Retinoic acid inhibits expression of TNF-α and iNOS in activated rat microglia
Retinoic acid inhibits expression of TNF-α and iNOS in activated rat microglia
复制标题
作者：
Dheen, ST;Jun, Y;Ling, EA
小胶质细胞释放促炎介质如肿瘤坏死因子-α和一氧化氮与阿尔茨海默病等慢性神经退行性疾病的神经毒性有关。鉴于全反式维甲酸(RA)已被报道在多种细胞类型中发挥抗炎作用，我们观察了全反式维甲酸对β-淀粉样肽(Abeta)和脂多糖(LPS)激活的小胶质细胞表达肿瘤坏死因子-α(TNF-α)和诱导型一氧化氮合酶(INOS)的影响。原代培养的大鼠小胶质细胞暴露于Abeta或LPS后，可显著刺激肿瘤坏死因子-α(6-116倍)和一氧化氮合酶(8-500倍)的mRNA表达。RA以剂量依赖的方式(0.1-10微米)抑制暴露于Abeta或内毒素的小胶质细胞的肿瘤坏死因子-α(29-97%)和诱导型一氧化氮合酶(61-96%)的mRNA表达。亚硝酸法和酶联免疫吸附试验显示，RA抑制活化的小胶质细胞中的肿瘤坏死因子-α和诱导型一氧化氮合酶的表达，并伴随着诱导型一氧化氮合酶和肿瘤坏死因子-α蛋白释放的减少。RA的抗炎作用与其促进维甲酸受体-β、转化生长因子-β1的表达及抑制核因子-kappaB转位有关。这些结果提示，RA可能通过抑制炎性细胞因子和细胞毒分子的产生而抑制激活的小胶质细胞的神经毒性作用。(C)2004年Wiley-Liss公司
The release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide by microglia has been implicated in neurotoxicity in chronic neurodegenerative diseases such as Alzheimer's disease. As all-trans-retinoic acid (RA) has been reported to exert anti-inflammatory actions in various cell types, we have examined its effects on the expression of TNF-alpha and inducible nitric oxide synthase (iNOS) in microglia activated by beta-amyloid peptide (Abeta) and lipopolysaccharide (LPS). Exposure of primary cultures of rat microglial cells to Abeta or LPS stimulated the mRNA expression level of TNF-alpha (6-116-fold) and NOS (8-500-fold) significantly. RA acted in a dose-dependent manner (0.1-10 muM) by attenuating both TNF-alpha (29-97%) and iNOS (61-96%) mRNA expression in microglia exposed to Abeta or LPS. RA-induced inhibition of TNF-a and iNOS mRNA expression in activated microglia was accompanied by the concomitant reduction in release of iNOS and TNF-alpha proteins as revealed by nitrite assay and ELISA, respectively. The anti-inflammatory effects of RA were correlated with the enhanced expression of retinoic acid receptor-beta, and transforming growth factor-beta1 as well as the inhibition of NF-kappaB translocation. These results suggest that RA may inhibit the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules. (C) 2004 Wiley-Liss, Inc.