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.
Vitamin D Rheumatoid arthritis T cells Cytokines Chinese Han
This is a preview of subscription content, log in to check access.
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.
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).
Compliance with ethical standards
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).
Conflict of interest
The authors declare that they have no conflicts of interest.
Wen H, Baker JF. Vitamin D immunoregulation, and rheumatoid arthritis. J Clin Rheumatol. 2011;17:102–7.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Rosen Y, Daich J, Soliman I, Brathwaite E, Shoenfeld Y. Vitamin D and autoimmunity. Scand J Rheumatol. 2016;45:439–47.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
Haque UJ, Bartlett SJ. Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:745–7.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
Salesi M, Farajzadegan Z. Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Rheumatol Int. 2012;32:2129–33.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in Autoimmunity: Molecular mechanisms and therapeutic potential. Front Immunol. 2016;7:697.Google Scholar
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.CrossRefGoogle Scholar