Monocyte 1 alpha-hydroxylase regulation: induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin.
Alveolar macrophages acquire 1 alpha-hydroxylase activity in inflammation, and thereby metabolize 25 hydroxyvitamin D3 (25 D3) to the active metabolite, 1 alpha,25-dihydroxyvitamin D3 (1,25 D3, calcitriol). Calcitriol is a potent differentiation agent that modulates mononuclear phagocyte activation and effector functions. The mediators that induce macrophage 1 alpha-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 1 alpha-hydroxylase activity, blood monocytes were cultured in the presence and absence of human recombinant tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), 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).
Gyetko
M R
MR
Division of Pulmonary and Critical Care Medicine, Ann Arbor Department of Veterans Affairs, MI.
Hsu
C H
CH
Wilkinson
C C
CC
Patel
S
S
Young
E
E
D002117:Calcitriol / Q000096:biosynthesis / Q000378:metabolism; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D016207:Cytokines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006099:Granuloma / Q000097:blood / Q000201:enzymology / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000201:enzymology* / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D010586:Phagocytes / Q000201:enzymology; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology*
D016207:Cytokines; D006146:Guanidines; D013386:Succinates; C001318:guanidinosuccinic acid; D003907:Dexamethasone; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D002117:Calcitriol