REGULATION OF 1,25-DIHYDROXYVITAMIN-D3 PRODUCTION BY CULTURED ALVEOLAR MACROPHAGES FROM NORMAL HUMAN DONORS AND FROM PATIENTS WITH PULMONARY SARCOIDOSIS
REGULATION OF 1,25-DIHYDROXYVITAMIN-D3 PRODUCTION BY CULTURED ALVEOLAR MACROPHAGES FROM NORMAL HUMAN DONORS AND FROM PATIENTS WITH PULMONARY SARCOIDOSIS
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DOI：
10.1210/jcem-65-6-1201
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发表时间：
1987-12-01
影响因子：
5.8
通讯作者：
NORMAN, AW
中科院分区：
文献类型：
--
作者：
REICHEL, H;KOEFFLER, HP;NORMAN, AW
本文研究了6例肺结节病患者和9例正常人培养的肺泡巨噬细胞（PAM）对生物活性维生素D_3甾醇1，25-二羟维生素D_3 [1，25-（OH）_2D_3]产生的调节作用。均从具有正常钙代谢的患者收集的类肉瘤细胞从底物25-羟基维生素[3 H] D3（25 OH-[3 H] D3）合成1，25-（OH）2-[3 H] D3，而在体外与重组人干扰素-γ孵育。（IFN γ）或脂多糖（LPS）是诱导正常PAM合成激素所必需的。外源1，25-（OH）_2D_3（10-100 nmol/L）使正常PAM的内源激素产生减少约45%。1，25-（OH）_2D_3对类肉瘤PAM的抑制作用较弱，10-100 nmol/L的1，25-（OH）_2D_3对250 HD_3 -1-羟化酶的抑制率约为25%。在10个实验中仅3个实验中发现了250 HD 3 -24-羟化酶的伴随诱导，这是肾细胞的典型诱导，水平较低;在这方面，结节病和正常PAM之间没有明显差异。PTH或forskolin不影响PAM代谢250 HD_3。通过类肉瘤PAM的1，25-（OH）2D 3产生被脂多糖和IFN γ增强。同样地，重组人白细胞介素-2刺激类肉瘤PAM产生1，25-（OH）2D 3，提示IFN γ和IFN γ都可能起作用。和白细胞介素-2在体内诱导类肉瘤PAM合成1，25-（OH）2D 3中的作用。重组人IFN α，IFN β，而粒-巨噬细胞集落刺激因子作用不大。地塞米松和氯喹在结节病中具有体内抗高钙活性，它们都抑制结节PAM合成1，25-（OH）2D 3;氯喹同时刺激24-羟化酶。我们的研究表明，PAM的250 HD_3代谢系统在某些方面不同于250 HD_3的肾脏代谢。
Regulation of the production of the biologically active vitamin D3 sterol 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] by cultured pulmonary alveolar macrophages (PAM) obtained from 6 patients with pulmonary sarcoidosis and from 9 normal subjects was studied. The sarcoid cells, all collected from patients with normal calcium metabolism, synthesized 1,25-(OH)2-[3H]D3 from the substrate 25-hydroxyvitamin [3H] D3 (25OH-[3H]D3), whereas in vitro incubation with recombinant human interferon-.gamma. (IFN.gamma.) or lipopolysaccharide (LPS) was required for induction of synthesis of the hormone by normal PAM. Exogenous 1,25-(OH)2D3 (10-100 nmol/L) decreased endogenous hormone production by normal PAM by approximately 45%. The relative inhibitory effect of 1,25-(OH)2D3 was less pronounced in sarcoid PAM in which 10-100 nmol/L 1,25-(OH)2D3 inhibited 250HD3-1-hydroxylase by approximately 25%. An accompanying induction of the 250HD3-24-hydroxylase, which is typical for renal cells, was found at low levels in only 3 of 10 experiments; in this regard, no differences between sarcoid and normal PAM were apparent. PTH or forskolin did not influence 250HD3 metabolism by PAM. 1,25-(OH)2D3 production by sarcoid PAM was enhanced by lipopolysaccharide and IFN.gamma.. Likewise, recombinant human interleukin-2 stimulated 1,25-(OH)2D3 production by sarcoid PAM, suggesting a possible role for both IFN.gamma. and interleukin-2 in the induction of 1,25-(OH)2D3 synthesis by sarcoid PAM in vivo. Recombinant human IFN.alpha., IFN.beta., and granulocyte-macrophage colony-stimulating factor had little effect. Dexamethasone and chloroquine which have in vivo antihypercalcemic activity in sarcoidosis, both inhibited 1,25-(OH)2D3 synthesis by sarcoid PAM; chloroquine simultaneously stimulated the 24-hydroxylase. Our studies suggest that 250HD3-metabolizing system in PAM is in some respects different from renal metabolism of 250HD3.