GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions
GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions
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DOI：
10.1002/glia.20436
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发表时间：
2007-01-01
期刊：
影响因子：
6.2
通讯作者：
Singh, Avtar K.
中科院分区：
文献类型：
--
作者：
Prasad, Ratna;Giri, Shailendra;Singh, Avtar K.
S-亚硝基谷胱甘肽(GSNO)是一种内源性一氧化氮载体，最近已记录其在脑缺血大鼠模型中的抗炎作用(Khan等人(2005)J Cereb Blood Flow Metab 25：177-192)。在这里，我们利用体外单核细胞-内皮细胞相互作用模型探讨了 GSNO 在 EAE Lewis 大鼠模型中介导的神经保护作用及其作用机制。口服 GSNO 通过抑制 CNS 中血管免疫细胞的浸润，从而减轻 EAE 动物的临床病程，随后导致促炎细胞因子表达减少，从而限制脱髓鞘。基于对免疫细胞浸润的抑制，我们假设 GSNO 调节内皮细胞活化，从而减少中枢神经系统中的细胞浸润。使用体外模型，我们确定 GSNO 抑制单核细胞与活化内皮细胞的粘附，这是通过下调内皮细胞粘附分子 (CAM) 介导的。 GSNO 调节 CAM 表达的机制似乎是通过 p65 的亚硝基化，从而抑制内皮细胞中核因子 kappa B (NF-kappa B) 的激活。这些观察结果表明，GSNO 通过 p65 的 S-亚硝基化抑制细胞浸润到 CNS，从而调节内皮细胞中的 NF-kappa B-CAM 通路，从而在 EAE 中发挥保护作用。 (c) 2006 Wiley-Liss, Inc.
S-Nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier and recently, has been documented for its anti-inflammatory effects in rat model of cerebral ischemia (Khan et al. (2005) J Cereb Blood Flow Metab 25:177-192). Here, we explored the neuroprotective effects mediated by GSNO in Lewis rat model of EAE and its mechanism of action using in vitro model of monocyte-endothelial cell interaction. Oral administration of GSNO attenuated the clinical disease course in EAE animals by inhibiting the infiltration of vascular immune cells in the CNS that subsequently led to the reduction in the expression of proinflammatory cytokines and consequently limited demyelination. Based on the inhibition in infiltration of immune cells, we hypothesized that GSNO modulated endothelial cell activation that led to reduce cellular infiltration in the CNS. Using an in vitro model, we established that GSNO inhibited monocyte adhesion to the activated endothelial cell, which was mediated by down regulation of endothelial cell adhesion molecules (CAMs). The mechanism by which GSNO modulated CAMs expression appeared to be via Snitrosylation of p65, which consequently inhibited nuclear factor kappa B (NF-kappa B) activation in endothelial cells. These observations suggest that GSNO exerts its protective effects in EAE by inhibition of cellular infiltration into the CNS by S-nitrosylation of p65, thereby modulating NF-kappa B-CAMs pathway in endothelial cells. (c) 2006 Wiley-Liss, Inc.