AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.
AMPK-Activated Protein Kinase Suppresses Ccr2 Expression by Inhibiting the NF-κB Pathway in RAW264.7 Macrophages.
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DOI：
10.1371/journal.pone.0147279
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Vavvas DG
中科院分区：
文献类型：
--
作者：
Kumase F;Takeuchi K;Morizane Y;Suzuki J;Matsumoto H;Kataoka K;Al-Moujahed A;Maidana DE;Miller JW;Vavvas DG
C-C 趋化因子受体 2 (Ccr2) 是经典 (M1) 巨噬细胞激活的关键促炎标志物。尽管已知 Ccr2 可以组成型和诱导型表达，但其表达的完整调控机制仍不清楚。 AMP 激活蛋白激酶 (AMPK) 不仅是能量稳态的主要调节因子，也是炎症的中心调节因子。在本研究中，我们试图评估 AMPK 在静息 (M0) 或 LPS 诱导的 M1 状态下调节 RAW264.7 巨噬细胞 Ccr2 蛋白水平的作用。在 M0 和 M1 RAW264.7 巨噬细胞中，siRNA 敲低 AMPKα1 亚基导致 Ccr2 水平增加，而 AMPK 的药理学 (A769662) 激活，以 AMPK 依赖性方式减弱 LPS 诱导的 Ccr2 表达增加。 AMPK 下调导致的 Ccr2 水平增加可被 NF-κB 抑制部分逆转，而 TNF-a 抑制则效果甚微。我们的结果表明，AMPK 是 RAW264.7 巨噬细胞中 Ccr2 表达的负调节因子，并且 AMPK 抑制 Ccr2 的作用机制部分是通过 NF-κB 途径介导的。
C-C chemokine receptor 2 (Ccr2) is a key pro-inflammatory marker of classic (M1) macrophage activation. Although Ccr2 is known to be expressed both constitutively and inductively, the full regulatory mechanism of its expression remains unclear. AMP-activated protein kinase (AMPK) is not only a master regulator of energy homeostasis but also a central regulator of inflammation. In this study, we sought to assess AMPK’s role in regulating RAW264.7 macrophage Ccr2 protein levels in resting (M0) or LPS-induced M1 states. In both M0 and M1 RAW264.7 macrophages, knockdown of the AMPKα1 subunit by siRNA led to increased Ccr2 levels whereas pharmacologic (A769662) activation of AMPK, attenuated LPS-induced increases in Ccr2 expression in an AMPK dependent fashion. The increases in Ccr2 levels by AMPK downregulation were partially reversed by NF-κB inhibition whereas TNF-a inhibition had minimal effects. Our results indicate that AMPK is a negative regulator of Ccr2 expression in RAW264.7 macrophages, and that the mechanism of action of AMPK inhibition of Ccr2 is mediated, in part, through the NF-κB pathway.