GSK-3 mediates differentiation and activation of proinflammatory dendritic cells
GSK-3 mediates differentiation and activation of proinflammatory dendritic cells
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DOI：
10.1182/blood-2006-06-028951
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发表时间：
2007-02-15
期刊：
影响因子：
20.3
通讯作者：
Luft, Thomas
中科院分区：
文献类型：
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作者：
Rodionova, Elena;Conzelmann, Michael;Luft, Thomas
树突状细胞（DC）表达特定功能所需的细胞内分子网络的关键组成部分尚未确定。使用人单核细胞来源的DC分化的体外模型，本研究调查糖原合成酶激酶3（GSK-3），一种多功能酶的细胞分化，凋亡，自我更新和运动的关键作用，在这种情况下。我们证明GSK-3（1）在DC分化过程中抑制巨噬细胞发育，（2）在未成熟DC中具有组成性活性并抑制自发成熟，（3）获得介导高水平IL-12、IL-6和TNF-α分泌的促炎功能状态，并在DC活化的背景下部分抑制IL-10。具体而言，GSK-3通过整合其他激酶引发GSK-3靶标的活性和Akt-1的抑制作用，增强IL-12 p35 mRNA表达，从而促进促炎细胞因子IL-12 p70的产生。因此，GSK-3可能作为参与促炎DC分化和活化的活化和抑制途径的关键整合剂。
The key components of the intracellular molecular network required for the expression of a specific function of dendritic cells (DCs) are as yet undefined. Using an in vitro model of human monocyte-derived DC differentiation, this study investigates the role of glycogen synthase kinase 3 (GSK-3), a multifunctional enzyme critical for cellular differentiation, apoptosis, self-renewal, and motility, in this context. We demonstrate that GSK-3 (1) inhibits macrophage development during differentiation of DCs, (2) is constitutively active in immature DCs and suppresses spontaneous maturation, and (3) acquires a proinflammatory functional status mediating high levels of IL-12, IL-6, and TNF-alpha secretion, and partially inhibits IL-10 in the context of DC activation. In particular, GSK-3 enhances IL-12p35 mRNA expression and thus the production of the proinflammatory cytokine IL-12p70 by integrating the activities of other kinases priming GSK-3 targets and the inhibitory effects of Akt-1. GSK-3 may therefore act as a key integrator of activating and inhibitory pathways involved in proinflammatory DC differentiation and activation.