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The role of microRNA-31 and microRNA-21 as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by familial aggregation and genetic predisposition. MicroRNAs (MiRNAs) serve as critical biomarkers in lupus patients because of their aberrant expression in different SLE stages. The study aimed to investigate the correlation of miR-31 and miR-21 with IL-2 in SLE patients as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients. Quantitative RT-PCR is carried out to estimate the expressions of miR-31 and miR-21, and IL-2 levels were determined using ELISA in plasma of 40 patients with SLE, 20 of their first-degree relatives and 20 healthy controls. The study also determined the systemic lupus erythematosus disease activity index (SLEDAI) score and proteinuria in SLE patients. The results revealed that miR-31 was lower expressed, while miR-21 was high expressed in SLE patients compared to their first-degree relatives and controls. MiR-31 was negatively correlated with SLEDAI and proteinuria in lupus patients, while miR-21 showed positive correlation with them. Also we found that there is a significant positive correlation between miR-31 and IL-2 in SLE patients, while miR-21 was negatively correlated with IL-2 level in patients. In conclusion, the study disclosed a significant association between miR-31 and miR-21 expression with IL-2 level in SLE patients. The regulatory biomarkers of miR-31 and miR-21 might have an impact on regulating IL-2 pathway expression and in turn on the activation of T lymphocytes in SLE.

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References

  1. Ramos PS, Brown EE, Kimberly RP, Langefeld CD (2010) Genetic factors predisposing to systemic lupus erythematosus and lupus nephritis. Semin Nephrol 30(2):164–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Qu B, Shen N (2015) MiRNAs in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci 16(5):9557–9572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xiao G, Zuo X (2016) Epigenetics in systemic lupus erythematosus. Biomed Rep 4(2):135–139

    PubMed  Google Scholar 

  4. Hochberg MC (1987) The application of genetic epidemiology to systemic lupus erythematosus. J Rheumatol 14:867–869

    CAS  PubMed  Google Scholar 

  5. Alarcón-Segovia D, Alarcón-Riquelme ME, Cardiel MH, Caeiro F, Massardo L, Villa AR, Pons-Estel BA, GrupoLatinoamericano de Estudio del Lupus Eritematoso (GLADEL) (2005) Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 52(4):1138–1147

    Article  PubMed  Google Scholar 

  6. Masi AT, Kaslow RA (1978) Sex effects in systemic lupus erythematosus: a clue to pathogenesis. Arthritis Rheum 21:480–484

    Article  CAS  PubMed  Google Scholar 

  7. Lu LJ, Wallace DJ, Ishimori ML, Scofield RH, Weisman MH (2010) Male systemic lupus erythematosus: a review of sex disparities in this disease. Lupus 19:119–129

    Article  PubMed  Google Scholar 

  8. Murphy G, Isenberg D (2013) Effect of gender on clinical presentation in systemic lupus erythematosus. Rheumatology 52:2108–2115

    Article  PubMed  Google Scholar 

  9. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  10. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP (2008) The impact of microRNAs on protein output. Nature 455:64–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mehta A, Baltimore D (2016) MicroRNAs as regulatory elements in immune system logic. Nat Rev Immunol 16(5):279–294

    Article  CAS  PubMed  Google Scholar 

  12. Stypińska B, Paradowska-Gorycka A (2015) Cytokines and MicroRNAs as candidate biomarkers for systemic lupus erythematosus. Int J Mol Sci 16(10):24194–24218

    Article  PubMed  PubMed Central  Google Scholar 

  13. Husakova M (2016) MicroRNAs in the key events of systemic lupus erythematosus pathogenesis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. doi:10.5507/bp.2016.004

    PubMed  Google Scholar 

  14. Martínez-Ramos R, García-Lozano JR, Lucena JM, Castillo-Palma MJ, García-Hernández F, Rodríguez MC, Núñez-Roldán A, González-Escribano MF (2014) Differential expression pattern of microRNAs in CD4+ and CD19+ cells from asymptomatic patients with systemic lupus erythematosus. Lupus 23(4):353–359

    Article  PubMed  Google Scholar 

  15. Liu YJ, Fan WJ, Bai JZ (2015) MicroRNA-126 expression and its mechanism of action in patients with systemic lupus erythematosus. Eur Rev Med Pharmacol Sci 19(20):3838–3842

    PubMed  Google Scholar 

  16. Tang Y, Luo X, Cui H, Ni Z, Yuan M, Guo Y et al (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60(4):1065–1075

    Article  CAS  PubMed  Google Scholar 

  17. Hai-yan W, Yang L, Mei-hong C, Hui Z (2011) Expression of MicroRNA-146a in peripheral blood mononuclear cells in patients with systemic lupus erythematosus. Zhongguo Yi XueKeXue Yuan XueBao 33(2):185–188

    Google Scholar 

  18. Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X, Li J, Zhou H, Tang Y, Shen N (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyl transferase 1. J Immunol 184(12):6773–6781

    Article  CAS  PubMed  Google Scholar 

  19. Fan W, Liang D, Tang Y, Qu B, Cui H, Luo X et al (2012) Identification of microRNA-31 as a novel regulator contributing to impaired interleukin-2 production in T cells from patients with systemic lupus erythematosus. Arthritis Rheum 64(11):3715–3725

    Article  CAS  PubMed  Google Scholar 

  20. Garchow B, Kiriakidou M (2016) MicroRNA-21 deficiency protects from lupus-like autoimmunity in the chronic graft-versus-host disease model of systemic lupus erythematosus. Clin Immunol 162:100–106

    Article  CAS  PubMed  Google Scholar 

  21. Lieberman LA, Tsokos GC (2010) The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J Biomed Biotechnol 2010:740619

    Article  PubMed  PubMed Central  Google Scholar 

  22. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor and β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178:280–290

    Article  CAS  PubMed  Google Scholar 

  23. Liao W, Lin JX, Leonard WJ (2013) Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38:13–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schorle H, Holtschke T, Hünig T, Schimpl A, Horak I (1991) Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352(6336):621–624

    Article  CAS  PubMed  Google Scholar 

  25. Horak I (1995) Immunodeficiency in IL-2-knockout mice. Clin Immunol Immunopathol 76(3 Pt 2):S172–S173

    Article  CAS  PubMed  Google Scholar 

  26. Horwitz DA (2010) The clinical significance of decreased T cell interleukin-2 production in systemic lupus erythematosus: connecting historical dots. Arthritis Rheum 62(8):2185–2187

    Article  CAS  PubMed  Google Scholar 

  27. 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  PubMed  Google Scholar 

  28. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang DH, The Committee on Prognosis Studies in SLE (1992) Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 35:630–640

    Article  CAS  PubMed  Google Scholar 

  29. Firestein GS (2008) Kelley’s textbook of rheumatology. W. B Saunders, Philadelphia

    Google Scholar 

  30. Chafin CB, Reilly CM (2013) MicroRNAs implicated in the immunopathogenesis of lupus nephritis. Clin Dev Immunol 2013:430239

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yan S, Yim LY, Lu L, Lau CS, Chan VS (2014) MicroRNA regulation in systemic lupus erythematosus pathogenesis. Immune Netw 14(3):138–148

    Article  PubMed  PubMed Central  Google Scholar 

  32. Miao CG, Yang YY, He X, Huang C, Huang Y, Zhang L, Lv XW, Jin Y, Li J (2013) The emerging role of microRNAs in the pathogenesis of systemic lupus erythematosus. Cell Signal 25(9):1828–1836

    Article  CAS  PubMed  Google Scholar 

  33. Fan W, Liang D, Tang Y, Qu B, Cui H, Luo X, Huang X, Chen S, Shen N (2011) Expression of miR-31 in peripheral blood of patients with systemic lupus erythematosus. J Shanghai Jiaotong Univ 31:39–42

    Google Scholar 

  34. Song YC, Tang SJ, Lee TP, Hung WC, Lin SC, Tsai CY, Ng WV, Wu MF, Sun KH (2010) Reversing interleukin-2 inhibition by anti–double-stranded DNA autoantibody ameliorates glomerulonephritis in MRL-lpr/lprmice. Arthritis Rheum 62:2401–2411

    Article  CAS  PubMed  Google Scholar 

  35. Tsokos GC (2011) Disease pathogenesis: systemic lupus erythematosus. N Engl J Med 365:2110–2121

    Article  CAS  PubMed  Google Scholar 

  36. Mellor-Pita S, Citores MJ, Castejon R, Tutor-Ureta P, Yebra-Bango M, Andreu JL, Vargas JA (2006) Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis 65:553–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW (2008) Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in autoimmunity. Clin Immunol 127:385–393

    Article  CAS  PubMed  Google Scholar 

  38. Webster KE, Walters S, Kohler R, Mrkvan T, Boyman O, Surh CD, Grey ST, Sprent J (2009) In vivo expansion of Treg cells with IL-2 mAb complexes; induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 206:751–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sgouroudis E, Kornete M, Piccirillo CA (2011) IL-2 production by dendritic cells promotes Foxp3 + regulatory T-cell expansion in autoimmune resistant NOD congenic mice. Autoimmunity 44:406–414

    Article  CAS  PubMed  Google Scholar 

  40. Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y et al (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 5:179ra43

    Article  PubMed  PubMed Central  Google Scholar 

  41. Mizui M, Koga T, Lieberman LA, Beltran J, Yoshida N, Johnson MC, Tisch R, Tsokos GC (2014) Interleukin-2 protects lupus-prone mice from multiple end organ damage by limiting CD4−CD8—Interleukin-17-producing T cells. J Immunol 193:2168–2177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xue F, Li H, Zhang J, Lu J, Xia Y, Xia Q (2013) MiR-31 regulates interleukin 2 and kinase suppressor of ras 2 during T cell activation. Genes Immun 14(2):127–131

    Article  CAS  PubMed  Google Scholar 

  43. Helms WS, Jeffrey JL, Holmes DA, Townsend MB, Clipstone NA, Su L (2007) Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells. J Leukoc Biol 82:361–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Crispin JC, Tsokos GC (2009) Transcriptional regulation of IL-2 in health and autoimmunity. Autoimmun Rev 8(3):190–195

    Article  CAS  PubMed  Google Scholar 

  45. Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR (1988) Identification of a putative regulator of early T cell activation genes. Science 241:202–205

    Article  CAS  PubMed  Google Scholar 

  46. Rooney JW, Sun YL, Glimcher LH, Hoey T (1995) Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation. Mol Cell Biol 15:6299–6310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chow CW, Rincon M, Davis RJ (1999) Requirement for transcription factor NFAT in interleukin-2 expression. Mol Cell Biol 19:2300–2307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Garchow BG, BartulosEncinas O, Leung YT, Tsao PY, Eisenberg RA, Caricchio R, Obad S, Petri A, Kauppinen S, Kiriakidou M (2011) Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice. EMBO Mol Med 3(10):605–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stagakis E, Bertsias G, Verginis P, Nakou M, Hatziapostolou M, Kritikos H, Iliopoulos D, Boumpas DT (2011) Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann Rheum Dis 70(8):1496–1506

    Article  CAS  PubMed  Google Scholar 

  50. Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothé F, Simion A et al (2009) Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol 39(6):1608–1618

    Article  CAS  PubMed  Google Scholar 

  51. Chen C, Rowell EA, Thomas RM, Hancock WW, Wells AD (2006) Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 281:36828–36834

    Article  CAS  PubMed  Google Scholar 

  52. Murugaiyan G, da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, Yosef N, Vaidya VS, Weiner HL (2015) MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest. 125(3):1069–1080

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was funded by National Research Centre, Cairo, Egypt.

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Authors and Affiliations

  1. Head of Medical Molecular Genetics Department, National Research Centre, Cairo, Egypt

    Khalda Sayed Amr

  2. Immunogenetics Department, National Research Centre, Cairo, Egypt

    Faten S. Bayoumi & Eman Eissa

  3. Head of Microbiology and Immunology Department, MSA University, Cairo, Egypt

    Faten S. Bayoumi

  4. Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, Cairo, Egypt

    Fatema T. Elgengehy & Hanan H. Ahmed

  5. Faculty of Science, Cairo University, Giza, Egypt

    Sanaa O. Abdallah

  6. Head of Medical Molecular Genetics Department, National Research Centre, El Buhouth St., Cairo, 12622, Dokki, Egypt

    Khalda Sayed Amr

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  1. Khalda Sayed Amr
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  2. Faten S. Bayoumi
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  3. Fatema T. Elgengehy
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Correspondence to Khalda Sayed Amr.

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All procedures performed in this study which involves 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.

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Amr, K.S., Bayoumi, F.S., Elgengehy, F.T. et al. The role of microRNA-31 and microRNA-21 as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients. Rheumatol Int 36, 1617–1625 (2016). https://doi.org/10.1007/s00296-016-3550-z

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  • DOI: https://doi.org/10.1007/s00296-016-3550-z

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