Glucocorticoids prime the inflammatory response of human hippocampal cells through up-regulation of inflammatory pathways
Glucocorticoids prime the inflammatory response of human hippocampal cells through up-regulation of inflammatory pathways
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DOI：
10.1016/j.bbi.2020.03.012
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发表时间：
2020-07-01
影响因子：
15.1
通讯作者：
Pariante, Carmine M.
中科院分区：
文献类型：
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作者：
Horowitz, Mark A.;Cattaneo, Annamaria;Pariante, Carmine M.
促炎细胞因子的增加和下丘脑-垂体-肾上腺（HPA）轴的过度活跃都与抑郁症的发病机制有关。然而，这些解释似乎是相互矛盾的，因为糖皮质激素被公认具有抗炎作用。有两种假说可以解决这一矛盾：糖皮质激素受体抵抗的中介存在，或者糖皮质激素在某些情况下可以增强炎症过程的可能性。我们试图在一个与抑郁症有重要关联的细胞模型中研究这些假设：人类海马祖细胞。体外给我们证明,地塞米松,后跟一个24小时休息24小时间隔强化免疫挑战前炎症影响在这些神经细胞,也就是说,il - 6蛋白分泌增加引起的刺激与il - 1β(24小时10 ng / mL) + 49% (P < 0.05)的浓度100海里,+ 70% (P < 0.01)为1μm .这些影响时间和剂量依赖性,需要糖皮质激素受体的激活。使用Human Gene 2.1 Array Strips进行基因表达微阵列分析表明，糖皮质激素治疗上调了几种先天免疫基因，包括趋化因子和nod样受体NLRP6；利用转录因子结合基序，我们发现细胞中诱导糖皮质激素耐药的证据有限。我们的数据提示了一种机制，通过这种机制，压力可能使免疫系统为增加炎症做好准备，并提示压力和炎症可能在抑郁症的发病机制中协同作用。
Increased pro-inflammatory cytokines and an overactive hypothalamic-pituitary-adrenal (HPA) axis have both been implicated in the pathogenesis of depression. However, these explanations appear contradictory because glucocorticoids are well recognised for their anti-inflammatory effects. Two hypotheses exist to resolve this paradox: the mediating presence of glucocorticoid receptor resistance, or the possibility that glucocorticoids can potentiate inflammatory processes in some circumstances. We sought to investigate these hypotheses in a cell model with significant relevance to depression: human hippocampal progenitor cells. We demonstrated that dexamethasone in vitro given for 24 hours and followed by a 24 hours rest interval before an immune challenge potentiates inflammatory effects in these neural cells, that is, increases the IL-6 protein secretion induced by stimulation with IL-1 beta (10 ng/mL for 24 hours) by + 49% (P < 0.05) at a concentration of 100 nM and by + 70% (P < 0.01) for 1 mu M. These effects are time- and dose-dependent and require activation of the glucocorticoid receptor. Gene expression microarray assays using Human Gene 2.1st Array Strips demonstrated that glucocorticoid treatment up-regulated several innate immune genes, including chemokines and Nod-like receptor, NLRP6; using transcription factor binding motifs we found limited evidence that glucocorticoid resistance was induced in the cells. Our data suggests a mechanism by which stress may prime the immune system for increased inflammation and suggests that stress and inflammation may be synergistic in the pathogenesis of depression.