Female sex steroids: effects upon microglial cell activation
Female sex steroids: effects upon microglial cell activation
复制标题
DOI：
10.1016/s0165-5728(00)00386-6
复制
发表时间：
2000-11-01
影响因子：
3.3
通讯作者：
Chavis, JA
中科院分区：
文献类型：
--
作者：
Drew, PD;Chavis, JA
多发性硬化症在女性中比男性更常见。然而，导致多发性硬化症性别差异的机制尚不清楚。活化的小胶质细胞被认为有助于多发性硬化症的病理学，可能部分是由于产生一氧化氮（NO）和TNF-α，这些分子对包括少突胶质细胞在内的细胞是有毒的。目前的研究表明，女性性类固醇雌三醇，β-雌二醇和孕酮抑制脂多糖（LPS）诱导的一氧化氮（NO）的生产由原代大鼠小胶质细胞和小鼠N9小胶质细胞系。这些激素通过抑制诱导型一氧化氮合酶（iNOS）的产生而起作用，所述诱导型一氧化氮合酶（iNOS）催化NO的合成。雌三醇可能抑制iNOS基因表达，因为激素阻断LPS诱导的iNOS RNA水平。促炎细胞因子IFN-γ和TNF-α被认为是多发性硬化症的重要调节剂。在这里，我们表明，雌激素和孕酮也抑制NO的产生，小胶质细胞激活这些细胞因子的反应。活化的小胶质细胞引发TNF-α。我们进一步证明雌激素和孕酮抑制这些细胞产生TNF-α。最后，雌三醇和孕酮，在浓度与妊娠晚期一致，抑制NO和TNF-α的生产激活的小胶质细胞，表明激素抑制小胶质细胞的活化可能有助于减少多发性硬化症的严重程度通常与怀孕。(C)2000 Elsevier Science B. V.保留所有权利。
Multiple sclerosis occurs more commonly in females than males. However, the mechanisms resulting in gender differences in multiple sclerosis are unknown. Activated microglia are believed to contribute to multiple sclerosis pathology, perhaps in part due to production of nitric oxide (NO) and TNF-alpha, molecules which can be toxic to cells including oligodendrocytes. The current study demonstrates that the female sex steroids estriol, beta -estradiol and progesterone inhibit Lipopolysaccharide (LPS)induction of nitric oxide (NO) production by primary rat microglia and by the mouse N9 microglial cell line. These hormones act by inhibiting the production of inducible nitric oxide synthase (iNOS) which catalyses the synthesis of NO. Estriol likely inhibits iNOS gene expression since the hormone blocks LPS induction of iNOS RNA levels. The pro-inflammatory cytokines IFN-gamma and TNF-alpha are believed to be important modulators of multiple sclerosis. Here, we demonstrate that estrogens and progesterone also inhibit NO production by microglial cells activated in response to these cytokines. Activated microglia elicit TNF-alpha. in addition to NO and we further demonstrate that estrogens and progesterone repress TNF-alpha production by these cells. Finally, estriol and progesterone, at concentrations consistent with late pregnancy, inhibit NO and TNF-alpha production by activated microglia, suggesting that hormone inhibition of microglial cell activation may contribute to the decreased severity of multiple sclerosis symptoms commonly associated with pregnancy. (C) 2000 Elsevier Science B.V. All rights reserved.