Reichel H, Koeffler H P, Barbers R, Norman A W
Department of Biochemistry, University of California, Riverside 92521.
J Clin Endocrinol Metab. 1987 Dec;65(6):1201-9. doi: 10.1210/jcem-65-6-1201.
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 the 250HD3-metabolizing system in PAM is in some respects different from renal metabolism of 250HD3.
研究了从6例肺结节病患者和9名正常受试者获取的培养肺泡巨噬细胞(PAM)对生物活性维生素D3甾醇1,25 - 二羟基维生素D3 [1,25 - (OH)2D3] 产生的调节作用。所有结节病细胞均取自钙代谢正常的患者,其可从底物25 - 羟基维生素[3H]D3(25OH - [3H]D3)合成1,25 - (OH)2 - [3H]D3,而正常PAM诱导该激素合成则需要与重组人干扰素 - γ(IFNγ)或脂多糖(LPS)进行体外孵育。外源性1,25 - (OH)2D3(10 - 100 nmol/L)可使正常PAM的内源性激素产生减少约45%。1,25 - (OH)2D3对结节病PAM的相对抑制作用较弱,其中10 - 100 nmol/L的1,25 - (OH)2D3可使250HD3 - 1 - 羟化酶活性抑制约25%。仅在10项实验中的3项实验中,发现低水平的250HD3 - 24 - 羟化酶(这是肾细胞的典型特征)有伴随性诱导;在这方面,结节病PAM与正常PAM之间无明显差异。甲状旁腺激素(PTH)或福斯高林不影响PAM对250HD3的代谢。脂多糖和IFNγ可增强结节病PAM产生1,25 - (OH)2D3。同样,重组人白细胞介素 - 2可刺激结节病PAM产生1,25 - (OH)2D3,提示IFNγ和白细胞介素 - 2在体内结节病PAM诱导1,25 - (OH)2D3合成中可能发挥作用。重组人IFNα、IFNβ和粒细胞 - 巨噬细胞集落刺激因子作用较小。地塞米松和氯喹在体内对结节病有抗高钙血症活性,二者均抑制结节病PAM合成1,25 - (OH)2D3;氯喹同时刺激24 - 羟化酶。我们的研究表明,PAM中250HD3代谢系统在某些方面不同于250HD3的肾代谢。