International Urology and Nephrology

, Volume 42, Issue 1, pp 181–185 | Cite as

Paricalcitol reduces basal and lipopolysaccharide-induced (LPS) TNF-α and IL-8 production by human peripheral blood mononuclear cells

  • Theodoros Eleftheriadis
  • Georgia Antoniadi
  • Vassilios Liakopoulos
  • Charalambos Kartsios
  • Ioannis Stefanidis
  • Grammati Galaktidou
Nephrology - Original Paper



Vitamin D and its analogues proved to exert immunomodulatory effects. Paricalcitol is a vitamin D analogue that is safe. It has been used for years in the treatment of secondary hyperparathyroidism in hemodialysis patients and, importantly, it is less calcemic than vitamin D. In this study the immunomodulatory/anti-inflammatory properties of paricalcitol were evaluated in vitro.

Subject and methods

Ten healthy volunteers enrolled into the study. Peripheral blood mononuclear cells (PBMC) at a concentration of 106 cells per well were cultured for 48 h in the presence or not of lipopolysaccharide (LPS) (100 ng/ml) and in the presence or not of paricalcitol (10−8 M). TNF-α and IL-8 were measured in the supernatants by ELISA.


Basal TNF-α concentration (50.3 ± 22 pg/ml) was reduced by paricalcitol (44.1 ± 23.2 pg/ml). LPS increased TNF-α concentration (150.0 ± 81.7 pg/ml), but paricalcitol reduced it (121.1 ± 69.0 pg/ml). The effect of paricalcitol on IL-8 production was more profound. Basal IL-8 concentration (1926 ± 455 pg/ml) was reduced by paricalcitol (1273 ± 472 pg/ml). LPS increased IL-8 concentration (2361 ± 385 pg/ml), but paricalcitol returned it to its basal level (1849 ± 417 pg/ml).


The in vitro inhibition of transforming growth factor alpha and interleukin 8 by paricalcitol confirms the immunomodulatory properties of this vitamin D analogue.


Cytokine inhibition Healthy volunteers Immunomodulatory effects Paricalcitol Vitamin D analogues 


  1. 1.
    Haussler MR, Whitfield GK, Haussler CA et al (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 13(3):325–349. doi: 10.1359/jbmr.1998.13.3.325 CrossRefPubMedGoogle Scholar
  2. 2.
    Mathieu C, Adorini L (2002) The coming of age of 1,25-dihydroxyvitamin D3 analogs as immunomodulatory agents. Trends Mol Med 8(4):174–179. doi: 10.1016/S1471-4914(02)02294-3 CrossRefPubMedGoogle Scholar
  3. 3.
    Jahnsen J, Falch JA, Mowinckel P, Aadland E (2002) Vitamin D status, parathyroid hormone and bone mineral density in patients with inflammatory bowel disease. Scand J Gastroenterol 37:192–199. doi: 10.1080/003655202753416876 CrossRefPubMedGoogle Scholar
  4. 4.
    Nieves J, Cosman F, Herbert J, Shen V, Lindsay R (1994) High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology 44:1687–1692PubMedGoogle Scholar
  5. 5.
    Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS (2006) Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 5:114–117. doi: 10.1016/j.autrev.2005.05.009 CrossRefPubMedGoogle Scholar
  6. 6.
    Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358:1500–1503. doi: 10.1016/S0140-6736(01)06580-1 CrossRefPubMedGoogle Scholar
  7. 7.
    Aguado P, del Campo MT, Garces MV et al (2000) Low vitamin D levels in outpatient postmenopausal women from a rheumatology clinic in Madrid, Spain: their relationship with bone mineral density. Osteoporos Int 11:739–744. doi: 10.1007/s001980070052 CrossRefPubMedGoogle Scholar
  8. 8.
    Cantorna MT, Munsick C, Bemiss C, Mahon BD (2000) Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J Nutr 130(11):2648–2652PubMedGoogle Scholar
  9. 9.
    Lemire JM, Archer DC (1991) 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest 87(3):1103–1107. doi: 10.1172/JCI115072 CrossRefPubMedGoogle Scholar
  10. 10.
    Lemire JM, Ince A, Takashima M (1992) 1,25-Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice. Autoimmunity 12(2):143–148. doi: 10.3109/08916939209150321 CrossRefPubMedGoogle Scholar
  11. 11.
    Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R (1994) Prevention of autoimmune diabetes in NOD mice by 1,25-dihydroxyvitamin D3. Diabetologia 37(6):552–558. doi: 10.1007/BF00403372 CrossRefPubMedGoogle Scholar
  12. 12.
    Larsson P, Mattsson L, Klareskog L, Johnsson C (1998) A Vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia. Clin Exp Immunol 114(2):277–283. doi: 10.1046/j.1365-2249.1998.00706.x CrossRefPubMedGoogle Scholar
  13. 13.
    Branisteanu DD, Leenaerts P, van Damme B, Bouillon R (1993) Partial prevention of active Heymann nephritis by 1-alpha,25-dihydroxyvitamin D3. Clin Exp Immunol 94(3):412–417PubMedCrossRefGoogle Scholar
  14. 14.
    Redaelli CA, Wagner M, Gunter-Duwe D et al (2002) 1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants. Kidney Int 61(1):288–296. doi: 10.1046/j.1523-1755.2002.00101.x CrossRefPubMedGoogle Scholar
  15. 15.
    Redaelli CA, Wagner M, Tien YH et al (2001) 1-alpha,25-Dihydroxycholecalciferol reduces rejection and improves survival in rat liver allografts. Hepatology 34(5):926–934. doi: 10.1053/jhep.2001.28705 CrossRefPubMedGoogle Scholar
  16. 16.
    Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L (2001) Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol 167(4):1945–1953PubMedGoogle Scholar
  17. 17.
    Hullett DA, Cantorna MT, Redaelli C et al (1998) Prolongation of allograft survival by 1,25-dihydroxyvitamin D3. Transplantation 66(7):824–828. doi: 10.1097/00007890-199810150-00002 CrossRefPubMedGoogle Scholar
  18. 18.
    Cantorna MT, Hullett DA, Redaelli C et al (1998) 1,25-Dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density. Transplantation 66(7):828–831. doi: 10.1097/00007890-199810150-00003 CrossRefPubMedGoogle Scholar
  19. 19.
    van Etten E, Mathieu C (2005) Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 97(1–2):93–101. doi: 10.1016/j.jsbmb.2005.06.002 CrossRefPubMedGoogle Scholar
  20. 20.
    Muller K, Haahr PM, Diamant M, Rieneck K, Kharazmi A, Bendtzen K (1992) 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level. Cytokine 4:506–512. doi: 10.1016/1043-4666(92)90012-G CrossRefPubMedGoogle Scholar
  21. 21.
    Cohen ML, Douvdevani A, Chaimovitz C, Shany S (2001) Regulation of TNF-alpha by 1alpha,25-dihydroxyvitamin D3 in human macrophages from CAPD patients. Kidney Int 59:69–75. doi: 10.1046/j.1523-1755.2001.00467.x CrossRefPubMedGoogle Scholar
  22. 22.
    Xu H, Soruri A, Gieseler RK, Peters JH (1993) 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 38(6):535–540. doi: 10.1111/j.1365-3083.1993.tb03237.x CrossRefPubMedGoogle Scholar
  23. 23.
    Lindberg J, Martin KJ, Gonzalez EA, Acchiardo SR, Valdin JR, Soltanek C (2001) A long-term, multicenter study of the efficacy and safety of paricalcitol in end-stage renal disease. Clin Nephrol 56(4):315–323PubMedGoogle Scholar
  24. 24.
    Llach F, Yudd M (2001) Paricalcitol in dialysis patients with calcitriol resistant secondary hyperparathyroidism. Am J Kidney Dis 38(5 Suppl 5):S45–S50. doi: 10.1053/ajkd.2001.28114 Google Scholar
  25. 25.
    Gannagé-Yared MH, Azoury M, Mansour I, Baddoura R, Halaby G, Naaman R (2003) Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy post-menopausal women. J Endocrinol Invest 26(8):748–753PubMedGoogle Scholar
  26. 26.
    Product information: ZemplarTM, paricalcitol (1998) Abbott Laboratories, North Chicago, ILGoogle Scholar
  27. 27.
    Aggarwal BB, Samanta A, Feldmann M (2000) TNFα. In: Oppenheim JJ, Feldman M (eds) Cytokine reference, 2nd edn. Academic Press, New YorkGoogle Scholar
  28. 28.
    Larsen CG, Kristensen M, Paludan K et al (1991) 1,25(OH)2-D3 is a potent regulator of interleukin-1 induced interleukin-8 expression and production. Biochem Biophys Res Commun 176(3):1020–1026. doi: 10.1016/0006-291X(91)90384-J CrossRefPubMedGoogle Scholar
  29. 29.
    Takahashi K, Horiuchi H, Ohta T, Komoriya K, Ohmori H, Kamimura T (2002) 1 alpha,25-dihydroxyvitamin D3 suppresses interleukin-1beta-induced interleukin-8 production in human whole blood: an involvement of erythrocytes in the inhibition. Immunopharmacol Immunotoxicol 24(1):1–15. doi: 10.1081/IPH-120003399 CrossRefPubMedGoogle Scholar
  30. 30.
    Lizasa H, Matsushima K (2000) IL-8. In: Oppenheim JJ, Feldman M (eds) Cytokine reference, 2nd edn. Academic Press, New YorkGoogle Scholar
  31. 31.
    Spasovski GB (2007) Bone health and vascular calcification relationships in chronic kidney disease. Int Urol Nephrol 39(4):1209–1216. doi: 10.1007/s11255-007-9276-9 CrossRefPubMedGoogle Scholar
  32. 32.
    Gelev S, Spasovski G, Dzikova S et al (2008) Vascular calcification and atherosclerosis in hemodialysis patients: what can we learn from the routine clinical practice? Int Urol Nephrol 40(3):763–770. doi: 10.1007/s11255-008-9379-y CrossRefPubMedGoogle Scholar
  33. 33.
    Alborzi P, Patel NA, Peterson C et al (2008) Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 52(2):249–255. doi: 10.1161/HYPERTENSIONAHA.108.113159 CrossRefPubMedGoogle Scholar
  34. 34.
    Tan X, Wen X, Liu Y (2008) Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol 19(9):1741–1752. doi: 10.1681/ASN.2007060666 CrossRefPubMedGoogle Scholar
  35. 35.
    Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C (1999) Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55(2):648–658. doi: 10.1046/j.1523-1755.1999.00273.x CrossRefPubMedGoogle Scholar
  36. 36.
    Eleftheriadis T, Antoniadi G, Liakopoulos V, Kartsios C, Stefanidis I (2007) Disturbances of acquired immunity in hemodialysis patients. Semin Dial 20(5):440–451. doi: 10.1111/j.1525-139X.2007.00283.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, B.V. 2009

Authors and Affiliations

  • Theodoros Eleftheriadis
    • 1
    • 2
  • Georgia Antoniadi
    • 2
  • Vassilios Liakopoulos
    • 3
  • Charalambos Kartsios
    • 1
  • Ioannis Stefanidis
    • 3
  • Grammati Galaktidou
    • 1
  1. 1.Research Institute, Theagenion Anticancer HospitalThessalonikiGreece
  2. 2.Department of NephrologyGeneral Hospital of SerresSerresGreece
  3. 3.Department of NephrologyUniversity Hospital of LarissaLarissaGreece

Personalised recommendations