical and laboratory parameters of SLE patients were also analyzed, but no significant correlations were found. Consistent with previous studies, SLE patients had increased IL-1β, IL-18, IL-6, IFN-α, TNF-α and IL-10 plasma concentrations than HC (P < 0.01). The expression level of plasma TGF-β1 was significantly decreased in SLE patients than in HC (P < 0.001). In SLE patients, the expression level of IL-1β was positive correlated with PU.1 mRNA expression in CD4+T cells (P = 0.001). Our study first time evaluated the expression profile of PU.1 in CD4+T cells from SLE patients confirming that PU.1 may participate in the pathogenesis of SLE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

References

  1. Rees F, Doherty M, Grainge MJ, et al. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology. 2017;56(11):1945–61.

    Article  PubMed  Google Scholar 

  2. Zhang S, Ye Z, Li C, et al. Chinese systemic lupus erythematosus treatment and research group (CSTAR) registry XI: gender impact on long-term outcome. Lupus. 2018;28(5):635–41.

    Article  Google Scholar 

  3. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110–21.

    Article  CAS  PubMed  Google Scholar 

  4. Gallant S, Gilkeson G. ETS transcription factors and regulation of immunity. Arch Immunol Ther Exp (Warsz). 2006;54(3):149–63.

    Article  CAS  Google Scholar 

  5. Moreau-Gachelin F, Tavitian A, Tambourin P. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature. 1988;331(6153):277–80.

    Article  CAS  PubMed  Google Scholar 

  6. Dakic A, Wu L, Nutt SL. Is PU.1 a dosage-sensitive regulator of haemopoietic lineage commitment and leukaemogenesis? Trends Immunol. 2007;28(3):108–14.

    Article  CAS  PubMed  Google Scholar 

  7. Turkistany SA, DeKoter RP. The transcription factor PU.1 is a critical regulator of cellular communication in the immune system. Arch Immunol Ther Exp (Warsz). 2011;59(6):431–40.

    Article  CAS  Google Scholar 

  8. Huang W, Horvath E, Eklund EA. PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. J Biol Chem. 2007;282(9):6629–43.

    Article  CAS  PubMed  Google Scholar 

  9. Cheng J, Wu R, Long L, et al. miRNA-451 a targets IFN regulatory factor 8 for the progression of systemic lupus erythematosus. Inflammation. 2017;40(2):676–87.

    Article  CAS  PubMed  Google Scholar 

  10. Javierre BM, Fernandez AF, Richter J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20(2):170–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hikami K, Kawasaki A, Ito I, et al. Association of a functional polymorphism in the 3’-untranslated region of SPI1 with systemic lupus erythematosus. Arthritis Rheum. 2011;63(3):755–63.

    Article  CAS  PubMed  Google Scholar 

  12. Fukai T, Nishiyama C, Kanada S, et al. Involvement of PU.1 in the transcriptional regulation of TNF-alpha. Biochem Biophys Res Commun. 2009;388(1):102–6.

    Article  CAS  PubMed  Google Scholar 

  13. Larsson L, Rymo L, Berglundh T. Sp1 binds to the G allele of the-1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production. Genes Immun. 2010;11(2):181–7.

    Article  CAS  PubMed  Google Scholar 

  14. Soroosh P, Doherty TA. Th9 and allergic disease. Immunology. 2009;127(4):450–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ouyang H, Shi Y, Liu Z, et al. Increased interleukin-9 and CD4+IL-9+ T cells in patients with systemic lupus erythematosus. Mol Med Rep. 2013;7(3):1031–7.

    Article  CAS  PubMed  Google Scholar 

  16. Chang HC, Sehra S, Goswami R, et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol. 2010;11(6):527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim YM, Kang HS, Paik SG, et al. Roles of IFN consensus sequence binding protein and PU.1 in regulating IL-18 gene expression. J Immunol. 1999;163(4):2000–7.

    Article  CAS  PubMed  Google Scholar 

  18. Kominato Y, Galson D, Waterman WR, et al. Monocyte expression of the human prointerleukin 1 beta gene (IL1B) is dependent on promoter sequences which bind the hematopoietic transcription factor Spi-1/PU.1. Mol Cell Biol. 1995;163(4):58–68.

    Google Scholar 

  19. Marín-Rosales M, Cruz A, Salazar-Camarena DC, et al. High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C>T polymorphism in TNFSF13B gene. Clin Exp Med. 2019;19(2):183–90.

    Article  PubMed  CAS  Google Scholar 

  20. Aboelenein HR, Hamza MT, Marzouk H, et al. Reduction of CD19 autoimmunity marker on B cells of paediatric SLE patients through repressing PU.1/TNF-α/BAFF axis pathway by miR-155. Growth Factors. 2017;35(2–3):49–60.

    Article  CAS  PubMed  Google Scholar 

  21. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.

    Article  CAS  PubMed  Google Scholar 

  22. Gladman DD, Iban~ez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29(2):288–91.

    PubMed  Google Scholar 

  23. Spain LM, Guerriero A, Kunjibettu S, et al. T cell development in PU.1-deficient mice. J Immunol. 1999;163(5):2681–7.

    CAS  PubMed  Google Scholar 

  24. Chang HC, Zhang S, Thieu VT, et al. PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity. 2005;22(6):693–703.

    Article  CAS  PubMed  Google Scholar 

  25. Chang HC, Han L, Jabeen R, et al. PU.1 regulates TCR expression by modulating GATA-3 activity. J Immunol. 2009;183(8):4887–94.

    Article  CAS  PubMed  Google Scholar 

  26. Ghisletti S, Barozzi I, Mietton F, et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity. 2010;32(3):317–28.

    Article  CAS  PubMed  Google Scholar 

  27. Heinz S, Benner C, Spann N, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38(4):576–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xie Z, Qu Y, Shen P, et al. PU.1 attenuates TNF-α-induced proliferation and cytokine release of rheumatoid arthritis fibroblast-like synoviocytes by regulating miR-155 activity. Mol Med Rep. 2018;17(6):8349–56.

    CAS  PubMed  Google Scholar 

  29. Umazume A, Kezuka T, Matsuda R, et al. Role of PU1 expression as an inflammatory marker in experimental autoimmune uveoretinitis. Ocul Immunol Inflamm. 2018;26(6):951–63.

    Article  CAS  PubMed  Google Scholar 

  30. Shakerian L, Ghorbani S, Talebi F, et al. MicroRNA-150 targets PU.1 and regulates macrophage differentiation and function in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2018;323:167–74.

    Article  CAS  PubMed  Google Scholar 

  31. Wu Z, Zhang S, Li P, et al. Association between complement 4 copy number variation and systemic lupus erythematosus: a meta-analysis. Clin Exp Med. 2020;20(4):627–34.

    Article  CAS  PubMed  Google Scholar 

  32. Dozmorov MG, Wren JD, Alarcón-Riquelme ME. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes. Epigenetics. 2014;9(2):276–85.

    Article  CAS  PubMed  Google Scholar 

  33. Huang Y, Chen L, Zhu B, et al. Evaluation of systemic lupus erythematosus disease activity using anti-α-enolase antibody and RDW. Clin Exp Med. 2020. https://doi.org/10.1007/s10238-020-00657-w.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Veldhoen M, Uyttenhove C, van Snick J, et al. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9(12):1341–6.

    Article  CAS  PubMed  Google Scholar 

  35. Ouyang H, Shi Y, Liu Z, et al. Increased interleukin-9 and CD4+IL-9+T cells in patients with systemic lupus erythematosus. Mol Med Rep. 2013;7(3):1031–7.

    Article  CAS  PubMed  Google Scholar 

  36. Elyaman W, Bradshaw EM, Uyttenhove C, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci USA. 2009;106(31):12885–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marecki S, Riendeau CJ, Liang MD, et al. PU.1 and multiple IFN regulatory factor proteins synergize to mediate transcriptional activation of the human IL-1 beta gene. J Immunol. 2001;166(11):6829–38.

    Article  CAS  PubMed  Google Scholar 

  38. Lemay S, Mao C, Singh AK. Cytokine gene expression in the MRL/lpr model of lupus nephritis. Kidney Int. 1996;50(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  39. McCarthy EM, Smith S, Lee RZ, et al. The association of cytokines with disease activity and damage scores in systemic lupus erythematosus patients. Rheumatol (Oxford). 2014;53(9):1586–94.

    Article  CAS  Google Scholar 

  40. Umare V, Pradhan V, Nadkar M, et al. Effect of proinflammatory cytokines (IL-6, TNFα, and IL-1β) on clinical manifestations in Indian SLE patients. Mediators Inflamm. 2014;2014:385297.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Mende R, Vincent FB, Kandane-Rathnayake R, et al. Analysis of serum interleukin (IL)-1β and IL-18 in systemic lupus erythematosus. Front Immunol. 2018;9:1250.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Koyama N, Hoelzer D, Ottmann OG. Regulation of human IL-18 gene expression: interaction of PU.1 with GC-box binding protein is involved in human IL-18 expression in myeloid cells. Eur J Immunol. 2004;34(3):817–26.

    Article  CAS  PubMed  Google Scholar 

  43. Sabry A, Sheashaa H, El-Husseini A, et al. Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine. 2006;35(3–4):148–53.

    Article  CAS  PubMed  Google Scholar 

  44. Paradowska-Gorycka A, Wajda A, Stypinska B, et al. Variety of endosomal TLRs and interferons (IFN-alpha, IFN-beta, IFN-gamma) expression profiles in patients with SLE, SSc and MCTD. Clin Exp Immunol. 2020. https://doi.org/10.1111/cei.13566.

    Article  Google Scholar 

  45. Uzrail AH, Assaf AM, Abdalla SS. Correlations of expression levels of a panel of genes (IRF5, STAT4, TNFSF4, MECP2, and TLR7) and cytokine levels (IL-2, IL-6, IL-10, IL-12, IFN-gamma, and TNF-alpha) with systemic lupus erythematosus outcomes in jordanian patients. Biomed Res Int. 2019;2019:1703842.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Niwa Y, Nishiyama C, Nakano N, et al. Opposite effects of PU.1 on mast cell stimulation. Biochem Biophys Res Commun. 2008;375(1):95–100.

    Article  CAS  PubMed  Google Scholar 

  47. Kanno Y, Levi BZ, Tamura T, et al. Immune cell-specific amplification of interferon signaling by the IRF-4/8-PU.1 complex. J Interferon Cytokine Res. 2005;25(12):770–9.

    Article  CAS  PubMed  Google Scholar 

  48. Lee YH, Bae SC. Association between circulating transforming growth factor-beta1 level and polymorphisms in systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. Cell Mol Biol (Noisy-le-grand). 2017;63(1):53–9.

    Article  CAS  Google Scholar 

  49. Sugimoto A, Kawakami R, Mikami N. Transcription factors downstream of IL-4 and TGF-beta signals: analysis by quantitative PCR, Western Blot, and Flow Cytometry. Methods Mol Biol. 2017;1585:141–53.

    Article  CAS  PubMed  Google Scholar 

  50. Jovanovic M, Rooney MS, Mertins P, et al. Immunogenetics. Dynamic profiling of the protein life cycle in response to pathogens[J]. Science. 2015;347(6226):1259038.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance [J]. Cell. 2016;165(3):535–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the volunteers who generously participated in this study.

Funding

This article was supported by the National Natural Science Foundation of China (No. 81871271), Anhui Key Research and Development Program (Grant Number 1804b06020354) and the Fundamental Research Funds for the Central Universities (Grant Number WK 9110000148).

Author information

Authors and Affiliations

  1. Department of Rheumatology and Immunology, Anhui Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Nan Xiang

  2. Department of Rheumatology and Immunology, Anhui Provincial Hospital, Hefei, 230001, Anhui, China

    Xuan Fang, Xiao-Ge Sun, Ying-Bo Zhou, Yan Ma, Chen Zhu, Xiang-Pei Li, Guo-sheng Wang, Jin-hui Tao & Xiao-Mei Li

Authors
  1. Nan Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuan Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Ge Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying-Bo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chen Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiang-Pei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guo-sheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jin-hui Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiao-Mei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NX conceived and designed the study, NX and XF performed the experiments, and XL reviewed and edited the manuscript.

Corresponding author

Correspondence to Xiao-Mei Li.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Consent for publication

All authors read and approved the manuscript.

Ethical approval

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Anhui Provincial Hospital. Written informed consent was obtained from individual participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiang, N., Fang, X., Sun, XG. et al. Expression profile of PU.1 in CD4+T cells from patients with systemic lupus erythematosus. Clin Exp Med 21, 621–632 (2021). https://doi.org/10.1007/s10238-021-00717-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-021-00717-9

Keywords

Search

Navigation