AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis.
AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis.
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DOI：
10.1371/journal.pone.0140452
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liu-Bryan R
中科院分区：
文献类型：
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作者：
Guma M;Wang Y;Viollet B;Liu-Bryan R
AMP活化蛋白激酶（AMPK）是一种丝氨酸/苏氨酸蛋白激酶，在调节细胞能量平衡中起重要作用。它是脂质和葡萄糖代谢的中心调节剂。许多研究表明，AMPK激活发挥显着的抗炎和免疫抑制作用。在这项研究中，我们评估了AMPK的靶向激活是否抑制体内炎性关节炎。我们在抗原诱导的关节炎（AIA）和被动K/BxN血清诱导的关节炎小鼠模型中检测了A-769662（一种特异性AMPK激动剂）（60 mg/kg/bid）的作用。被动K/BxN血清诱导的关节炎模型也应用于AMPKα1缺陷小鼠。采集关节并进行组织学分析。通过ELISA测定关节组织和血清中的IL-6表达。在体外检测了A-769662对骨髓源性巨噬细胞（BMDM）对TLR 2和TLR 4激动剂刺激反应的影响。在两种小鼠模型中，A-769662激活AMPK可减少炎症浸润和关节损伤。在A-769662处理的小鼠中，血清和关节炎关节中的IL-6表达显著降低。AMPKα1缺陷小鼠轻度引起临床关节炎增加。在用TLR 2或TLR 4激动剂刺激的BMDM中，A-769662在mRNA和蛋白水平上抑制IL-6表达、p65 NF-κB磷酸化和MAPK磷酸化。通过特异性AMPK激动剂A-769662激活AMPK抑制小鼠的炎性关节炎以及血清和关节炎关节中的IL-6表达。这些数据表明，AMPK的靶向激活有可能成为IL-6依赖性炎性关节炎的有效治疗策略。
AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase critically involved in the regulation of cellular energy homeostasis. It is a central regulator of both lipid and glucose metabolism. Many studies have suggested that AMPK activation exert significant anti-inflammatory and immunosuppressive effects. In this study, we assessed whether targeted activation of AMPK inhibits inflammatory arthritis in vivo. We tested the effect of A-769662, a specific AMPK agonist (60mg/kg/bid) in mouse models of antigen-induced arthritis (AIA) and passive K/BxN serum-induced arthritis. The passive K/BxN serum-induced arthritis model was also applied to AMPKα1-deficient mice. Joints were harvested and subjected to histological analysis. IL-6 expression was measured in both joint tissues and sera by ELISA. The effect of A-769662 on bone marrow derived macrophage (BMDM) response to stimulation with TLR2 and TLR4 agonists was tested in vitro. AMPK activation by A-769662 reduced inflammatory infiltration and joint damage in both mouse models. IL-6 expression in serum and arthritic joints was significantly decreased in A-769662-treated mice. AMPKα1 deficient mice mildly elicited an increase of clinical arthritis. IL-6 expression at both mRNA and protein levels, phosphorylation of p65 NF-κB and MAPK phosphorylation were inhibited by A-769662 in BMDMs stimulated with either TLR2 or TLR4 agonists. AMPK activation by specific AMPK agonist A-769662 suppressed inflammatory arthritis in mice as well as IL-6 expression in serum and arthritic joints. These data suggest that targeted activation of AMPK has a potential to be an effective therapeutic strategy for IL-6 dependent inflammatory arthritis.