1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes.

OBJECTIVE To study the effects of the active metabolite of vitamin D(3), 1,25(OH)(2)D(3), an immunomodulatory hormone, on the generation of so-called immature dendritic cells (iDCs) generated from monocytes (Mo-iDCs). DESIGN AND METHODS Human peripheral blood monocytes were cultured to iDCs in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 1 week, with or without the extra addition of 10(-8) M 1,25(OH)(2)D(3) to the culture. Their phenotypes (CD14, CD1a, CD83, HLA-DR, CD80, CD86 and CD40 expression) were examined by fluorescence-activated cell sorting, and their T-cell stimulatory potential was investigated in allogeneic mixed lymphocyte reaction (allo-MLR). Additionally, their in vitro production of IL-10, IL-12 and transforming growth factor beta (TGF-beta) were examined by using the enzyme-linked immunosorbent assay. RESULTS When 1,25(OH)(2)D(3) was added to monocytes in culture with GM-CSF and IL-4, it hampered the maturation of Mo-iDCs. First, the phenotype of the 1,25(OH)(2)D(3)-differentiated DCs was affected, there being impaired downregulation of the monocytic marker CD14 and impaired upregulation of the markers CD1a, CD83, HLA-DR, CD80 and CD40. CD86 was expressed on more 1,25(OH)(2)D(3)-differentiated DCs. Secondly, the T-cell stimulatory capability of 1,25(OH)(2)D(3)-differentiated DCs was upregulated relative to the original monocytes to a lesser degree than DCs differentiated without 1,25(OH)(2)D(3) when tested in an allo-MLR. With regard to the production of cytokines, Staphylococcus aureus cowan 1 strain (SAC)-induced IL-10 production, although not enhanced, remained high in 1,25(OH)(2)D(3)-differentiated DCs, but was strongly downregulated in DCs generated in the absence of 1,25(OH)(2)D(3). SAC/interferon-gamma-induced IL-12 production was clearly upregulated in both types of DC relative to those of the original monocytes, and TGF-beta production was downregulated. CONCLUSION Our data confirm earlier reports showing that 1,25(OH)(2)D(3) hampers the maturation of fully active immunostimulatory major histocompatibility complex (MHC) class II+, CD1a+, CD80+ DCs from monocytes. Our data supplement the data from other reports by showing that the expression of CD86 was upregulated in 1,25(OH)(2)D(3)-differentiated DCs, whilst the capacity for IL-10 production remained high. Collectively, these data are in line with earlier descriptions of suppressive activities of this steroid-like hormone with respect to the stimulation of cell-mediated immunity.

[1]  O. Majdic,et al.  1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in vitro. , 2000, Experimental hematology.

[2]  P. Allavena,et al.  Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells1 , 2000, The Journal of Immunology.

[3]  L. Adorini,et al.  1α,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation , 2000, The Journal of Immunology.

[4]  L. Adorini,et al.  1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. , 2000, Journal of immunology.

[5]  S. Dyderski.  [Vitamin D3]. , 1999, Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego.

[6]  Anita B. Roberts,et al.  REGULATION OF IMMUNE RESPONSES BY TGF-β* , 1998 .

[7]  I. Denis,et al.  TGF-β and calcitriol , 1998 .

[8]  A. Roberts,et al.  Regulation of immune responses by TGF-beta. , 1998, Annual review of immunology.

[9]  I. Denis,et al.  TGF-beta and calcitriol. , 1998, General pharmacology.

[10]  M. Cippitelli,et al.  Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. , 1998, The Journal of clinical investigation.

[11]  A. Enk,et al.  Interleukin‐12 is produced by dendritic cells and mediates T helper 1 development as well as interferon‐γ production by T helper 1 cells , 1996, European journal of immunology.

[12]  K. Kragballe,et al.  The vitamin D3 analog calcipotriol suppresses the number and antigen-presenting function of Langerhans cells in normal human skin. , 1996, The journal of investigative dermatology. Symposium proceedings.

[13]  D. Danielpour.  Induction of transforming growth factor‐β autocrine activity by all‐trans‐retinoic acid and 1α,25‐dihydroxyvitamin D3 in NRP‐152 rat prostatic epithelial cells , 1996 .

[14]  C Danieli,et al.  Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products , 1995, The Journal of experimental medicine.

[15]  G. Trinchieri,et al.  Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. , 1995, Journal of immunology.

[16]  P. Martel,et al.  Constitutive overexpression of c-fos protein in rat liver epithelial cells decreases TGF-β synthesis and increases TGF-β1 receptors , 1995 .

[17]  C. Mathieu,et al.  Prevention of type I diabetes in NOD mice by nonhypercalcemic doses of a new structural analog of 1,25-dihydroxyvitamin D3, KH1060. , 1995, Endocrinology.

[18]  L. Binderup,et al.  New 20-epi-vitamin D3 analogs: immunosuppressive effects on skin allograft survival. , 1995, Transplantation proceedings.

[19]  P. Martel,et al.  Constitutive overexpression of c-fos protein in rat liver epithelial cells decreases TGF-beta synthesis and increases TGF-beta 1 receptors. , 1995, Biochimica et biophysica acta.

[20]  F. Sallusto,et al.  Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha , 1994, The Journal of experimental medicine.

[21]  J. Peters,et al.  1,25‐Dihydroxyvitamin D3 Exerts Opposing Effects to IL‐4 on MHC Class‐II Antigen Expression, Accessory Activity, and Phagocytosis of Human Monocytes , 1993, Scandinavian journal of immunology.

[22]  K. Miyazono,et al.  Induction of transforming growth factor-beta during cardiac allograft rejection. , 1993, Journal of immunology.

[23]  L. Binderup,et al.  Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice. , 1993, Transplant immunology.

[24]  R. Bouillon,et al.  1,25-Dihydroxyvitamin D3 Prevents Insulitis in NOD Mice , 1992, Diabetes.

[25]  J. Lemire,et al.  Prolongation of the survival of murine cardiac allografts by the vitamin D3 analogue 1,25-dihydroxy-delta 16-cholecalciferol. , 1992, Transplantation.

[26]  J. Lemire.  Immunomodulatory role of 1,25‐dihydroxyvitamin D3 , 1992, Journal of cellular biochemistry.

[27]  R. Kerman,et al.  1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. , 1992, Cellular immunology.

[28]  M. Kasahara,et al.  1,25-Dihydroxyvitamin D3 down-regulation of HLA-DR on human peripheral blood monocytes. , 1992, Immunology.

[29]  J M Lemire,et al.  1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. , 1991, The Journal of clinical investigation.

[30]  S. Manolagas,et al.  Immunomodulating properties of 1,25-dihydroxyvitamin D3. , 1990, Kidney international. Supplement.

[31]  R. Andreesen,et al.  Induction of human monocyte to macrophage maturation in vitro by 1,25-dihydroxyvitamin D3. , 1990, Blood.

[32]  J. Ceuppens,et al.  T lymphocytes and their CD4 subset are direct targets for the inhibitory effect of calcitriol. , 1989, Cellular immunology.

[33]  R. Koren,et al.  1,25-Dihydroxyvitamin D3 acts directly on human lymphocytes and interferes with the cellular response to interleukin-2. , 1989, Immunopharmacology.

[34]  S. Manolagas,et al.  The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. , 1986, The Journal of clinical endocrinology and metabolism.

[35]  S. Krane,et al.  Differential effects of 1,25-dihydroxyvitamin D3 on human lymphocytes and monocyte/macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production. , 1986, Cellular immunology.

[36]  S. Iho,et al.  Effect of 1,25-dihydroxyvitamin D3 on the immunocompetent cells. , 1986, Methods and findings in experimental and clinical pharmacology.

[37]  S. Manolagas,et al.  1,25-Dihydroxyvitamin D3 promotes in vitro morphologic and enzymatic changes in normal human monocytes consistent with their differentiation into macrophages. , 1986, Bone.

[38]  T. Matsui,et al.  1,25-Dihydroxyvitamin D3 regulates proliferation of activated T-lymphocyte subsets. , 1985, Life sciences.

[39]  S. Iho,et al.  The role of monocytes in the suppression of PHA-induced proliferation and IL 2 production of human mononuclear cells by 1,25-dihydroxyvitamin D3. , 1985, Immunology letters.

[40]  J. Adams,et al.  1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. , 1984, The Journal of clinical investigation.

[41]  S. Manolagas,et al.  1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. , 1984, Science.

[42]  H. Drexhage,et al.  A simple cytochemical method for distinguishing EAC rosettes formed by lymphocytes and monocytes. , 1979, Journal of immunological methods.