FOXO3 as a new IKK-ε-controlled check-point of regulation of IFN-β expression
FOXO3 as a new IKK-ε-controlled check-point of regulation of IFN-β expression
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DOI：
10.1002/eji.201141969
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发表时间：
2012-04-01
影响因子：
5.4
通讯作者：
Udalova, Irina A.
中科院分区：
文献类型：
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作者：
Luron, Lionel;Saliba, David;Udalova, Irina A.
细胞存活转录因子FOXO 3最近被认为与调节树突状细胞（DC）产生促炎细胞因子有关，但其分子机制尚不清楚。提示FOXO_3可拮抗NF-？B活性，而IKK-β被证明可抑制FOXO 3，表明两种途径之间存在交叉作用。因此，必须严格调节FOXO 3活性以允许适当的炎症反应。在这里，我们表明，在人单核细胞衍生的DC（MDDC），FOXO 3能够拮抗信号转导中间体下游的Toll样受体（TLR）4，如NF-？B和干扰素调节因子（IRF），导致干扰素（IFN）-β表达的抑制。我们还证明了FOXO 3本身的活性受IKK-e的调节，IKK-e是一种参与IFN-β产生的激酶，其磷酸化并灭活FOXO 3以响应TLR 4激动剂。因此，我们确定FOXO 3作为IRF激活和IFN-β表达调节的新IKK-e控制检查点，为FOXO 3在免疫应答控制中的作用提供了新的见解。
Cell survival transcription factor FOXO3 has been recently implicated in moderating pro-inflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-?B activity, while IKK-beta was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-?B and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-beta expression. We also demonstrate that the activity of FOXO3 itself is regulated by IKK-e, a kinase involved in IFN-beta production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-e-controlled check-point of IRF activation and regulation of IFN-beta expression, providing new insight into the role of FOXO3 in immune response control.