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High interleukin-18 and low FOXP3 mRNAs in peripheral blood of women with severe systemic lupus erythematosus: a cross-sectional study

  • Observational Research
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Abstract

Gene expression analysis of peripheral blood cells may provide valuable information about the triggered molecular processes in systemic lupus erythematosus (SLE). The study aimed to quantify the mRNA in peripheral blood of seven target genes, including inflammatory cytokine genes (IL23A, IL12B, TNFA, IL18), and T regulatory-related genes (FOXP3, TGFB1, IL10) in patients with SLE and to correlate expression levels with disease activity and/or clinical manifestations. The relative quantification of target genes was performed using real-time polymerase chain reaction in peripheral blood obtained from 28 adult SLE females and 17 healthy women. The highest up-regulation in the blood of SLE patients was observed for IL23A with a median 9.54 (p < 0.0001), followed by TGFB1 (median: 2.07; p = 0.047) and IL10 (median: 1.84; p = 0.013). IL12B and TNFA were significantly down-regulated in patients compared to controls (median: 0.521; p = 0.0023, and median: 0.519; p = 0.0003, respectively). FOXP3 mRNA was lower among patients with higher degree of disease activity (median: 0.338; p = 0.029) and showed inverse correlation with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). IL18 mRNA correlated positively with the SLEDAI and was highly expressed during severe flares (median: 1.216; p = 0.021). IL18 up-regulation was associated with anti-dsDNA antibody positivity, while FOXP3 down-regulation with lupus nephritis. Our study pointed out the relationship of SLE disease activity and particular clinical manifestations with IL18 and FOXP3 expression, and the significant contribution of IL23A in the SLE immunopathogenesis. Hence, the peripheral blood cytokine mRNAs should be exploited as novel prognostic and diagnostic biomarkers.

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References

  1. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci 100:2610–2615. https://doi.org/10.1073/pnas.0337679100

    Article  CAS  PubMed  Google Scholar 

  2. Zhu H, Mi W, Luo H, Chen T, Liu S, Raman I, Zuo X, Li QZ (2016) Whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulation pathways in systemic lupus erythematosus. Arthritis Res Ther 18:162. https://doi.org/10.1186/s13075-016-1050-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Teruel M, Sawalha AH (2017) Epigenetic variability in systemic lupus erythematosus: what we learned from genome-wide DNA methylation studies. Curr Rheumatol Rep 19:32. https://doi.org/10.1007/s11926-017-0657-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Petri M, Fu W, Ranger A, Allaire N, Cullen P, Magder LS, Zhang Y (2019) Association between changes in gene signatures expression and disease activity among patients with systemic lupus erythematosus. BMC Med Genomics 12:4. https://doi.org/10.1186/s12920-018-0468-1

    Article  PubMed  PubMed Central  Google Scholar 

  5. Edwards CK 3rd, Green JS, Volk HD, Schiff M, Kotzin BL, Mitsuya H, Kawaguchi T, Sakata KM, Cheronis J, Trollinger D, Bankaitis-Davis D, Dinarello CA, Norris DA, Bevilacqua MP, Fujita M, Burmester GR (2012) Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritispatients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone. Front Immunol 3:366. https://doi.org/10.3389/fimmu.2012.00366

    Article  PubMed  PubMed Central  Google Scholar 

  6. Larosa M, Zen M, Gatto M, Jesus D, Zanatta E, Iaccarino L, Inês L, Doria A (2019) IL-12 and IL-23/Th17 axis in systemic lupus erythematosus. Exp Biol Med 244:42–51. https://doi.org/10.1177/1535370218824547

    Article  CAS  Google Scholar 

  7. Qiu F, Song L, Yang N, Li X (2013) Glucocorticoid downregulates expression of IL-12 family cytokines in systemic lupus erythematosus patients. Lupus 22:1011–1016. https://doi.org/10.1177/0961203313498799

    Article  CAS  PubMed  Google Scholar 

  8. Xia LP, Li BF, Shen H, Lu J (2015) Interleukin-27 and interleukin-23 in patients with systemic lupus erythematosus: possible role in lupus nephritis. Scand J Rheumatol 44:200–205. https://doi.org/10.3109/03009742.2014.962080

    Article  CAS  PubMed  Google Scholar 

  9. Fischer K, Przepiera-Będzak H, Sawicki M, Walecka A, Brzosko I, Brzosko M (2017) Serum interleukin-23 in polish patients with systemic lupus erythematosus: association with lupus nephritis, obesity, and peripheral vascular disease. Mediat Inflamm 2017:9401432. https://doi.org/10.1155/2017/9401432

    Article  CAS  Google Scholar 

  10. Mende R, Vincent FB, Kandane-Rathnayake R, Koelmeyer R, Lin E, Chang J, Hoi AY, Morand EF, Harris J, Lang T (2018) Analysis of serum interleukin (IL)-1β and IL-18 in systemic lupus erythematosus. Front Immunol 9:1250. https://doi.org/10.3389/fimmu.2018.01250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Deuteraiou K, Kitas G, Garyfallos A, Dimitroulas T (2018) Novel insights into the role of inflammasomes in autoimmune and metabolic rheumatic diseases. Rheumatol Int 38:1345–1354. https://doi.org/10.1007/s00296-018-4074-5

    Article  CAS  PubMed  Google Scholar 

  12. Zhu Q, Kanneganti TD (2017) Cutting Edge: distinct regulatory mechanisms control proinflammatory cytokines IL-18 and IL-1β. J Immunol 198:4210–4215. https://doi.org/10.4049/jimmunol.1700352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li W, Deng C, Yang H, Wang G (2019) The regulatory T cell in active systemic lupus erythematosus patients: a systemic review and meta-analysis. Front Immunol 10:159. https://doi.org/10.3389/fimmu.2019.00159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352. https://doi.org/10.1038/ni1178

    Article  CAS  PubMed  Google Scholar 

  15. Godsell J, Rudloff I, Kandane-Rathnayake R, Hoi A, Nold MF, Morand EF, Harris J (2016) Clinical associations of IL-10 and IL-37 in systemic lupus erythematosus. Sci Rep 6:34604. https://doi.org/10.1038/srep34604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277

    Article  CAS  Google Scholar 

  17. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 35:630–640

    Article  CAS  Google Scholar 

  18. Abrahamowicz M, Fortin PR, du Berger R, Nayak V, Neville C, Liang MH (1998) The relationship between disease activity and expert physician’s decision to start major treatment in active systemic lupus erythematosus: a decision aid for development of entry criteria for clinical trials. J Rheumatol 25:277–284

    CAS  PubMed  Google Scholar 

  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  20. Miteva L, Goycheva MI, Manolova I, Vasilev G, Stoilov R, Stanilova S (2017) AB0005 Cytokine mRNAs gene expression associated with systemic lupus erythematosus. Ann Rheum Dis 76:1048–1048. https://doi.org/10.1136/annrheumdis-2017-eular.2299

    Article  Google Scholar 

  21. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725. https://doi.org/10.1016/s1074-7613(00)00070-4

    Article  CAS  PubMed  Google Scholar 

  22. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748. https://doi.org/10.1038/nature01355

    Article  CAS  PubMed  Google Scholar 

  23. van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, Werth VP, Gordon RM, Zhou B, Hsu B, Chevrier M, Triebel M, Jordan JL, Rose S (2018) Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 392:1330–1339. https://doi.org/10.1016/S0140-6736(18)32167-6

    Article  PubMed  Google Scholar 

  24. Du J, Li Z, Shi J, Bi L (2014) Associations between serum interleukin-23 levels and clinical characteristics in patients with systemic lupus erythematosus. J Int Med Res 42:1123–1130. https://doi.org/10.1177/0300060513509130

    Article  CAS  PubMed  Google Scholar 

  25. Wang X, Liu X, Zhang Y, Wang Z, Zhu G, Han G, Chen G, Hou C, Wang T, Ma N, Shen B, Li Y, Xiao H, Wang R (2016) Interleukin (IL)-39 [IL-23p19/Epstein–Barr virus-induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus-prone mice. Clin Exp Immunol 186:144–156. https://doi.org/10.1111/cei.12840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tselios K, Sarantopoulos A, Gkougkourelas I, Boura P (2014) CD4+ CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study. Clin Exp Rheumatol 32:630–639

    PubMed  Google Scholar 

  27. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Nochy D, Debre P, Piette JC, Gorochov G (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175:8392–8400. https://doi.org/10.4049/jimmunol.175.12.8392

    Article  CAS  PubMed  Google Scholar 

  28. Bai Y, Tong Y, Liu Y, Hu H (2018) Self-dsDNA in the pathogenesis of systemic lupus erythematosus. Clin Exp Immunol 191:1–10. https://doi.org/10.1111/cei.13041

    Article  CAS  PubMed  Google Scholar 

  29. Italiani P, Manca ML, Angelotti F, Melillo D, Pratesi F, Puxeddu I, Boraschi D, Migliorini P (2018) IL-1 family cytokines and soluble receptors in systemic lupus erythematosus. Arthritis Res Ther 20:27. https://doi.org/10.1186/s13075-018-1525-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jafari-Nakhjavani MR, Abedi-Azar S, Nejati B (2016) Correlation of plasma interleukin-18 concentration and severity of renal involvement and disease activity in systemic lupus erythematosus. J Nephropathol 5:28–33. https://doi.org/10.15171/jnp.2016.05

    Article  PubMed  Google Scholar 

  31. El-Fetouh SA, Mohammed RHA, Abozaid HSM (2014) Serum interleukin-18 and interleukin-10 levels in systemic lupus erythematosus: correlation with SLEDAI score and disease activity parameters. Egypt Rheumatol Rehabil 41:160–166. https://doi.org/10.4103/1110-161X.147358

    Article  Google Scholar 

  32. Pisetsky DS (2016) Anti-DNA antibodies-quintessential biomarkers of SLE. Nat Rev Rheumatol 12:102–110. https://doi.org/10.1038/nrrheum.2015.151

    Article  CAS  PubMed  Google Scholar 

  33. Mistry P, Kaplan MJ (2017) Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin Immunol 185:59–73. https://doi.org/10.1016/j.clim.2016.08.010

    Article  CAS  PubMed  Google Scholar 

  34. Jeremic I, Djuric O, Nikolic M, Vlajnic M, Nikolic A, Radojkovic D, Bonaci-Nikolic B (2019) Neutrophil extracellular traps-associated markers are elevated in patients with systemic lupus erythematosus. Rheumatol Int 39:1849–1857. https://doi.org/10.1007/s00296-019-04426-1

    Article  CAS  PubMed  Google Scholar 

  35. Magna M, Pisetsky DS (2015) The role of cell death in the pathogenesis of SLE: is pyroptosis the missing link? Scand J Immunol 82:218–224. https://doi.org/10.1111/sji.12335

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by Grants No. 2/2017 and No. 2/2018 from the Fund for Scientific and Mobile Project from the Trakia University, Medical Faculty, Stara Zagora, Bulgaria.

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Authors and Affiliations

  1. Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Armeiska 11 St, 6000, Stara Zagora, Bulgaria

    Lyuba D. Miteva, Irena M. Manolova & Spaska A. Stanilova

  2. Clinic of Rheumatology, Medical Faculty, University Hospital “St. Ivan Rilski”, Medical University, Sofia, Bulgaria

    Mariana G. Ivanova & Rumen M. Stoilov

Authors
  1. Lyuba D. Miteva
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Contributions

LM, IM, MI, RS, and SS made substantial contributions to the conception or design of the work. MI and RS, assessed participants, analyzed and interpreted the data. LM, IM and SS performed the analyses, collected and interpreted the data. LM drafted the manuscript. RS and SS supervised the project. All authors read, revising and approved the final manuscript version and take full responsibility for the integrity of the study and the manuscript.

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Correspondence to Lyuba D. Miteva.

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Miteva L, Manolova I, Ivanova M, Stoilov R and Stanilova S declare that they have no conflict of interests.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the local Ethics Committee of the University Hospital “St. Ivan Rilski”, Sofia, Bulgaria with a decision number #6, 29 Nov 2016.

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Informed consent was obtained from all individual participants involved in the study.

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Miteva, L.D., Manolova, I.M., Ivanova, M.G. et al. High interleukin-18 and low FOXP3 mRNAs in peripheral blood of women with severe systemic lupus erythematosus: a cross-sectional study. Rheumatol Int 40, 727–735 (2020). https://doi.org/10.1007/s00296-020-04542-3

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