Skip to main content
SpringerLink
Log in

Calcitriol effect on natural killer cells from hemodialyzed and normal subjects

  • Clinical Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Patients with chronic renal failure have a decreased secretion of calcitriol (CTR). They also show an impaired cellular immune response including a defective natural killer (NK) cell-mediated activity. The aim of this study was to analyze, in vivo and in vitro, the effect of CTR on NK cell cytotoxicity in healthy control subjects and in hemodialyzed (HD) patients. Our results show that HD patients had baseline-depressed NK cell activity when compared with controls (P<0.001), which increased significantly after 1 month of oral CTR treatment (0.5 μg/day) (P<0.001). Calcitriol treatment also induced a significant increase in CTR serum levels (P<0.001) and a significant decrease (P<0.001) in total parathyroid hormone (PTH). In vitro CTR treatment (10-7 M) of peripheral blood mononuclear cells (PBMC) increased NK cell-mediated cytotoxicity after 24 hours of incubation with a maximum at 48 hours (P<0.001). In vitro CTR treatment at doses of 10-11 and 10-9 M did not significantly increase NK cytotoxic activity. The enhanced NK activity after CTR treatment was not the consequence of increased numbers of CD56 positive cells, nor to lymphocyte activation, as tested by the expression of the interleukin 2 receptor p55 α chain (CD25) on their surface. In vitro treatment of PBMC from HD patients with CTR (10-7 M, during 48 hours) also induced a strong increase in NK cell cytotoxicity (P<0.001). These results demonstrate a positive role of CTR in the stimulation of NK cell activity and support the hypothesis of a direct steroid-mediated action of CTR on NK cells, although an indirect effect mediated by the CTR-induced PTH decrease in vivo cannot be excluded. Our data also raise the possibility for potential therapeutic uses of this hormone in immunomodulation of patients with depressed NK cell activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Solana R, Peña J (eds) (1994) NK cells and MHC antigens, R G Landes Company, Austin, TX

    Google Scholar 

  2. Borrego F, Peña J, Solana R (1993) Regulation of CD69 expression on human NK cells: differential involvement of protein kinase C and protein tyrosine kinases. Eur J Immunol 23:1039–1043

    Google Scholar 

  3. Ritz J (1989) The role of natural killer cells in immune surveillance. N Engl J Med 320:1748–1749

    Google Scholar 

  4. Kurz P, Köler H, Meuer S, Hütteroth T, Büchenfelde KHM (1986) Impaired cellular immune responses in chronic renal failure: evidence for a T cell defect. Kidney Int 29:1209–1214

    Google Scholar 

  5. Asaka M, Iida H, Izumino K, Sasayama S (1988) Depressed natural killer cell activity in uremia. Evidence for immunosuppressive factor in uremic sera. Nephron 49:291–295

    Google Scholar 

  6. Kamata K, Okubo M, Sada M (1983) Immunosuppressive factors in uraemic sers are composed of both dialysable and nondialysable components. Clin Exp Immunol 54:277–281

    Google Scholar 

  7. Kai NE, Raij LE (1987) Differential effect of hemodialysis membranes on human lymphocyte natural killer function. Artif Organ 11:165–167

    Google Scholar 

  8. Zaoui P, Hakin RM (1993) Natural killer-cell function in hemodialysis patients: effect of dialysis membrane. Kidney Int 43: 1298–1305

    Google Scholar 

  9. Reichel H, Koeffler HP, Norman AW (1989) The role of the vitamin D endocrine system in health and disease. N Engl J Med 320:980–991

    Google Scholar 

  10. Braidman IP, Anderson DC (1985) Extraendocrine functions of vitamin D. Clin Endocrinol 23:445–460

    Google Scholar 

  11. Provedini DM, Tsoukas CD, Deftos LJ, Manolangas SC (1983) 1,25 dihydroxyvitamin D3 receptors in human leukocytes. Science 221:1181–1183

    Google Scholar 

  12. Bhalla AK, Amento EP, Clemens EL, Holick MF, Krame SM (1983) Specific high-affinity receptors for 1,25 dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab 57:1308–1310

    Google Scholar 

  13. Fagan DL, Adams JS, Becker T, Lemire JM (1991) Inhibition by 1,25-dihydroxyvitamin D3, of interleukin 2 stimulated human natural killer cells. In: Norman AW, Bouillon R, Thomasset M (eds) Vitamin D. Gene regulation, structure function analysis and clinical application. Walter de Gruyter, Berlin, pp 492–493

    Google Scholar 

  14. Tsoukas CD, Provvedini DM, Manolagas SC (1984) 1,25 dihydroxy vitamin D3: a novel immunoregulatory hormone. Science 224:1438–1440

    Google Scholar 

  15. Feinfeld DA, Sherwood LM (1988) Parathyroid hormone and 1,25(OH)2D3 in chronic renal failure. Kidney Int 33:1049–1058

    Google Scholar 

  16. Quesada JM, Solana R, Serrano I, Barrio V, Martinez ME, Santamaria M, Martin A, Peña J (1990) Immunologic effects of vitamin D. N Engl J Med 321:833–834

    Google Scholar 

  17. Quesada JM, Solana R, Martin M, Santamaria M, Serrano I, Martinez ME, Peña J (1989) The effect of calcitriol on natural killer cell activity in hemodialyzed patients. J Steroid Biochem 34:425–432

    Google Scholar 

  18. Reinhart TA, Horst RL, Orf JW, Hollis BW (1984) A microassay for 1,25 dihydroxyvitamin D not requiring high performance liquid chromatography. J Clin Endocrinol Metab 58:91–98

    Google Scholar 

  19. Serrano R, Solana R, Alonso MC, Monserrat J, Muñoz J, Peña J (1988) Identification of a tumor factor inducing resistance to NK mediated lysis. Immun Lett 20:311–316

    Google Scholar 

  20. Merkel J, Hugel U, Zlotkowski A, Szabo A, Bommer J, Mall G, et al. (1987) Diminished parathyroid 1,25(OH)2D3 receptors in experimental uremia. Kidney Int 32:350–353

    Google Scholar 

  21. Korkor AB (1987) Reduced binding of (3H)1,25-dihydroxyvitamin D3 in patients with renal failure. N Engl J Med 316:1573–1577

    Google Scholar 

  22. Slatopolsky E, Lopez-Hilker, Delmez J, Dusso A, Brown A, Martin KJ (1990) The parathyroid-calcitriol axis in health and chronic renal failure. Kidney Int 38:S41–47

    Google Scholar 

  23. Quesada JM, Coopmans W, Ruiz P, Aljama P, Jans I, Bouillon R (1992) Influence of vitamin D on parathyroid function in the elderly. J Clin Endocrinol Metab 75:494–501

    Google Scholar 

  24. Perry HM, Chappel JC, Bellorin-Font E, Tamao J, Martin KJ (1984) Parathyroid hormone receptors in circulating human mononuclear leukocytes. J Biol Chem 259:5531–5535

    Google Scholar 

  25. Elias AN, Sharma BS, Valenta LJ, Kyaw T (1988) Immunomodulatory effect of bovine PTH extract on lymphocytic response to plants mitogens. J Med 10:109–117

    Google Scholar 

  26. Shasha SM, Kristal B, Barzilai M, Makov VE, Shkolnik T (1988) In vitro effect of PTH on normal T cell function. Nephron 56:212–216

    Google Scholar 

  27. Doherty CC, Labelle P, Collins JF, Brautbar N, Massry SG (1989) Effect of parathyroid hormone on random migration of human polymorphonuclear leukocytes. Am J Nephrol 8:212–219

    Google Scholar 

  28. Giacchino F, Quattrocchio G, Picoli G (1984) Parathyroid hormone as a uremic toxin: its influence on T lymphocyte receptors. Clin Nephrol 19:105–106

    Google Scholar 

  29. Shasha SM, Kristal B, Steimberg O, Shkolnik T (1989) Effect of parathyroidectomy on T cell functions in patients with primary hyperparathyroidism. Am J Nephrol 9:25–29

    Google Scholar 

  30. Walters M (1992) Newly identified actions of the vitamin D endocrine system. Endocrinol Rev 13:719–764

    Google Scholar 

  31. Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH (1986) The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 136:4480–4486

    Google Scholar 

  32. Amento EP, Bhalla AK, Kurnick JT, Kradin RL, Clemens TL, Holick SA, et al., (1984) 1α25-dihydroxyvitamin D3 induces maturation of the human monocyte cell U937 and in association with a factor from human lymphocytes augments production of the monokine mononuclear cell factors. J Clin Invest 73:731–739

    Google Scholar 

  33. Herman J, Dinarello CA, Kew MC, Rabson AR (1985) The role of interleukin 1 (IL 1) in tumor NK cell interactions: correction of defective NK cell activity in cancer patients by treating target cells with IL 1. J Immunol 135:2882–2886

    Google Scholar 

  34. Manolangas SC, Provvedini EJ, Murray CD, Tsoukas CD, Deftos LJ (1986) The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. J Clin Endocrinol Metab 63:394–400

    Google Scholar 

  35. Lemire JM, Adams JS, Sakai R, Jordan SC (1984) 1,25 dihydroxy vitamin D3 suppresses proliferation and immunoglobulin production by human peripheral blood mononuclear cells. J Clin Invest 74:657–661

    Google Scholar 

  36. Tabata T, Suzuki R, Kikunami K, Matsushita Y, Inoue T, Okamoto T, Miki T, Nishizawa Y, Morii H (1986) The effect of 1α-hydroxyvitamin D3 on cell-mediated immunity in hemodialyzed patients. J Clin Endocrinol 63:1218–1221

    Google Scholar 

  37. Tabata T, Shoji T, Kikunami K, Matsushita Y, Inoue T, Tanaka S, Hino M, Miki T, Nishizawa Y, Morii H (1988) In vivo effect of 1α-hydroxyvitamin D3 on Interleukin-2 production in hemodialysis patients. Nephron 50:295–298

    Google Scholar 

  38. Dennert G (1985) Mechanism of cell-mediated cytolysis by natural killer cells. Surv Synth Pathol Res 4:69–74

    Google Scholar 

  39. Young JD, Leong GL, Chau Ching L, Damiano A, Cohn ZA (1986) Extracellular release of lymphocyte cytolytic pore forming +protein (perforin) after ionophore stimulation. J Exp Med 83:5668–5673

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unidad de Metabolismo Mineral and Servicio de Inmunologia, Hospital Universitario Reina Sofia, AVDA Menendez Pidal S/N, 14004, Cordoba, Spain

    J. M. Quesada, I. Serrano, F. Borrego, A. Martin, J. Peña & R. Solana

  2. Facultad de Medicina, Universidad de Cordoba, AVDA Menendez Pidal S/N, 14004, Cordoba, Spain

    J. M. Quesada, I. Serrano, F. Borrego, A. Martin, J. Peña & R. Solana

Authors
  1. J. M. Quesada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Borrego
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Peña
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Solana
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quesada, J.M., Serrano, I., Borrego, F. et al. Calcitriol effect on natural killer cells from hemodialyzed and normal subjects. Calcif Tissue Int 56, 113–117 (1995). https://doi.org/10.1007/BF00296341

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00296341

Key words

Search

Navigation