Adiponectin Blocks Interleukin-18-mediated Endothelial Cell Death via APPL1-dependent AMP-activated Protein Kinase (AMPK) Activation and IKK/NF-κB/PTEN Suppression
Adiponectin Blocks Interleukin-18-mediated Endothelial Cell Death via APPL1-dependent AMP-activated Protein Kinase (AMPK) Activation and IKK/NF-κB/PTEN Suppression
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DOI：
10.1074/jbc.m804236200
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发表时间：
2008-09-05
影响因子：
4.8
通讯作者：
Valente, Anthony J.
中科院分区：
文献类型：
--
作者：
Chandrasekar, Bysani;Boylston, William H.;Valente, Anthony J.
已知脂肪细胞衍生的细胞因子脂联素具有抗炎和抗凋亡作用。在动脉粥样硬化性心血管疾病患者中，循环中的脂联素水平与促炎、促凋亡细胞因子白介素-18的水平呈负相关。IL-18和脂联素对细胞存活和炎症的相反作用促使我们研究脂联素信号是否能拮抗IL-18介导的内皮细胞死亡，并确定其潜在的分子机制。IL-18抑制Akt磷酸化及其相关激酶活性，诱导I κ B激酶(IKK)- nf - κ B依赖性PTEN活化，促进内皮细胞死亡。脂联素预处理刺激appl1依赖性AMPK活化，以磷脂酰肌醇3激酶依赖性方式逆转Akt抑制，阻断IKK-NF-kappa B-PTEN信号通路，降低caspase-3活性，阻断Bax易位，抑制内皮细胞死亡。脂联素信号传导的细胞保护作用通过AMPK激活剂5-氨基咪唑-4-羧酰胺-1- β -核苷治疗得到了再现。总的来说，这些结果表明脂联素通过ampk相关机制逆转il -18介导的内皮细胞死亡，因此可能具有减少il -18依赖性血管损伤和炎症的治疗潜力。
The adipocyte-derived cytokine adiponectin is known to exert anti-inflammatory and anti-apoptotic effects. In patients with atherosclerotic cardiovascular disease, circulating levels of adiponectin correlate inversely with those of the proinflammatory, proapoptotic cytokine interleukin (IL)-18. The opposing actions of IL-18 and adiponectin on both cell survival and inflammation led us to investigate whether adiponectin signaling antagonizes IL-18-mediated endothelial cell death and to identify the underlying molecular mechanisms. Treatment with IL-18 suppressed Akt phosphorylation and its associated kinase activity, induced I kappa B kinase (IKK)-NF-kappa B-dependent PTEN activation, and promoted endothelial cell death. Pretreatment with adiponectin stimulated APPL1-dependent AMPK activation, reversed Akt inhibition in a phosphatidylinositol 3-kinase-dependent manner, blocked IKK-NF-kappa B-PTEN signaling, reduced caspase-3 activity, blocked Bax translocation, and inhibited endothelial cell death. The cytoprotective effect of adiponectin signaling was recapitulated by treatment with the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-riboside. Collectively, these results demonstrated that adiponectin reverses IL-18-mediated endothelial cell death through an AMPK-associated mechanism, which may thus have therapeutic potential for diminishing IL-18-dependent vascular injury and inflammation.