Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain.
Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain.
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脑内脂多糖诱导的白介素-6的产生是由糖原合成酶激酶3和STAT3控制的。
DOI：
10.1186/1742-2094-6-9
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发表时间：
2009-03-11
影响因子：
9.3
通讯作者：
Jope RS
中科院分区：
文献类型：
--
作者：
Beurel E;Jope RS
感染性休克是一种普遍的疾病，当不致命时，通常会导致认知、情绪和行为障碍，特别是由于炎性细胞因子白细胞介素-6（IL-6）的中枢作用。为了确定控制脑IL-6的潜在靶点，我们测试了神经胶质细胞产生的IL-6是否受信号转导和转录激活因子-3（STAT 3）和糖原合成酶激酶-3（GSK 3）的调节。用脂多糖（LPS）诱导小鼠或培养的原代胶质细胞的炎症反应。通过ELISA测量IL-6，并使用阵列测量其他炎性分子。小鼠脑IL-6水平增加后，中央，以及周边，LPS管理，与神经胶质细胞产生一部分的脑IL-6。在外周或中枢给予LPS后，以及在LPS刺激的培养的原代胶质细胞中，脑中的STAT 3被激活。抑制STAT 3的表达、功能或活化可使原代神经胶质细胞的IL-6产生减少约80%，表明对活性STAT 3的依赖性。GSK 3促进STAT 3活化，并且对由LPS刺激的原代神经胶质细胞产生的炎性分子的阵列分析表明，IL-6是通过GSK 3抑制而减少最多（>90%）的细胞因子。抑制GSK 3和敲低GSK 3 β（而非GSK 3 α）可显著抑制LPS刺激的原代胶质细胞产生IL-6。相反，活性STAT 3和活性GSK 3的表达促进IL-6的产生。体内抑制GSK 3降低了LPS给药后血清和脑IL-6水平、脑STAT 3活化和GFAP上调。STAT 3和GSK 3协同促进神经炎症，为抗炎干预提供了新的靶点。
Septic shock is a prevalent condition that, when not lethal, often causes disturbances in cognition, mood, and behavior, particularly due to central actions of the inflammatory cytokine interleukin-6 (IL-6). To identify potential targets to control brain IL-6, we tested if IL-6 produced by glia is regulated by signal transducer and activator of transcription-3 (STAT3) and glycogen synthase kinase-3 (GSK3). Lipopolysaccharide (LPS) was used to induce inflammatory responses in mice or cultured primary glia. IL-6 was measured by ELISA and other inflammatory molecules were measured using an array. Mouse brain IL-6 levels increased after central, as well as peripheral, LPS administration, consistent with glia producing a portion of brain IL-6. STAT3 in the brain was activated after peripheral or central LPS administration, and in LPS-stimulated cultured primary glia. Inhibition of STAT3 expression, function, or activation reduced by ~80% IL-6 production by primary glia, demonstrating the dependence on active STAT3. GSK3 promotes STAT3 activation, and array analysis of inflammatory molecules produced by LPS-stimulated primary glia demonstrated that IL-6 was the cytokine most diminished (>90%) by GSK3 inhibition. Inhibition of GSK3, and knockdown of GSK3β, not GSK3α, greatly inhibited IL-6 production by LPS-stimulated primary glia. Conversely, expression of active STAT3 and active GSK3 promoted IL-6 production. In vivo inhibition of GSK3 reduced serum and brain IL-6 levels, brain STAT3 activation, and GFAP upregulation following LPS administration. STAT3 and GSK3 cooperatively promote neuroinflammation, providing novel targets for anti-inflammatory intervention.
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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
DOI：
10.1084/jem.20030077
发表时间：
2003-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kano A;Wolfgang MJ;Gao Q;Jacoby J;Chai GX;Hansen W;Iwamoto Y;Pober JS;Flavell RA;Fu XY
通讯作者：
Fu XY
影响因子：
56.9
作者：
Bonni, A;Sun, Y;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.8
作者：
Beurel, Eleonore;Jope, Richard S.
通讯作者：
Jope, Richard S.
DOI：
10.1186/cc5783
发表时间：
2007
期刊：
Critical care (London, England)
影响因子：
--
作者：
Bozza FA;Salluh JI;Japiassu AM;Soares M;Assis EF;Gomes RN;Bozza MT;Castro-Faria-Neto HC;Bozza PT
通讯作者：
Bozza PT