MONOCYTE 1-ALPHA-HYDROXYLASE REGULATION - INDUCTION BY INFLAMMATORY CYTOKINES AND SUPPRESSION BY DEXAMETHASONE AND UREMIA TOXIN
MONOCYTE 1-ALPHA-HYDROXYLASE REGULATION - INDUCTION BY INFLAMMATORY CYTOKINES AND SUPPRESSION BY DEXAMETHASONE AND UREMIA TOXIN
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DOI：
10.1002/jlb.54.1.17
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发表时间：
1993-07-01
影响因子：
5.5
通讯作者：
YOUNG, E
中科院分区：
文献类型：
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作者：
GYETKO, MR;HSU, CH;YOUNG, E
肺泡巨噬细胞在炎症中获得1 α-羟化酶活性，从而将25羟维生素D3（25 D3）代谢为活性代谢物1 α，25-二羟维生素D3（1，25 D3，骨化三醇）。骨化三醇是一种有效的分化剂，调节单核吞噬细胞活化和效应功能。介导巨噬细胞1 α-羟化酶活性的介质还没有被很好地描述。此外，还不清楚骨化三醇是否仅是终末分化的巨噬细胞的产物，或者不太成熟的单核吞噬细胞是否也能产生骨化三醇。新募集的单核细胞产生骨化三醇作为自分泌分化剂的能力在炎症中特别重要，因为它可以大大扩展这些细胞的功能库。为了评估细胞因子对1 α-羟化酶活性的影响，在存在和不存在人重组肿瘤坏死因子α（TNF-α）、干扰素-γ（IFN-γ）和白细胞介素1和2的情况下培养血液单核细胞，然后与25 D3底物孵育。通过高效液相色谱法和竞争性受体结合试验测定条件培养基中的骨化三醇。未受刺激的单核细胞未产生可检测的骨化三醇。然而，所有细胞因子均显著增加单核细胞骨化三醇的产生（范围133-151 pg/mg蛋白;在所有情况下P < .001）。然后，我们确定是否骨化三醇生产抑制预孵育与地塞米松或推定的尿毒症毒素胍基琥珀酸（GSA）。地塞米松预处理显着抑制随后的奎宁诱导的单核细胞骨化三醇的生产，GSA（平均69和63%的控制，分别）。
Alveolar macrophages acquire 1alpha-hydroxylase activity in inflammation, and thereby metabolize 25 hydroxyvitamin D3 (25 D3) to the active metabolite, 1alpha,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 1alpha-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 1alpha-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).