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Immunology. 1992 Oct; 77(2): 304–311.
PMCID: PMC1421610

The comparative role of 1,25-dihydroxycholecalciferol and phorbol esters in the differentiation of the U937 cell line.


The active metabolite of cholecalciferol, 1,25-dihydroxycholecalciferol (1,25-DHCC), is a mononuclear phagocyte product with immunoregulatory properties which can influence not only surrounding T cells but also other mononuclear phagocytes; and which acts in an autocrine fashion. In this study we have used the U937 cell line as a starting point model to investigate further the comparative role of 1,25-DHCC and phorbol myristate acetate (PMA) upon growth, differentiation and phenotype in the mononuclear phagocyte system, and have correlated our findings with changes in 1,25-DHCC metabolism and receptor expression. Both 1,25-DHCC and PMA inhibit growth and differentiate U937 cells in a dose-dependent fashion. When used together, however, at low doses of PMA, 1,25-DHCC protects against the PMA-induced growth inhibition. At high concentrations of both compounds there is a decrease (1,25-DHCC) or an increase (PMA) in 1,25-DHCC receptor expression, with either 24-OHase (1,25-DHCC) or 1-OHase (PMA) synthesis. If the compounds are used in combination the receptor levels are equivalent to controls, and both enzymes are produced. The phenotype of the 1,25-DHCC-induced cells shows light adherence, class I+, increase in CD4 and CD14 and decrease in CD71. The PMA-induced cell is tightly adherent, class I+, and strongly positive for CD13 with a concomitant decrease in both CD4 and CD71. These findings suggest another role for 1,25-DHCC in the mononuclear phagocyte system, as a potential mitogenic agent. They also suggest that 1,25-DHCC may act at both membrane and nuclear levels within this model of the mononuclear phagocyte pathway and demonstrate one possible way in which physiological peripheral macrophage heterogeneity might be induced, i.e. due to the nature of the signals which are implicated during differentiation. The presence of increased CD4 and decreased CD13 on the surface of 1,25-DHCC-differentiated cells, and vice versa on PMA-differentiated cells, illustrates how this may then be reflected in functional mononuclear phagocyte heterogeneity, which may in turn be reflected in differential peripheral function.

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  • Nunn JD, Katz DR, Barker S, Fraher LJ, Hewison M, Hendy GN, O'Riordan JL. Regulation of human tonsillar T-cell proliferation by the active metabolite of vitamin D3. Immunology. 1986 Dec;59(4):479–484. [PMC free article] [PubMed]
  • Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest. 1984 Oct;74(4):1451–1455. [PMC free article] [PubMed]
  • Reichel H, Koeffler HP, Bishop JE, Norman AW. 25-Hydroxyvitamin D3 metabolism by lipopolysaccharide-stimulated normal human macrophages. J Clin Endocrinol Metab. 1987 Jan;64(1):1–9. [PubMed]
  • Reichel H, Koeffler HP, Norman AW. Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages. J Biol Chem. 1987 Aug 15;262(23):10931–10937. [PubMed]
  • Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM. 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. 1983 Dec;57(6):1308–1310. [PubMed]
  • Polla BS, Werlen G, Clerget M, Pittet D, Rossier MF, Capponi AM. 1,25-dihydroxyvitamin D3 induces responsiveness to the chemotactic peptide f-Met-Leu-Phe in the human monocytic line U937: dissociation between calcium and oxidative metabolic responses. J Leukoc Biol. 1989 May;45(5):381–388. [PubMed]
  • Rasmussen H, Matsumoto T, Fontaine O, Goodman DB. Role of changes in membrane lipid structure in the action of 1,25-dihydroxyvitamin D3. Fed Proc. 1982 Jan;41(1):72–77. [PubMed]
  • Hewison M, Barker S, Brennan A, Katz DR, O'Riordan JL. Modulation of myelomonocytic U937 cells by vitamin D metabolites. Bone Miner. 1989 Mar;5(3):323–333. [PubMed]
  • Hewison M, Barker S, Brennan A, Nathan J, Katz DR, O'Riordan JL. Autocrine regulation of 1,25-dihydroxycholecalciferol metabolism in myelomonocytic cells. Immunology. 1989 Oct;68(2):247–252. [PMC free article] [PubMed]
  • Karmali R, Bhalla AK, Farrow SM, Williams MM, Lal S, Lydyard PM, O'Riordan JL. Early regulation of c-myc mRNA by 1,25-dihydroxyvitamin D3 in human myelomonocytic U937 cells. J Mol Endocrinol. 1989 Jul;3(1):43–48. [PubMed]
  • Reitsma PH, Rothberg PG, Astrin SM, Trial J, Bar-Shavit Z, Hall A, Teitelbaum SL, Kahn AJ. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature. 1983 Dec 1;306(5942):492–494. [PubMed]
  • Eil C, Lippman ME, Loriaux DL. A dispersed-whole cell method for the determination of androgen receptors in human skin fibroblasts. Steroids. 1980 Apr;35(4):389–404. [PubMed]
  • Rosenfeld ME, Ross R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 1990 Sep-Oct;10(5):680–687. [PubMed]
  • Knapp W, Rieber P, Dörken B, Schmidt RE, Stein H, vd Borne AE. Towards a better definition of human leucocyte surface molecules. Immunol Today. 1989 Aug;10(8):253–258. [PubMed]
  • Clapham PR, Weiss RA, Dalgleish AG, Exley M, Whitby D, Hogg N. Human immunodeficiency virus infection of monocytic and T-lymphocytic cells: receptor modulation and differentiation induced by phorbol ester. Virology. 1987 May;158(1):44–51. [PubMed]
  • Ways DK, Dodd RC, Bennett TE, Gray TK, Earp HS. 1,25-Dihydroxyvitamin D3 enhances phorbol ester-stimulated differentiation and protein kinase C-dependent substrate phosphorylation activity in the U937 human monoblastoid cell. Endocrinology. 1987 Nov;121(5):1654–1661. [PubMed]
  • May WS, Jr, Sahyoun N, Wolf M, Cuatrecasas P. Role of intracellular calcium mobilization in the regulation of protein kinase C-mediated membrane processes. Nature. 1985 Oct 10;317(6037):549–551. [PubMed]
  • Ferns G, Reidy M, Ross R. Vascular effects of cyclosporine A in vivo and in vitro. Am J Pathol. 1990 Aug;137(2):403–413. [PMC free article] [PubMed]

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