Cross Talk between the Akt and p38α Pathways in Macrophages Downstream of Toll-Like Receptor Signaling
Cross Talk between the Akt and p38α Pathways in Macrophages Downstream of Toll-Like Receptor Signaling
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DOI：
10.1128/mcb.01691-12
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发表时间：
2013-11-01
影响因子：
5.3
通讯作者：
Arthur, J. Simon C.
中科院分区：
文献类型：
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作者：
McGuire, Victoria A.;Gray, Alexander;Arthur, J. Simon C.
通过病原体相关分子模式（pathogen-associated molecular patterns, PAMPs）刺激巨噬细胞上的toll样受体（Toll-like receptor, TLRs），导致启动宿主免疫应答所需的细胞内信号通路的激活。磷脂酰肌醇3-激酶(PI3K)-Akt和p38丝裂原活化蛋白激酶（MAPK）信号通路在TLR激活后被快速激活，并且需要协调宿主对病原体入侵的有效反应。在本研究中，我们分析了p38依赖性激酶MK2/3在Akt活化中的作用，并发现脂多糖（LPS）诱导的Akt对Thr308和Ser473的磷酸化需要p38 α和MK2/3。在使用p38抑制剂或MK2/3抑制剂处理的细胞中，Akt对Ser473和Thr308的磷酸化降低，Akt活性被抑制。此外，在TLR刺激下，缺乏MK2/3的bmdm显示Ser473和Thr308的磷酸化大大降低。然而，在巨噬细胞中，MK2/3并不直接磷酸化Akt，而是在PDK1和mTORC2的上游作用，调节Akt的磷酸化。Akt被募集到膜中的磷脂酰肌醇3,4,5-三磷酸（PIP3），在那里它被PDK1和mTORC2激活。对MK2/3缺陷骨髓源性巨噬细胞（bmdm）脂质水平的分析显示，MK2/3通过影响PIP3在膜上的可用性来调节Akt活性。这些数据描述了p38 α - mk2 /3在调节tlr诱导的巨噬细胞中Akt活化中的新作用。
The stimulation of Toll-like receptors (TLRs) on macrophages by pathogen-associated molecular patterns (PAMPs) results in the activation of intracellular signaling pathways that are required for initiating a host immune response. Both phosphatidylinositol 3-kinase (PI3K)-Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways are activated rapidly in response to TLR activation and are required to coordinate effective host responses to pathogen invasion. In this study, we analyzed the role of the p38-dependent kinases MK2/3 in the activation of Akt and show that lipopolysaccharide (LPS)-induced phosphorylation of Akt on Thr308 and Ser473 requires p38 alpha and MK2/3. In cells treated with p38 inhibitors or an MK2/3 inhibitor, phosphorylation of Akt on Ser473 and Thr308 is reduced and Akt activity is inhibited. Furthermore, BMDMs deficient in MK2/3 display greatly reduced phosphorylation of Ser473 and Thr308 following TLR stimulation. However, MK2/3 do not directly phosphorylate Akt in macrophages but act upstream of PDK1 and mTORC2 to regulate Akt phosphorylation. Akt is recruited to phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the membrane, where it is activated by PDK1 and mTORC2. Analysis of lipid levels in MK2/3-deficient bone marrow-derived macrophages (BMDMs) revealed a role for MK2/3 in regulating Akt activity by affecting availability of PIP3 at the membrane. These data describe a novel role for p38 alpha-MK2/3 in regulating TLR-induced Akt activation in macrophages.