Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.
Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.
复制标题
在高免疫球蛋白血症 D 和周期性发热综合征中，类异戊二烯产物的缺乏会增加体外白细胞介素 1β 的分泌。
作者：
J. Frenkel;G. Rijkers;Saskia H. L. Mandey;Sandra W. M. Buurman;S. Houten;R. Wanders;H. Waterham;W. Kuis
目的
研究高免疫球蛋白血症D和周期性发热综合征患者白细胞介素-1 β（IL-1 β）分泌增加是否是由于甲羟戊酸激酶（MK）（缺陷酶的底物）的积聚或其产物（类异戊二烯化合物）的缺乏所致。
方法
研究了洛伐他汀和法尼醇（FOH）、香叶基香叶醇（GGOH）和甲羟戊酸对8例MK缺乏症患者和13例对照者外周血单个核细胞（PBMC）的影响。洛伐他汀通过减少甲羟戊酸的产生来抑制类异戊二烯的生物合成。FOH和GGOH恢复MK下游的类异戊二烯生物合成。在用抗CD 2 + CD 28的单克隆抗体刺激后48小时收集培养物上清液用于细胞因子分析。
结果
洛伐他汀诱导正常抗CD 2 + CD 28刺激细胞IL-1 β分泌增加15倍（P < 0.001）。甲羟戊酸可以抵消这种效应，FOH和GGOH也可以抵消这种效应，但程度较轻。在没有洛伐他汀的情况下，甲羟戊酸没有改变IL-1 β的分泌。刺激MK缺陷细胞分泌的IL-1 β比对照PBMC多9倍（P < 0.005），在洛伐他汀存在下增加2.4倍。甲羟戊酸、FOH和GGOH可降低洛伐他汀对IL-1 β分泌的影响。由于内源性MK缺乏，患者PBMC中类异戊二烯生物合成受损。在没有洛伐他汀的情况下，用FOH弥补这一缺陷，导致这些细胞分泌IL-1 β减少62%（P < 0.02）。
结论
在该模型中，类异戊二烯终产物的缺乏导致MK缺陷型PBMC分泌IL-1 β增加，而过量的甲羟戊酸则不会。
OBJECTIVE
To investigate whether the increased interleukin-1beta (IL-1beta) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds.
METHODS
The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 + CD28.
RESULTS
Lovastatin induced a 15-fold rise in IL-1beta secretion by normal anti-CD2 + CD28-stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1beta secretion. Stimulated MK-deficient cells secreted 9-fold more IL-1beta than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1beta secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1beta secretion by these cells.
CONCLUSION
In this model, shortage of isoprenoid end products contributes to increased IL-1beta secretion by MK-deficient PBMCs, whereas excess mevalonate does not.
来自高 IgD 综合征患者的未刺激外周血单核细胞产生能够有效诱导 Hep3B 细胞中 C 反应蛋白和血清淀粉样蛋白 A 的细胞因子。
DOI：
--
发表时间：
1996
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Drenth,JP;vanderMeer,JW;Kushner,I
通讯作者：
Kushner,I
影响因子：
16
作者：
Chae, JJ;Komarow, HD;Kastner, DL
通讯作者：
Kastner, DL
DOI：
10.1006/bbrc.1995.1854
发表时间：
1995-06-15
影响因子：
3.1
作者：
CRICK, DC;ANDRES, DA;WAECHTER, CJ
通讯作者：
WAECHTER, CJ