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Glucocorticoid-induced leucine zipper expression is associated with response to treatment and immunoregulation in systemic lupus erythematosus

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder in which cytokine balance is disturbed. Glucocorticoids (GCs) are shown to balance immune response by transcriptional regulation of glucocorticoid receptor target genes such as Glucocorticoid-induced leucine zipper (GILZ) which has been introduced as an endogenous anti-inflammatory mediator. In the present study, we assessed the expression of GILZ in association with interferon-γ (IFN-γ), interleukine-10 (IL-10), and B lymphocyte stimulator (BLyS) plasma levels in SLE patients. A total of 40 female patients (18 under treatment and 22 newly diagnosed) were recruited in this study. Real-time RT PCR was conducted to quantify the mRNA expression of GILZ. The plasma levels of IFN-γ, IL-10, and BLyS were evaluated using ELISA method. GILZ was overexpressed among under treatment SLE patients. The mRNA expression of GILZ was significantly correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. IFN-γ and BLyS were downregulated in response to therapies with negative correlations to GILZ. Moreover, IL-10 was upregulated among treated patients. The levels of IFN-γ and BLyS were correlated with the severity of disease, while IL-10 was negatively correlated with SLEDAI score. GILZ could be introduced as one of the acting molecules in mediating the regulatory effects of GCs on producing pro- and anti-inflammatory cytokines in SLE.

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References

  1. Murphy G, Lisnevskaia L, Isenberg D (2013) Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet 382(9894):809–818. doi:10.1016/S0140-6736(13)60889-2

    Article  CAS  PubMed  Google Scholar 

  2. Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y (2012) Systemic lupus erythematosus one disease or many? Autoimmun Rev 11(8):593–595. doi:10.1016/j.autrev.2011.10.020

    Article  CAS  PubMed  Google Scholar 

  3. Mohammadoo-Khorasani M, Musavi M, Mousavi M, Moossavi M, Khoddamian M, Sandoughi M, Zakeri Z (2016) Deoxyribonuclease I gene polymorphism and susceptibility to systemic lupus erythematosus. Clin Rheumatol 35(1):101–105. doi:10.1007/s10067-015-3111-y

    Article  PubMed  Google Scholar 

  4. Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M et al (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75(1):3–15. doi:10.1136/annrheumdis-2015-207524

    Article  PubMed  Google Scholar 

  5. Beaulieu E, Morand EF (2011) Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. Nat Rev Rheumatol 7(6):340–348. doi:10.1038/nrrheum.2011.59

    Article  CAS  PubMed  Google Scholar 

  6. Hoppstadter J, Kessler SM, Bruscoli S, Huwer H, Riccardi C, Kiemer AK (2015) Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin tolerance. J Immunol 194(12):6057–6067. doi:10.4049/jimmunol.1403207

    Article  PubMed  Google Scholar 

  7. Yang N, Zhang W, Shi XM (2008) Glucocorticoid-induced leucine zipper (GILZ) mediates glucocorticoid action and inhibits inflammatory cytokine-induced COX-2 expression. J Cell Biochem 103(6):1760–1771. doi:10.1002/jcb.21562

    Article  CAS  PubMed  Google Scholar 

  8. Berrebi D, Bruscoli S, Cohen N, Foussat A, Migliorati G et al (2003) Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. Blood 101(2):729–738. doi:10.1182/blood-2002-02-0538

    Article  CAS  PubMed  Google Scholar 

  9. Jones SA, Perera DN, Fan H, Russ BE, Harris J, Morand EF (2015) GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation. J Autoimmun 61:73–80. doi:10.1016/j.jaut.2015.05.010

    Article  CAS  PubMed  Google Scholar 

  10. Hamdi H, Godot V, Maillot M-C, Prejean MV, Cohen N et al (2007) Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper. Blood 110(1):211–219. doi:10.1182/blood-2006-10-052506

    Article  CAS  PubMed  Google Scholar 

  11. Cohen N, Mouly E, Hamdi H, Maillot M-C, Pallardy M et al (2006) GILZ expression in human dendritic cells redirects their maturation and prevents antigen-specific T lymphocyte response. Blood 107(5):2037–2044. doi:10.1182/blood-2005-07-2760

    Article  CAS  PubMed  Google Scholar 

  12. Karaki S, Garcia G, Tcherakian C, Capel F, Tran T, Pallardy M, Humbert M, Emilie D, Godot V (2014) Enhanced glucocorticoid-induced leucine zipper in dendritic cells induces allergen-specific regulatory CD4+ T-cells in respiratory allergies. Allergy 69(5):624–631

    Article  CAS  PubMed  Google Scholar 

  13. Fairfax K, Mackay IR, Mackay F (2012) BAFF/BLyS inhibitors: a new prospect for treatment of systemic lupus erythematosus. IUBMB life 64(7):595–602. doi:10.1002/iub.1046

    Article  CAS  PubMed  Google Scholar 

  14. Grondal G, Gunnarsson I, Ronnelid J, Rogberg S, Klareskog L, Lundberg I (2000) Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 18(5):565–570

    CAS  PubMed  Google Scholar 

  15. Crow MK (2014) Type I interferon in the pathogenesis of lupus. J Immunol 192(12):5459–5468. doi:10.4049/jimmunol.1002795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mohammadi S, Sedighi S, Memarian A, Yazdani Y (2017) Overexpression of interferon-γ and indoleamine 2, 3-dioxygenase in systemic lupus erythematosus: relationship with the disease activity. LaboratoriumsMedizin 41(1):41–47

    Article  CAS  Google Scholar 

  17. Yazici MU, Orhan D, Kale G, Besbas N, Ozen S (2014) Studying IFN-gamma, IL-17 and FOXP3 in pediatric lupus nephritis. Pediatr Nephrol 29(5):853–862. doi:10.1007/s00467-013-2695-1

    Article  PubMed  Google Scholar 

  18. Theofilopoulos AN, Koundouris S, Kono DH, Lawson BR (2001) The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity. Arthritis Res 3(3):136–141. doi:10.1186/ar290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hu X, Li WP, Meng C, Ivashkiv LB (2003) Inhibition of IFN-gamma signaling by glucocorticoids. J Immunol 170(9):4833–4839

    Article  CAS  PubMed  Google Scholar 

  20. Delfino DV, Agostini M, Spinicelli S, Vacca C, Riccardi C (2006) Inhibited cell death, NF-kappaB activity and increased IL-10 in TCR-triggered thymocytes of transgenic mice overexpressing the glucocorticoid-induced protein GILZ. Int Immunopharmacol 6(7):1126–1134. doi:10.1016/j.intimp.2006.02.001

    Article  CAS  PubMed  Google Scholar 

  21. Ogden CA, Pound JD, Batth BK, Owens S, Johannessen I, Wood K, Gregory CD (2005) Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma. J Immunol 174(5):3015–3023

    Article  CAS  PubMed  Google Scholar 

  22. Yap DY, Lai KN (2013) The role of cytokines in the pathogenesis of systemic lupus erythematosus—from bench to bedside. Nephrology 18(4):243–255. doi:10.1111/nep.12047

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. General Assembly of the World Medical A (2014) World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Dent Assoc 81(3):14–18

    Google Scholar 

  25. Touma Z, Urowitz MB, Gladman DD (2013) Systemic lupus erythematosus disease activity index 2000 responder index-50 website. J Rheumatol 40(5):733. doi:10.3899/jrheum.130030

    Article  PubMed  Google Scholar 

  26. Memarian A, Nourizadeh M, Masoumi F, Tabrizi M, Emami AH et al (2013) Upregulation of CD200 is associated with Foxp3+ regulatory T cell expansion and disease progression in acute myeloid leukemia. Tumour Biol 34(1):531–542. doi:10.1007/s13277-012-0578-x

    Article  CAS  PubMed  Google Scholar 

  27. Faul F, Erdfelder E, Buchner A, Lang A-G (2009) Statistical power analyses using G* Power 3.1: tests for correlation and regression analyses. Behav Res Methods 41(4):1149–1160

    Article  PubMed  Google Scholar 

  28. Harigai M, Kawamoto M, Hara M, Kubota T, Kamatani N, Miyasaka N (2008) Excessive production of IFN-γ in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B. J Immunol 181(3):2211–2219

    Article  CAS  PubMed  Google Scholar 

  29. Ramamoorthy S, Cidlowski JA (2013) Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance. Endocr Dev 24:41–56. doi:10.1159/000342502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fan H, Morand EF (2012) Targeting the side effects of steroid therapy in autoimmune diseases: the role of GILZ. Discov Med 13(69):123–133

    PubMed  Google Scholar 

  31. Jones SA, Toh AE, Odobasic D, Oudin MA, Cheng Q et al (2016) Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus. Ann Rheum Dis 75(4):739–747. doi:10.1136/annrheumdis-2015-207744

    Article  CAS  PubMed  Google Scholar 

  32. Munroe ME, Young KA, Kamen DL, Guthridge JM, Niewold TB et al (2016) Soluble mediators and clinical features discern risk of transitioning to classified disease in relatives of systemic lupus erythematosus patients. Arthritis Rheum. doi:10.1002/art.40004

  33. Frodl T, Carballedo A, Hughes MM, Saleh K, Fagan A et al (2012) Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder. Transl Psychiat 2:e88. doi:10.1038/tp.2012.14

    Article  CAS  Google Scholar 

  34. Harigai M, Kawamoto M, Hara M, Kubota T, Kamatani N, Miyasaka N (2008) Excessive production of IFN-gamma in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B. J Immunol 181(3):2211–2219

    Article  CAS  PubMed  Google Scholar 

  35. Heinemann K, Wilde B, Hoerning A, Tebbe B, Kribben A et al (2016) Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients. Scand J Rheumatol 45(4):312–316. doi:10.3109/03009742.2015.1126346

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research project is financially supported by Golestan University of Medical Sciences, Gorgan, Iran (Grant Number: 940631161, Code of Ethics: IR.GOUMS.REC.1394.173).

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Authors and Affiliations

  1. Student Research Committee, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Saeed Mohammadi

  2. Student Research Committee, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Mohammad Reza Ebadpour

  3. Joint, Bone and Connective tissue Research Center (JBCRC), Golestan University of Medical Sciences, Gorgan, Iran

    Sima Sedighi

  4. Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Mohsen Saeedi & Ali Memarian

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  1. Saeed Mohammadi
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Correspondence to Ali Memarian.

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Mohammadi, S., Ebadpour, M.R., Sedighi, S. et al. Glucocorticoid-induced leucine zipper expression is associated with response to treatment and immunoregulation in systemic lupus erythematosus. Clin Rheumatol 36, 1765–1772 (2017). https://doi.org/10.1007/s10067-017-3711-9

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  • DOI: https://doi.org/10.1007/s10067-017-3711-9

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