脂联素通过 caveolin 介导的 ceramidase 募集和激活抑制肿瘤坏死因子-α诱导的血管炎症反应。
Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.
机构信息
From the Department of Emergency Medicine (Y.W., X.W., W.B.L., Y.Y., J.-J.L., X.-L.M.) and Department of Pathology (D.B.), Thomas Jefferson University, Philadelphia, PA; and Department of Physiology, Cardiovascular Research Center (R.S., K.P.) and Center for Translational Medicine (E.G., W.K.), Temple University, Philadelphia, PA.
出版信息
Circ Res. 2014 Feb 28;114(5):792-805. doi: 10.1161/CIRCRESAHA.114.302439. Epub 2014 Jan 7.
RATIONALE
Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered.
OBJECTIVE
The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling.
METHODS AND RESULTS
Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P<0.01). AdipoR1-KD markedly reduced globular adiponectin-induced nCDase activation, whereas AdipoR2-KD only slightly reduced. More importantly, small interfering RNA-mediated nCDase-KD markedly blocked the effect of adiponectin on TNFα-induced intercellular adhesion molecule-1 expression. AMP-activated protein kinase-KD failed to block adiponectin-induced nCDase activation and modestly inhibited adiponectin anti-inflammatory effect. In contrast, in caveolin-1 KD (Cav1-KD) cells, >87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNFα-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo.
CONCLUSIONS
These results demonstrate for the first time that adiponectin inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.
背景
脂联素具有抗炎和血管保护作用，这一点已得到广泛认可。然而，许多基本问题仍未得到解答。
目的
本研究旨在确定负责脂联素血管保护作用的脂联素受体亚型，并探讨神经酰胺酶激活在脂联素抗炎信号转导中的作用。
方法和结果
脂联素显著降低肿瘤坏死因子（TNF）α诱导的细胞间黏附分子-1表达，并减轻 TNFα诱导的人脐静脉内皮细胞氧化/硝化应激。脂联素受体 1（AdipoR1）-而非 AdipoR2-敲低（KD）几乎完全消除了这些抗炎作用。脂联素处理显著增加了中性神经酰胺酶（nCDase）活性（3.7 倍；P<0.01）。AdipoR1-KD 显著降低了球形脂联素诱导的 nCDase 激活，而 AdipoR2-KD 仅略有降低。更重要的是，小干扰 RNA 介导的 nCDase-KD 显著阻断了脂联素对 TNFα 诱导的细胞间黏附分子-1 表达的作用。AMP 激活的蛋白激酶-KD 未能阻断脂联素诱导的 nCDase 激活，仅适度抑制了脂联素的抗炎作用。相反，在 caveolin-1 KD（Cav1-KD）细胞中，>87%的脂联素诱导的 nCDase 激活丢失。虽然脂联素处理不能抑制 TNFα 诱导的细胞间黏附分子-1 表达，但在 Cav1-KD 细胞中，鞘氨醇 1-磷酸或 SEW（鞘氨醇 1-磷酸受体激动剂）的处理仍然有效。AdipoR1 和 Cav1 在人脐静脉内皮细胞中存在共定位和共沉淀。脂联素处理不影响这种相互作用。存在基础较弱的 Cav1/nCDase 相互作用，脂联素处理后显著增加。AdipoR1 或 Cav1 的敲除消除了脂联素对体内白细胞滚动和黏附的抑制作用。
结论
这些结果首次表明，脂联素通过 AdipoR1 依赖性方式抑制 Cav1 介导的神经酰胺酶募集和激活，从而抑制 TNFα 诱导的炎症反应。
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