Distinct Functions of the Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinases MK2 and MK3 MK2 MEDIATES LIPOPOLYSACCHARIDE-INDUCED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION BY PREVENTING NEGATIVE REGULATORY EFFECTS OF MK3
Distinct Functions of the Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinases MK2 and MK3 MK2 MEDIATES LIPOPOLYSACCHARIDE-INDUCED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION BY PREVENTING NEGATIVE REGULATORY EFFECTS OF MK3
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DOI：
10.1074/jbc.m111.235275
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发表时间：
2011-07-08
影响因子：
4.8
通讯作者：
Bode, Johannes G.
中科院分区：
文献类型：
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作者：
Ehlting, Christian;Ronkina, Natalia;Bode, Johannes G.
在LPS处理的巨噬细胞中，STAT 3的激活被认为是终止炎性细胞因子产生的关键。通过分析MAPK活化的蛋白激酶（MK）2和MK 3在LPS诱导的巨噬细胞中的STAT 3活化中的作用，本研究提供了证据，表明MK 2对于应答LPS的STAT 3活化是至关重要的，因为它阻止MK 3阻碍IFN β基因表达。因此，LPS诱导的IFN β基因表达在MK2缺陷型巨噬细胞中下调，并且可以通过MK2/3（-/-）巨噬细胞中MK 3基因的额外消融来重建。这与LPS诱导的IL-10表达相反，后者基本上需要MK2的存在。进一步分析参与IFN β基因表达的转录调控的下游信号事件表明，在MK2不存在的情况下，MK 3损害干扰素调节因子3蛋白的表达和活化，并抑制p65的核转位。p65核转位的这种抑制与I κ B α的表达增强和降解延迟相一致，而I κ B α mRNA和蛋白质的表达在不存在MK 2的情况下受损。针对I κ B α的siRNA能够重建MK 2（-/-）巨噬细胞中的I κ B α表达的观察结果表明，I κ B α的表达增强和降解延迟与NF κ B依赖性I κ B α表达受损在功能上相关。总之，提供的证据表明，MK2调节LPS诱导的IFN β表达和下游STAT 3活化，因为它抑制MK 3介导对NF κ B和干扰素调节因子3依赖性LPS信号传导的负调节作用。
In LPS-treated macrophages, activation of STAT3 is considered to be crucial for terminating the production of inflammatory cytokines. By analyzing the role of MAPK-activated protein kinase (MK) 2 and MK3 for LPS-induced STAT3 activation in macrophages, the present study provides evidence that MK2 is crucial for STAT3 activation in response to LPS because it prevents MK3 from impeding IFN beta gene expression. Accordingly, LPS-induced IFN beta gene expression is down-regulated in MK2-deficient macrophages and can be reconstituted by additional ablation of the MK3 gene in MK2/3(-/-) macrophages. This is in contrast to LPS-induced IL-10 expression, which essentially requires the presence of MK2. Further analysis of downstream signaling events involved in the transcriptional regulation of IFN beta gene expression suggests that, in the absence of MK2, MK3 impairs interferon regulatory factor 3 protein expression and activation and inhibits nuclear translocation of p65. This inhibition of p65 nuclear translocation coincides with enhanced expression and delayed degradation of I kappa B alpha, whereas expression of I kappa B alpha mRNA and protein is impaired in the absence of MK2. The observation that siRNA directed against I kappa B alpha is able to reconstitute I kappa B alpha expression in MK2(-/-) macrophages suggests that enhanced expression and delayed degradation of I kappa B alpha and impaired NF kappa B-dependent I kappa B alpha expression are functionally linked. In summary, evidence is provided that MK2 regulates LPS-induced IFN beta expression and downstream STAT3 activation as it restrains MK3 from mediating negative regulatory effects on NF kappa B-and interferon regulatory factor 3-dependent LPS signaling.