Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347
Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347
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DOI：
10.4049/jimmunol.173.4.2762
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发表时间：
2004-08-15
影响因子：
4.4
通讯作者：
Leist, M
中科院分区：
文献类型：
--
作者：
Falsig, J;Pörzgen, P;Leist, M
小鼠星形胶质细胞的炎症转化与多种MAPK的激活相关，抑制JNK或p38等末端MAPK可抑制炎症反应。混合谱系激酶（MLKs）是MAPK激酶的一个家族，因此可能参与星形胶质细胞炎症。在这项研究中，我们探讨了MLK抑制剂CEP-1347和CEP-11004对TNF + IL-1或含有额外ifn - γ的完整细胞因子混合物对小鼠星形胶质细胞激活的影响。这些化合物阻断NO-、PG-和IL-6的释放，中位抑制浓度约为100 nM。这种活性与JNK和p38通路在完全细胞因子混合处理的星形胶质细胞中被激活的阻断相关。虽然CEP-1347不影响NF-kappaB的激活，但在转录水平上阻滞了环氧化酶-2和诱导型NO合成酶的表达。17个炎症相关基因的定量转录谱分析揭示了MLK抑制星形胶质细胞活化的特定调节模式，如抗应激因子凋亡蛋白2抑制剂和活化转录因子4上调，对锰超氧化物歧化酶和caspase-11无影响，TNF、GM-CSF、尿激酶型纤溶酶原激活物、IL-6等主要炎症因子下调。总之，MLK抑制剂如CEP-1347是一种高效的星形胶质细胞免疫调节剂，具有新的活性谱。
Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-gamma. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of similar to100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-kappaB it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astrocyte activation by MLK inhibition, for instance, characterized by up-regulation of the anti-stress factors inhibitor of apoptosis protein-2 and activated transcription factor 4, no effect on manganese superoxide dismutase and caspase-11, and down-regulation of major inflammatory players like TNF, GM-CSF, urokinase-type plasminogen activator, and IL-6. In conclusion, MLK inhibitors like CEP-1347 are highly potent astrocyte immune modulators with a novel spectrum of activity.