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1,25-Dihydroxyvitamin D3 modulates T cell differentiation and impacts on the production of cytokines from Chinese Han patients with early rheumatoid arthritis

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Abstract

To study the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the differentiation of T cells and the levels of cytokines in patients with early rheumatoid arthritis (eRA). The levels of Th1, Th2, Th17, and Treg cells were detected with BDFACS Calibur flow cytometer. The expression of IFN-ɤ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17, and IL-22 was examined in 54 patients with eRA using a cytometric bead array (CBA). After 72 h of incubation of PBMCs from eRA patients with 1,25(OH)2D3, the levels of IFN-ɤ, TNF-α, IL-2, IL-6, and IL-17 significantly decreased compared to those of the control. 1,25(OH)2D3 had no significantly impact on the levels of IL-4, IL-10, and IL-22. The proportion of Th17 and the ratio of Th17/Treg significantly decreased in 1,25(OH)2D3-treated groups compared to those of the control. 1,25(OH)2D3 had no significantly impact on the proportion of Th1, Th2, Treg, and the ratio of Th1/Th2. Although no statistically significant difference was observed, proportion of Th1 was decreased after 1,25(OH)2D3 treatment compared with anti-CD3/CD28 only. The present study demonstrated that 1,25(OH)2D3 inhibited the synthesis of specific cytokines: Th1 (IFN-ɤ) and Th17 (IL-17, IL-22, IL-6, TNF-α) might upregulated Th2 cytokine (IL-4), which indicated the possible immunoregulatory roles and bone-sparing effects of 1,25(OH)2D3 in eRA through modulation of the Th1 and Th17 cytokine balance.

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References

  1. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023–38.

    Article  CAS  PubMed  Google Scholar 

  2. Wen H, Baker JF. Vitamin D immunoregulation, and rheumatoid arthritis. J Clin Rheumatol. 2011;17:102–7.

    Article  PubMed  Google Scholar 

  3. Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999;265:144–50.

    Article  CAS  PubMed  Google Scholar 

  4. Choi Y, Woo KM, Ko SH, Lee YJ, Park SJ, Kim HM, et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8(+) T cells. Eur J Immunol. 2001;31:2179–88.

    Article  CAS  PubMed  Google Scholar 

  5. Dai SM, Matsuno H, Nakamura H, Nishioka K, Yudoh K. Interleukin-18 enhances monocyte tumor necrosis factor alpha and interleukin-1beta production induced by direct contact with T lymphocytes: implications in rheumatoid arthritis. Arthritis Rheum. 2004;50:432–43.

    Article  CAS  PubMed  Google Scholar 

  6. Rosen Y, Daich J, Soliman I, Brathwaite E, Shoenfeld Y. Vitamin D and autoimmunity. Scand J Rheumatol. 2016;45:439–47.

    Article  CAS  PubMed  Google Scholar 

  7. Gardner DH, Jeffery LE, Soskic B, Briggs Z, Hou TZ, Raza K, et al. 1,25(OH)2D3 promotes the efficacy of CD28 costimulation blockade by abatacept. J Immunol. 2015;195:2657–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jekic B, Vejnovic D, Milic V, Maksimovic N, Damnjanovic T, Bunjevacki V, et al. Association of 63/91 length polymorphism in the DHFR gene major promoter with toxicity of methotrexate in patients with rheumatoid arthritis. Pharmacogenomics. 2016;17:1687–91.

    Article  CAS  PubMed  Google Scholar 

  9. Kremer JM, Lawrence DA, Hamilton R, McInnes IB. Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures. RMD Open. 2016;2:e000287.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.

    Article  CAS  PubMed  Google Scholar 

  11. Kim KW, Kim HR, Park JY, Park JS, Oh HJ, Woo YJ, et al. Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts. Arthritis Rheum. 2012;64:1015–23.

    Article  CAS  PubMed  Google Scholar 

  12. Luo J, Wen H, Guo H, Cai Q, Li S, Li X. 1,25-dihydroxyvitamin D3 inhibits the RANKL pathway and impacts on the production of pathway-associated cytokines in early rheumatoid arthritis. Biomed Res Int. 2013;2013:101805.

    PubMed  PubMed Central  Google Scholar 

  13. Janssen KM, Westra J, Chalan P, Boots AM, de Smit MJ, van Winkelhoff AJ, et al. Regulatory CD4+ T-cell subsets and anti-citrullinated protein antibody repertoire: potential biomarkers for arthritis development in seropositive arthralgia patients? PLoS One. 2016;11:e0162101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Rantapaa Dahlqvist S. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 2010;62:383–91.

    CAS  PubMed  Google Scholar 

  15. Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int. 2012;32:887–93.

    Article  CAS  PubMed  Google Scholar 

  16. Buondonno I, Rovera G, Sassi F, Rigoni MM, Lomater C, Parisi S, et al. Vitamin D and immunomodulation in early rheumatoid arthritis: a randomized double-blind placebo-controlled study. PLoS One. 2017;12:e0178463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ishikawa LL, Colavite PM, Fraga-Silva TF, Mimura LA, Franca TG, Zorzella-Pezavento SF, et al. Vitamin D deficiency and rheumatoid arthritis. Clin Rev Allergy Immunol. 2017;52:373–388.

  18. Mattner F, Smiroldo S, Galbiati F, Muller M, Di Lucia P, Poliani PL, et al. Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D(3). Eur J Immunol. 2000;30:498–508.

    Article  CAS  PubMed  Google Scholar 

  19. Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167:4974–80.

    Article  CAS  PubMed  Google Scholar 

  20. Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther. 2008;324:23–33.

    Article  CAS  PubMed  Google Scholar 

  21. Cutolo M, Otsa K, Laas K, Yprus M, Lehtme R, Secchi ME, et al. Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: northern versus southern Europe. Clin Exp Rheumatol. 2006;24:702–4.

    CAS  PubMed  Google Scholar 

  22. Haque UJ, Bartlett SJ. Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:745–7.

    CAS  PubMed  Google Scholar 

  23. Hong Q, Xu J, Xu S, Lian L, Zhang M, Ding C. Associations between serum 25-hydroxyvitamin D and disease activity, inflammatory cytokines and bone loss in patients with rheumatoid arthritis. Rheumatology (Oxford). 2014;53:1994–2001.

    Article  CAS  Google Scholar 

  24. Sharma R, Saigal R, Goyal L, Mital P, Yadav RN, Meena PD, et al. Estimation of vitamin D levels in rheumatoid arthritis patients and its correlation with the disease activity. J Assoc Physicians India. 2014;62:678–81.

    PubMed  Google Scholar 

  25. Rajaee E, Ghorbani A, Mowla K, Zakerkish M, Mohebi M, Dargahi-Malamir M. The relationship between serum level of vitamin D3 and the severity of new onset rheumatoid arthritis activity. J Clin Diagn Res. 2017;11:OC28–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Salesi M, Farajzadegan Z. Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Rheumatol Int. 2012;32:2129–33.

    Article  CAS  PubMed  Google Scholar 

  27. Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T, et al. IL-1beta and TNFalpha-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol. 2011;23:701–12.

    Article  CAS  PubMed  Google Scholar 

  28. Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, et al. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum. 2002;46:3143–50.

    Article  CAS  PubMed  Google Scholar 

  29. Jiang Y, Genant HK, Watt I, Cobby M, Bresnihan B, Aitchison R, et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum. 2000;43:1001–9.

    Article  CAS  PubMed  Google Scholar 

  30. Buch MH, Bingham SJ, Bryer D, Emery P. Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders. Rheumatology (Oxford). 2007;46:1153–6.

    Article  CAS  Google Scholar 

  31. Hajjaj-Hassouni N, Mawani N, Allali F, Rkain H, Hassouni K, Hmamouchi I, et al. Evaluation of vitamin D status in rheumatoid arthritis and its association with disease activity across 15 countries: “the COMORA study”. Int J Rheumatol. 2017;2017:5491676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in Autoimmunity: Molecular mechanisms and therapeutic potential. Front Immunol. 2016;7:697.

    PubMed  Google Scholar 

  33. Franco AS, Freitas TQ, Bernardo WM, Pereira RMR. Vitamin D supplementation and disease activity in patients with immune-mediated rheumatic diseases: a systematic review and meta-analysis. Medicine (Baltimore). 2017;96:e7024.

    Article  CAS  Google Scholar 

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Acknowledgments

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication, and took responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: Hong-yan Wen. Acquisition of data: Hong-yan Wen, Jing Luo, Xiao-feng Li, Dan-dan Wei, and Yang Liu. Analysis and interpretation of data: Hong-yan Wen. Manuscript preparation: Hong-yan Wen. Statistical analysis: Hong-yan Wen. The authors thank Dr. Alexis Ogdie for reviewing the manuscript.

Funding

This study was supported by research grants from the National Nature Science Foundation of China (no.81301532/H0603), Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province-2017, the Shanxi Science and Technology Research Projects of China (no. 201603D321074), and the Shanxi Scholarship Council of China (2017-119).

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Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, Shanxi Medical University, the Second Hospital of Shanxi Medical University, 56 South Xinjian Road, Taiyuan, Shanxi Province, China

    Hong-yan Wen, Jing Luo, Xiao-feng Li, Dan-dan Wei & Yang Liu

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  1. Hong-yan Wen
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  2. Jing Luo
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  3. Xiao-feng Li
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  4. Dan-dan Wei
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  5. Yang Liu
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Corresponding author

Correspondence to Hong-yan Wen.

Ethics declarations

The study was approved by the Research Ethics Committee of the Second Hospital of Shanxi Medical University and conducted in accordance with the Declaration of Helsinki (approval number 2013ky007).

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The authors declare that they have no conflicts of interest.

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Wen, Hy., Luo, J., Li, Xf. et al. 1,25-Dihydroxyvitamin D3 modulates T cell differentiation and impacts on the production of cytokines from Chinese Han patients with early rheumatoid arthritis. Immunol Res 67, 48–57 (2019). https://doi.org/10.1007/s12026-018-9033-4

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  • DOI: https://doi.org/10.1007/s12026-018-9033-4

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