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Monocyte 1α‐hydroxylase regulation: induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin
Author(s) -
Gyetko Margaret R.,
Hsu Chen Hsaing,
Wilkinson Camille C.,
Patel Sanjeev,
Young Eric
Publication year - 1993
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.54.1.17
Subject(s) - calcitriol , endocrinology , medicine , monocyte , biology , cytokine , tumor necrosis factor alpha , inflammation , immunology , vitamin d and neurology
Alveolar macrophages acquire lα‐hydroxylase activity in inflammation, and thereby metabolize 25 hydroxyvitamin D3 (25 D3) to the active metabolite, la,25‐dihydroxyvitamin D3 (1,25 D3, calcitriol). Cal‐ citriol is a potent differentiation agent that modulates mononuclear phagocyte activation and effector functions. The mediators that induce macrophage lα‐hydroxylase activity are not well delineated. Furthermore, it is unclear whether calcitriol is a product only of terminally differentiated macrophages or whether less mature mononuclear phagocytes can produce it as well. The ability of newly recruited monocytes to produce calcitriol as an autocrine differentiation agent is particularly important in inflammation, as it may substantially expand the functional repertoire of these cells. To assess the effects of cytokines on lα‐hydroxylase activity, blood monocytes were cultured in the presence and absence of human recombinant tumor necrosis factor a (TNF‐α), interferon‐7 (IFN‐γ), and interleukins 1 and 2 and then incubated with 25 D3 substrate. The conditioned media were assayed for calcitriol by high‐performance liquid chromatography and competitive receptor binding assay. No detectable calcitriol was produced by unstimulated monocytes. However, all the cytokines markedly increased monocyte calcitriol production (range 133‐151 pg/mg protein; in all cases P < .001). We then determined whether calcitriol production was suppressed by preincubation with either dexamethasone or the putative uremia toxin guanidinosuccinic acid (GSA). Dexamethasone pretreatment significantly inhibited subsequent cytokine‐induced calcitriol production by monocytes, as did GSA (average 69 and 63% of control, respectively).