Immunoregulatory Effect of Calcitriol on Experimental Autoimmune Encephalomyelitis (EAE) Mice
Calcitriol Immunoregulatory Effect on EAE
-
Behrouz Robat-Jazi
,
Mona Oraei
,
Sama Bitarafan
,
Seyed Alireza Mesbah-Namin
,
Ali Noori-Zadeh
,
Fatemeh Mansouri
,
Karim Parastouei
,
Ali Anissian
,
Mir Saeed Yekaninejad
,
Ali Akbar Saboor Yaraghi
Abstract
Previous studies noted an imbalance in T helper (Th) 17 and regulatory T cells (Tregs) in experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis animal model. calcitriol, vitamin D's active form, was found to ameliorate EAE symptoms by favoring Tregss over Th17 cells, suggesting immunomodulatory effects. This study aimed to assess calcitriol's impact on EAE manifestations and cytokine profile in mice.
In this study, we recruited twenty-eight C57BL/6 mice and divided them into 4 groups: healthy controls, EAE, EAE with calcitriol treatment, and healthy mice with calcitriol treatment. CD4+ T cells were isolated from splenocytes using magnetic-activated cell sorting. Real-time polymerase chain reaction was employed to quantify the genes associated with Th9 cells (i.e., SPI1 encoding PU.1 and IL9 encoding interleukin [IL]-9). Moreover, the levels of IL-17 and transforming growth factor beta (TGF-β) were evaluated through enzyme-linked immunosorbent assay in the supernatant of CD4+ T cell culture stimulated by anti-CD3 and anti-CD28 antibodies for 72 hours.
In the supernatant of CD4+ T cell cultures, the levels of interleukin-17 (IL-17) were significantly increased, while the levels of transforming growth factor beta (TGF-β) were decreased in the EAE Group compared to the healthy control group. Calcitriol treatment reversed these changes and attenuated EAE symptoms, as confirmed in hematoxylin and eosin, and luxol fast blue stains. Notably, calcitriol increased IL9 gene expression in both EAE and healthy mice.
This study provides further evidence of the anti-inflammatory effects of calcitriol and its role in attenuating EAE.
1. Chakamian K, Robat-Jazi B, Naser Moghadasi A, Mansouri F, Nodehi M, Motevaseli E, et al. Immunosuppressive Effects of Two Probiotics, Lactobacillus paracasei DSM 13434 and Lactobacillus plantarum DSM 15312, on CD4+ T Cells of Multiple Sclerosis Patients. Iran J Allergy Asthma Immunol. 2023;22(1):34-45.
2. Glatigny S, Bettelli E. Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS). Cold Spring Harb Perspect Med. 2018;8(11).
3. Gärtner D, Hoff H, Gimsa U, Burmester GR, Brunner-Weinzierl MC. CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression. J Neuroimmunol. 2006;172(1-2):73-84.
4. Smolders J, Torkildsen Ø, Camu W, Holmøy T. An Update on Vitamin D and Disease Activity in Multiple Sclerosis. CNS Drugs. 2019;33(12):1187-99.
5. Jafarzadeh A, Azizi SV, Nemati M, Khoramdel-Azad H, Shamsizadeh A, Ayoobi F, et al. Ginger Extract Reduces the Expression of IL-17 and IL-23 in the Sera and Central Nervous System of EAE Mice. Iran J Immunol. 2015;12(4):288-301.
6. Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1-13.
7. Jafari Rad M, Navi Z, Heidari AR, Lavi Arab F, Tabasi N, Rastin M, et al. Evaluation of the immunoregulatory effect of Dicrocoelium dendriticum eggs on inflammatory and anti-inflammatory cytokines in EAE model. Parasite Immunol. 2022;44(10):e12942.
8. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9(12):1341-6.
9. Schmitt E, Klein M, Bopp T. Th9 cells, new players in adaptive immunity. Trends Immunol. 2014;35(2):61-8.
10. Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol.. 2010;11(6):527-34.
11. Haghmorad D, Yazdanpanah E, Jadid Tavaf M, Zargarani S, Soltanmohammadi A, Mahmoudi MB, et al. Prevention and treatment of experimental autoimmune encephalomyelitis induced mice with 1, 25-dihydroxyvitamin D(3). Neurol Res. 2019;41(10):943-57.
12. Parastouei K, Mirshafiey A, Eshraghian MR, Shiri-Shahsavar MR, Solaymani-Mohammadi F, Chahardoli R, et al. The effect of 1, 25(OH)2 D3 (calcitriol) alone and in combination with all-trans retinoic acid on ROR-γt, IL-17, TGF-β, and FOXP3 gene expression in experimental autoimmune encephalomyelitis. Nutr Neurosci. 2018;21(3):210-8.
13. Noori-Zadeh A, Mesbah-Namin SA, Saboor-Yaraghi AA. Epigenetic and gene expression alterations of FOXP3 in the T cells of EAE mouse model of multiple sclerosis. J Neurol Sci. 2017;375:203-8.
14. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-81.
15. Yang K, Liu J, Fu S, Tang X, Ma L, Sun W, et al. Vitamin D Status and Correlation with Glucose and Lipid Metabolism in Gansu Province, China. Diabetes Metab Syndr Obes. 2020;13:1555-63.
16. De Pergola G, Martino T, Zupo R, Caccavo D, Pecorella C, Paradiso S, et al. 25 Hydroxyvitamin D Levels are Negatively and Independently Associated with Fat Mass in a Cohort of Healthy Overweight and Obese Subjects. Endocr Metab Immune Disord Drug Targets. 2019;19(6):838-44.
17. Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J. Lean phenotype and resistance to diet-induced obesity in vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocrinology. 2009;150(2):651-61.
18. Marcotorchino J, Tourniaire F, Astier J, Karkeni E, Canault M, Amiot MJ, et al. Vitamin D protects against diet-induced obesity by enhancing fatty acid oxidation. J Nutr Biochem. 2014;25(10):1077-83.
19. Wenclewska S, Szymczak-Pajor I, Drzewoski J, Bunk M, Śliwińska A. Vitamin D Supplementation Reduces Both Oxidative DNA Damage and Insulin Resistance in the Elderly with Metabolic Disorders. Int J Mol Sci. 2019;20(12).
20. Guo YD, Strugnell S, Back DW, Jones G. Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. Proc Natl Acad Sci U S A. 1993;90(18):8668-72.
21. Song Y, Wang L, Pittas AG, Del Gobbo LC, Zhang C, Manson JE, et al. Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care. 2013;36(5):1422-8.
22. Zhang H, Shen Z, Lin Y, Zhang J, Zhang Y, Liu P, et al. Vitamin D receptor targets hepatocyte nuclear factor 4α and mediates protective effects of vitamin D in nonalcoholic fatty liver disease. J Biol Chem. 2020;295(12):3891-905.
23. Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science. 1980;209(4458):823-5.
24. Soares MJ, Pathak K, Calton EK. Calcium and vitamin D in the regulation of energy balance: where do we stand? Int J Mol Sci. 2014;15(3):4938-45.
25. Turner JE, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H, Renauld JC, et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J Exp Med. 2013;210(13):2951-65.
26. Jäger A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009;183(11):7169-77.
27. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(31):12885-90.
28. Yoshimura S, Thome R, Konno S, Mari ER, Rasouli J, Hwang D, et al. IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production. J Immunol. 2020;204(3):531-9.
29. Muls N, Jnaoui K, Dang HA, Wauters A, Van Snick J, Sindic CJ, et al. Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network. J Neuroimmunol. 2012;243(1-2):73-80.
30. Matsushita T, Tateishi T, Isobe N, Yonekawa T, Yamasaki R, Matsuse D, et al. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. PLoS One. 2013;8(4):e61835.
31. Ruocco G, Rossi S, Motta C, Macchiarulo G, Barbieri F, De Bardi M, et al. T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis. Clin Sci (Lond). 2015;129(4):291-303.
32. Kumar N, Lyda B, Chang MR, Lauer JL, Solt LA, Burris TP, et al. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem Biol. 2012;7(4):672-7.
33. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41.
34. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8(5):500-8.
35. Yong VW, Zabad RK, Agrawal S, Goncalves Dasilva A, Metz LM. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci. 2007;259(1-2):79-84.
36. O'Connor RA, Anderton SM. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J Neuroimmunol. 2008;193(1-2):1-11.
37. Yurchenko E, Shio MT, Huang TC, Da Silva Martins M, Szyf M, Levings MK, et al. Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. PLoS One. 2012;7(4):e35572.
38. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54(1):92-9.
39. Palmer MT, Lee YK, Maynard CL, Oliver JR, Bikle DD, Jetten AM, et al. Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells. J Biol Chem. 2011;286(2):997-1004.
40. Urry Z, Chambers ES, Xystrakis E, Dimeloe S, Richards DF, Gabryšová L, et al. The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur J Immunol. 2012;42(10):2697-708.
41. .Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity. 2010;32(5):616-27.
42. .Nanduri R, Mahajan S, Bhagyaraj E, Sethi K, Kalra R, Chandra V, et al. The Active Form of Vitamin D Transcriptionally Represses Smad7 Signaling and Activates Extracellular Signal-regulated Kinase (ERK) to Inhibit the Differentiation of a Inflammatory T Helper Cell Subset and Suppress Experimental Autoimmune Encephalomyelitis. J Biol Chem. 2015;290(19):12222-36.
43. Spach KM, Nashold FE, Dittel BN, Hayes CE. IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol. 2006;177(9):6030-7.
44. Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One. 2009;4(8):e6635.
45. Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS, et al. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol. 2012;188(11):5276-82.
46. Correale J, Ysrraelit MC, Gaitán MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain. 2009;132(Pt 5):1146-60.
47. Farias AS, Spagnol GS, Bordeaux-Rego P, Oliveira CO, Fontana AG, de Paula RF, et al. Vitamin D3 induces IDO+ tolerogenic DCs and enhances Treg, reducing the severity of EAE. CNS Neurosci Ther. 2013;19(4):269-77.
48. Sloka S, Silva C, Wang J, Yong VW. Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. J Neuroinflammation. 2011;8:56.
49. Ahangar-Parvin R, Mohammadi-Kordkhayli M, Azizi SV, Nemati M, Khorramdelazad H, Taghipour Z, et al. The Modulatory Effects of Vitamin D on the Expression of IL-12 and TGF-β in the Spinal Cord and Serum of Mice with Experimental Autoimmune Encephalomyelitis. Iran J Pathol. 2018;13(1):10-22.
50. Soleimani M, Jameie SB, Mehdizadeh M, Keradi M, Masoumipoor M, Mehrabi S. Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis. Iran J Basic Med Sci. 2014;17(10):785-92.
2. Glatigny S, Bettelli E. Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS). Cold Spring Harb Perspect Med. 2018;8(11).
3. Gärtner D, Hoff H, Gimsa U, Burmester GR, Brunner-Weinzierl MC. CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression. J Neuroimmunol. 2006;172(1-2):73-84.
4. Smolders J, Torkildsen Ø, Camu W, Holmøy T. An Update on Vitamin D and Disease Activity in Multiple Sclerosis. CNS Drugs. 2019;33(12):1187-99.
5. Jafarzadeh A, Azizi SV, Nemati M, Khoramdel-Azad H, Shamsizadeh A, Ayoobi F, et al. Ginger Extract Reduces the Expression of IL-17 and IL-23 in the Sera and Central Nervous System of EAE Mice. Iran J Immunol. 2015;12(4):288-301.
6. Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1-13.
7. Jafari Rad M, Navi Z, Heidari AR, Lavi Arab F, Tabasi N, Rastin M, et al. Evaluation of the immunoregulatory effect of Dicrocoelium dendriticum eggs on inflammatory and anti-inflammatory cytokines in EAE model. Parasite Immunol. 2022;44(10):e12942.
8. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9(12):1341-6.
9. Schmitt E, Klein M, Bopp T. Th9 cells, new players in adaptive immunity. Trends Immunol. 2014;35(2):61-8.
10. Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol.. 2010;11(6):527-34.
11. Haghmorad D, Yazdanpanah E, Jadid Tavaf M, Zargarani S, Soltanmohammadi A, Mahmoudi MB, et al. Prevention and treatment of experimental autoimmune encephalomyelitis induced mice with 1, 25-dihydroxyvitamin D(3). Neurol Res. 2019;41(10):943-57.
12. Parastouei K, Mirshafiey A, Eshraghian MR, Shiri-Shahsavar MR, Solaymani-Mohammadi F, Chahardoli R, et al. The effect of 1, 25(OH)2 D3 (calcitriol) alone and in combination with all-trans retinoic acid on ROR-γt, IL-17, TGF-β, and FOXP3 gene expression in experimental autoimmune encephalomyelitis. Nutr Neurosci. 2018;21(3):210-8.
13. Noori-Zadeh A, Mesbah-Namin SA, Saboor-Yaraghi AA. Epigenetic and gene expression alterations of FOXP3 in the T cells of EAE mouse model of multiple sclerosis. J Neurol Sci. 2017;375:203-8.
14. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-81.
15. Yang K, Liu J, Fu S, Tang X, Ma L, Sun W, et al. Vitamin D Status and Correlation with Glucose and Lipid Metabolism in Gansu Province, China. Diabetes Metab Syndr Obes. 2020;13:1555-63.
16. De Pergola G, Martino T, Zupo R, Caccavo D, Pecorella C, Paradiso S, et al. 25 Hydroxyvitamin D Levels are Negatively and Independently Associated with Fat Mass in a Cohort of Healthy Overweight and Obese Subjects. Endocr Metab Immune Disord Drug Targets. 2019;19(6):838-44.
17. Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J. Lean phenotype and resistance to diet-induced obesity in vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocrinology. 2009;150(2):651-61.
18. Marcotorchino J, Tourniaire F, Astier J, Karkeni E, Canault M, Amiot MJ, et al. Vitamin D protects against diet-induced obesity by enhancing fatty acid oxidation. J Nutr Biochem. 2014;25(10):1077-83.
19. Wenclewska S, Szymczak-Pajor I, Drzewoski J, Bunk M, Śliwińska A. Vitamin D Supplementation Reduces Both Oxidative DNA Damage and Insulin Resistance in the Elderly with Metabolic Disorders. Int J Mol Sci. 2019;20(12).
20. Guo YD, Strugnell S, Back DW, Jones G. Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. Proc Natl Acad Sci U S A. 1993;90(18):8668-72.
21. Song Y, Wang L, Pittas AG, Del Gobbo LC, Zhang C, Manson JE, et al. Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care. 2013;36(5):1422-8.
22. Zhang H, Shen Z, Lin Y, Zhang J, Zhang Y, Liu P, et al. Vitamin D receptor targets hepatocyte nuclear factor 4α and mediates protective effects of vitamin D in nonalcoholic fatty liver disease. J Biol Chem. 2020;295(12):3891-905.
23. Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science. 1980;209(4458):823-5.
24. Soares MJ, Pathak K, Calton EK. Calcium and vitamin D in the regulation of energy balance: where do we stand? Int J Mol Sci. 2014;15(3):4938-45.
25. Turner JE, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H, Renauld JC, et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J Exp Med. 2013;210(13):2951-65.
26. Jäger A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009;183(11):7169-77.
27. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(31):12885-90.
28. Yoshimura S, Thome R, Konno S, Mari ER, Rasouli J, Hwang D, et al. IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production. J Immunol. 2020;204(3):531-9.
29. Muls N, Jnaoui K, Dang HA, Wauters A, Van Snick J, Sindic CJ, et al. Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network. J Neuroimmunol. 2012;243(1-2):73-80.
30. Matsushita T, Tateishi T, Isobe N, Yonekawa T, Yamasaki R, Matsuse D, et al. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. PLoS One. 2013;8(4):e61835.
31. Ruocco G, Rossi S, Motta C, Macchiarulo G, Barbieri F, De Bardi M, et al. T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis. Clin Sci (Lond). 2015;129(4):291-303.
32. Kumar N, Lyda B, Chang MR, Lauer JL, Solt LA, Burris TP, et al. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem Biol. 2012;7(4):672-7.
33. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41.
34. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8(5):500-8.
35. Yong VW, Zabad RK, Agrawal S, Goncalves Dasilva A, Metz LM. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci. 2007;259(1-2):79-84.
36. O'Connor RA, Anderton SM. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J Neuroimmunol. 2008;193(1-2):1-11.
37. Yurchenko E, Shio MT, Huang TC, Da Silva Martins M, Szyf M, Levings MK, et al. Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. PLoS One. 2012;7(4):e35572.
38. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54(1):92-9.
39. Palmer MT, Lee YK, Maynard CL, Oliver JR, Bikle DD, Jetten AM, et al. Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells. J Biol Chem. 2011;286(2):997-1004.
40. Urry Z, Chambers ES, Xystrakis E, Dimeloe S, Richards DF, Gabryšová L, et al. The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur J Immunol. 2012;42(10):2697-708.
41. .Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity. 2010;32(5):616-27.
42. .Nanduri R, Mahajan S, Bhagyaraj E, Sethi K, Kalra R, Chandra V, et al. The Active Form of Vitamin D Transcriptionally Represses Smad7 Signaling and Activates Extracellular Signal-regulated Kinase (ERK) to Inhibit the Differentiation of a Inflammatory T Helper Cell Subset and Suppress Experimental Autoimmune Encephalomyelitis. J Biol Chem. 2015;290(19):12222-36.
43. Spach KM, Nashold FE, Dittel BN, Hayes CE. IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol. 2006;177(9):6030-7.
44. Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One. 2009;4(8):e6635.
45. Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS, et al. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol. 2012;188(11):5276-82.
46. Correale J, Ysrraelit MC, Gaitán MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain. 2009;132(Pt 5):1146-60.
47. Farias AS, Spagnol GS, Bordeaux-Rego P, Oliveira CO, Fontana AG, de Paula RF, et al. Vitamin D3 induces IDO+ tolerogenic DCs and enhances Treg, reducing the severity of EAE. CNS Neurosci Ther. 2013;19(4):269-77.
48. Sloka S, Silva C, Wang J, Yong VW. Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. J Neuroinflammation. 2011;8:56.
49. Ahangar-Parvin R, Mohammadi-Kordkhayli M, Azizi SV, Nemati M, Khorramdelazad H, Taghipour Z, et al. The Modulatory Effects of Vitamin D on the Expression of IL-12 and TGF-β in the Spinal Cord and Serum of Mice with Experimental Autoimmune Encephalomyelitis. Iran J Pathol. 2018;13(1):10-22.
50. Soleimani M, Jameie SB, Mehdizadeh M, Keradi M, Masoumipoor M, Mehrabi S. Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis. Iran J Basic Med Sci. 2014;17(10):785-92.
| Files | ||
| Issue | Vol 22 No 5 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i5.13995 | |
| Keywords | ||
| Calcitriol Experimental autoimmune encephalomyelitis IL-9 IL-17 Transforming growth factor beta Th9 Cells | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Robat-Jazi B, Oraei M, Bitarafan S, Mesbah-Namin SA, Noori-Zadeh A, Mansouri F, Parastouei K, Anissian A, Yekaninejad MS, Saboor Yaraghi AA. Immunoregulatory Effect of Calcitriol on Experimental Autoimmune Encephalomyelitis (EAE) Mice. Iran J Allergy Asthma Immunol. 2023;22(5):452-467.
