gamma-interferon-induced resistance to 1,25-(OH)(2)D-3 in human monocytes and macrophages: A mechanism for the hypercalcemia of various granulomatoses
gamma-interferon-induced resistance to 1,25-(OH)(2)D-3 in human monocytes and macrophages: A mechanism for the hypercalcemia of various granulomatoses
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DOI：
10.1210/jc.82.7.2222
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发表时间：
1997-07-01
影响因子：
5.8
通讯作者：
Slatopolsky, E
中科院分区：
文献类型：
--
作者：
Dusso, AS;Kamimura, S;Slatopolsky, E
各种肉芽肿病的高钙血症是由疾病激活的巨噬细胞过度产生内源性 1,25-二羟基维生素 D [1,25-(OH)2(D3)] 引起的。 1,25(OH)(2)D-3 无法抑制其在巨噬细胞中的合成，这与它在巨噬细胞前体、外周血单核细胞 (PBM) 中的产生受到严格控制形成鲜明对比。我们检查了 1,25(OH)(2)D-3 耐药性是否随着 PBM 分化为巨噬细胞或巨噬细胞激活而产生。尽管维生素 D 受体含量相似，但正常人肺泡巨噬细胞 (PAM) 对 1,25(OH)(2)D-3 的敏感性低于 PBM；然而，PBM 和 PAM 均通过抑制 1,25(OH)(2)D-3 合成并通过增强 24-羟化酶 mRNA 水平和活性诱导 1,25(OH)(2)D-3 降解来对外源 1,25-(OH)(2)D-3 作出反应。人单核细胞系 THP-1 在 1,25(OH)(2)D-3 合成和对外源 1,25(OH)(2)D-3 敏感性方面模拟 PAM。我们利用 THP-1 细胞来检查巨噬细胞激活对 1,25(OH)(2)D-3 的反应。用γ-干扰素 (gamma-IFN) 激活 THP-1 细胞可将 1,25(OH)(2)D-3 合成增强 30 倍，阻断 1,25-(OH)(2)D-3 对其合成的抑制，并减少 42.2% 1,25-(OH)(2)D-3 对其降解的诱导。 γ-IFN 的拮抗作用不仅限于酶活性。在 THP-1 细胞和正常 PBM 中，γ-IFN 抑制 1,25-(OH)(2)D-3 诱导的 24-羟化酶 mRNA 水平，而不降低 mRNA 稳定性，表明γ-IFN 抑制 1,25(OH)(2)D-3 反式激活功能。这些结果解释了肉芽肿病中 1,25(OH)(2)D-3 的过量产生，并证明了 γ-IFN 对免疫细胞中 1,25(OH)(2)D-3 作用的有效抑制。
The hypercalcemia of various granulomatoses is caused by endogenous 1,25-dihydroxyvitamin D [1,25-(OH)2(D3)] overproduction by disease-activated macrophages. The inability of 1,25(OH)(2)D-3 to suppress its synthesis in macrophages contrasts with the tight control of its production in macrophage precursors, peripheral blood monocytes (PBM). We examined whether 1,25(OH)(2)D-3 resistance develops as PBM differentiate to macrophages or with macrophage activation. Normal human pulmonary alveolar macrophages (PAM) are less sensitive to 1,25(OH)(2)D-3 than PBM, despite similar vitamin D receptor content; however, both PBM and PAM respond to exogenous 1,25-(OH)(2)D-3 by inhibiting 1,25(OH)(2)D-3 synthesis and inducing 1,25(OH)(2)D-3 degradation through enhancement of 24-hydroxylase mRNA levels and activity. The human monocytic cell Line THP-1 mimics PAM in 1,25(OH)(2)D-3 synthesis and sensitivity to exogenous 1,25(OH)(2)D-3. We utilized THP-1 cells to examine the response to 1,25(OH)(2)D-3 with macrophage activation. Activation of THP-1 cells with gamma-interferon (gamma-IFN) enhances 1,25(OH)(2)D-3 synthesis 30-fold, blocks 1,25-(OH)(2)D-3 suppression of its synthesis, and reduces by 42.2% 1,25-(OH)(2)D-3 induction of its degradation. The antagonistic effects of gamma-IFN are not merely restricted to enzymatic activities. In THP-1 cells and in normal PBM, gamma-IFN inhibits 1,25-(OH)(2)D-3 induction of 24-hydroxylase mRNA levels without reducing mRNA stability, suggesting gamma-IFN inhibition of 1,25(OH)(2)D-3 transactivating function. These results explain 1,25(OH)(2)D-3 overproduction in granulomatoses and demonstrate potent inhibition by gamma-IFN of 1,25(OH)(2)D-3 action in immune cells.