Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes.
Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes.
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DOI：
10.1016/j.neuroscience.2010.05.044
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发表时间：
2010-09-01
期刊：
影响因子：
3.3
通讯作者：
Jope, R. S.
中科院分区：
文献类型：
--
作者：
Beurel, E.;Jope, R. S.
炎症耐受是在反复刺激后炎症的下调，其在外周免疫细胞中发生是公认的。然而，对大脑中的炎症耐受性知之甚少，尽管它可能提供了一种重要的保护机制，使其免受长期炎症的有害后果，这似乎发生在许多精神和神经退行性疾病中。用脂多糖（LPS）连续刺激小鼠原代星形胶质细胞两次后产生的308种炎症分子的阵列分析将其分为三类，耐受组、致敏组和未改变组。对于许多这些炎症分子，抑制糖原合成酶激酶-3（GSK 3）可增加耐受性并降低致敏性。专注于LPS耐受性的白细胞介素-6（IL-6）的生产，我们发现，小胶质细胞表现出强烈的耐受性反应，匹配的巨噬细胞，而星形胶质细胞仅表现出部分耐受性。发现星形胶质细胞半耐受性受GSK 3调节。GSK 3抑制剂或敲低GSK 3水平促进LPS耐受性，表达组成型活性GSK 3的星形胶质细胞不产生LPS耐受性。这些发现确定了GSK 3在抵消CNS细胞中IL-6炎性耐受中的关键作用，支持GSK 3抑制剂通过促进耐受来减少神经炎症的治疗潜力。
Inflammatory tolerance is the down-regulation of inflammation upon repeated stimuli, which is well-established to occur in peripheral immune cells. However, less is known about inflammatory tolerance in the brain although it may provide an important protective mechanism from detrimental consequences of prolonged inflammation, which appears to occur in many psychiatric and neurodegenerative conditions. Array analysis of 308 inflammatory molecules produced by mouse primary astrocytes after two sequential stimulations with lipopolysaccharide (LPS) distinguished three classes, tolerant, sensitized and unaltered groups. For many of these inflammatory molecules, inhibition of glycogen synthase kinase-3 (GSK3) increased tolerance and reduced sensitization. Focusing on LPS-tolerance in interleukin-6 (IL-6) production, we found that microglia exhibited a strong tolerance response that matched that of macrophages, whereas astrocytes exhibited only partial tolerance. The astrocyte semi-tolerance was found to be regulated by GSK3. GSK3 inhibitors or knocking down GSK3 levels promoted LPS-tolerance and astrocytes expressing constitutively active GSK3 did not develop LPS-tolerance. These findings identify the critical role of GSK3 in counteracting IL-6 inflammatory tolerance in cells of the CNS, supporting the therapeutic potential of GSK3 inhibitors to reduce neuroinflammation by promoting tolerance.
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影响因子：
3.7
作者：
Dugan LL;Ali SS;Shekhtman G;Roberts AJ;Lucero J;Quick KL;Behrens MM
通讯作者：
Behrens MM
DOI：
10.1083/jcb.85.3.890
发表时间：
1980-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy KD;de Vellis J
通讯作者：
de Vellis J
影响因子：
10.6
作者：
Miller, Andrew H.;Maletic, Vladimir;Raison, Charles L.
通讯作者：
Raison, Charles L.
DOI：
10.1186/cc5055
发表时间：
2006
期刊：
Critical care (London, England)
影响因子：
--
作者：
Cavaillon JM;Adib-Conquy M
通讯作者：
Adib-Conquy M
影响因子：
6.2
作者：
Cerciat, M.;Unkila, M.;Arevalo, M. -A.
通讯作者：
Arevalo, M. -A.