过氧化体增殖物激活型受体γ配体抑制巨噬—泡沫细胞炎性介质和基质金属蛋白酶2的分泌
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国家自然科学基金资助项目(30070869)


Inhibitory Effect of Peroxisome Proliferator Activated Receptor γ Ligands on Secretion of Inflammatory Cytokine and Matrix Metalloproteinase in Macrophages and Foam Cell
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    摘要:

    目的在证实泡沫细胞有过氧化体增殖物激活型受体γ表达的基础上,探讨其配体对巨噬细胞、泡沫细胞炎性介质和基质金属蛋白酶分泌的影响。方法体外诱导THP-1单核细胞分化为巨噬细胞,给予氧化型低密度脂蛋白进一步诱导其转变为泡沫细胞,应用逆转录聚合酶链反应检测过氧化体增殖物激活型受体γmRNA表达;过氧化体增殖物激活型受体γ配体吡格列酮干预后用Western blot检测巨噬细胞CD40蛋白的表达;用酶联免疫吸附测定法测定泡沫细胞培养上清液中白细胞介素6、肿瘤坏死因子α、基质金属蛋白酶2和9的浓度,Gelatin Zymog-raphy测定基质金属蛋白酶活性。结果巨噬细胞转化为泡沫细胞后其过氧化体增殖物激活型受体γ基因表达无显著变化。吡格列酮可显著抑制巨噬细胞CD40的表达,呈剂量依赖性;显著抑制泡沫细胞白细胞介素6、肿瘤坏死因子α和基质金属蛋白酶9的分泌(p<0.05),抑制基质金属蛋白酶9的活性,对基质金属蛋白酶2的分泌和活性无影响。结论巨噬细胞、泡沫细胞中过氧化体增殖物激活型受体γ基因表达无变化。过氧化体增殖物激活型受体γ配体从多个环节抑制致动脉粥样硬化炎性因子的分泌,减少基质金属蛋白酶的释放并抑制其活性,对防治动脉粥样硬化有利。

    Abstract:

    Aim To investigate the effect of peroxisome proliferator-activated receptor γ(PPARγ) ligands on inflammatory cytokine and matrix metalloproteinase(MMP) secretion by macrophages and foam cell. Methods THP-1 monocytes were differentiated to macrophages in vitro by addition of PMA,and then induced into foam cell by oxidized low density lipoprotein(ox-LDL).Semi-quantitative reverse transcription polymerase chain reaction(RT-PCR) was performed to detect the expression of PPARγ.Macrophage CD40 protein expression was detected by Western blot.Interleukin 6(IL-6),tumor necrosis factor α(TNF-α) and MMP-9 secretion in foam cell culture medium was measured by enzyme-linked immunosorbent assay(ELISA).MMP-9 activities were determined by gelatin zymography. Results Macrophages expressed PPARγ and treatment with ox-LDL did not affect the expression.PPARγ ligand pioglitazone greatly inhibited macrophage expression of CD40 in a dose-dependent manner.Moreover,pioglitazone significantly inhibited the secretion of IL-6,TNF-α and MMP-9 by foam cell as well as the activity of MMP9(p<0.05),although it had no effect on MMP-2 secretion or activity. Conclusions peroxisome proliferator-activated receptor γ ligands significantly inhibited the secretion of several inflammatory molecules by macrophages/foam cell which were closely related to atherosclerotic (As) plaque development and plaque instability.Thus,PPARγ ligands may have potential advantages in As therapy.

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张俊峰,葛恒,王长谦,邵琴.过氧化体增殖物激活型受体γ配体抑制巨噬—泡沫细胞炎性介质和基质金属蛋白酶2的分泌[J].中国动脉硬化杂志,2006,14(4):281~284.

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  • 收稿日期:2005-05-17
  • 最后修改日期:2006-02-08
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