Toll-Like Receptor 4 Engagement Inhibits Adenosine 5′-Monophosphate-Activated Protein Kinase Activation through a High Mobility Group Box 1 Protein-Dependent Mechanism
Toll-Like Receptor 4 Engagement Inhibits Adenosine 5′-Monophosphate-Activated Protein Kinase Activation through a High Mobility Group Box 1 Protein-Dependent Mechanism
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DOI：
10.2119/molmed.2011.00401
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发表时间：
2012-04-01
影响因子：
5.7
通讯作者：
Zmijewski, Jaroslaw W.
中科院分区：
文献类型：
--
作者：
Tadie, Jean-Marc;Bae, Hong-Beom;Zmijewski, Jaroslaw W.
尽管药理学诱导的腺苷5′-单磷酸激酶（AMPK）激活对toll样受体4 （TLR4）诱导的细胞活化具有有效的抗炎作用，但很少有证据表明AMPK在炎症条件下被激活。在目前的研究中，我们研究了TLR4参与可能影响中性粒细胞和巨噬细胞在体外条件下以及在脂多糖（LPS）诱导的急性肺损伤期间在肺中激活AMPK的能力的机制。我们发现，中性粒细胞或巨噬细胞与LPS孵化会降低5-氨基咪唑-4-羧酰胺-1- β - d -核呋喃苷（AICAR）或过氧化氢（H2O2）激活AMPK的能力。尽管在LPS处理的中性粒细胞和LPS暴露小鼠的肺部中，AMP与腺苷5'-三磷酸（ATP）的比例增加，这一情况应该导致AMPK活化，但没有发现AMPK活化。免疫细胞化学和Western blot分析显示，促炎介质高迁移率组盒1蛋白（HMGB1）的核向胞质易位与lps刺激的巨噬细胞中AMPK活化的抑制相关。此外，虽然诱导HMGB1过表达导致AMPK活化受到抑制，但小干扰RNA （Small interfering RNA, siRNA）诱导的HMGB1敲低与AICAR培养的巨噬细胞AMPK活化增强相关。在LPS刺激的巨噬细胞和暴露于LPS的小鼠肺中，发现AMPK的上游激活剂肝激酶B1 （LKB1）与HMGB1之间的相互作用增加。这些结果表明，在tlr4激活的细胞中，HMGB1的核向细胞质易位通过与LKB1结合来增强炎症反应，从而抑制AMPK激活的抗炎作用。在线地址：http://www.molmed.org doi: 10.2119/molmed.2011.00401
Despite the potent antiinflammatory effects of pharmacologically induced adenosine 5'-monophosphate kinase (AMPK) activation on Toll-like receptor 4 (TLR4)-induced cellular activation, there is little evidence that AMPK is activated during inflammatory conditions. In the present studies, we examined mechanisms by which TLR4 engagement may affect the ability of AMPK to become activated in neutrophils and macrophages under in vitro conditions and in the lungs during lipopolysaccharide (LPS)-induced acute lung injury. We found that incubation of neutrophils or macrophages with LPS diminished the ability of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) or hydrogen peroxide (H2O2) to activate AMPK. Although ratios of AMP to adenosine 5'-triphosphate (ATP) were increased in LPS-treated neutrophils and in the lungs of LPS exposed mice, a condition that should result in AMPK activation, no activation of AMPK was found. Immunocytochemistry and Western blot analysis revealed that nuclear to cytosolic translocation of the proinflammatory mediator high mobility group box 1 protein (HMGB1) correlated with inhibition of AMPK activation in LPS-stimulated macrophages. Moreover, while induced overexpression of HMGB1 resulted in inhibition of AMPK activation, Small interfering RNA (siRNA)-induced knockdown of HMGB1 was associated with enhanced activation of AMPK in macrophages incubated with AICAR. Increased interaction between liver kinase B1 (LKB1), an upstream activator of AMPK, and HMGB1 was found in LPS-stimulated macrophages and in the lungs of mice exposed to LPS. These results suggest that nuclear to cytoplasmic translocation of HMGB1 in TLR4-activated cells potentiates inflammatory responses by binding to LKB1, thereby inhibiting the antiinflammatory effects of AMPK activation. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00401