Differential regulation of chemokine expression by peroxisome proliferator-activated receptor γ agonists -: Interactions with glucocorticoids and β2-agonists
Differential regulation of chemokine expression by peroxisome proliferator-activated receptor γ agonists -: Interactions with glucocorticoids and β2-agonists
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DOI：
10.1074/jbc.m410616200
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发表时间：
2005-01-28
影响因子：
4.8
通讯作者：
Pang, LH
中科院分区：
文献类型：
--
作者：
Nie, M;Corbett, L;Pang, LH
趋化因子介导的炎性细胞浸润是哮喘的标志。我们最近证实，糖皮质激素和β 2受体激动剂分别在人气道平滑肌（HASM）细胞中叠加或协同抑制肿瘤坏死因子-α（TNF α）诱导的趋化因子嗜酸性粒细胞趋化因子和白细胞介素-8（IL-8）的产生，这可能部分解释了它们在哮喘中的联合益处。过氧化物酶体增殖物激活受体（PPARs）也调节炎症基因的表达。我们在此报道了PPARgamma激动剂15-deoxy-Delta（12，14）- PGJ（2）（15 d-PGJ（2））和troglitazone抑制TNF α诱导的嗜酸性粒细胞趋化蛋白和单核细胞趋化蛋白-1（MCP-1）的产生，但不能抑制IL-8的产生，而PPARalpha激动剂VVY-14643则不能。糖皮质激素氟替卡松和β 2受体激动剂沙美特罗可使嗜酸性粒细胞趋化因子的抑制作用在转录水平上叠加增强，而氟替卡松和沙美特罗可分别使MCP-1的抑制作用在转录后水平上叠加增强和协同增强。Coinunoprecipitation显示，15 d-PGJ 2诱导的蛋白质-蛋白质之间的相互作用的PPARgamma和糖皮质激素受体（GR）在TNFa处理的HASM细胞，这是增强氟替卡松和沙美特罗。15 d-PGJ 2、氟替卡松和沙美特罗均抑制TNF α诱导的嗜酸细胞活化趋化因子启动子处的组蛋白H4乙酰化和NF-κ B p65与嗜酸细胞活化趋化因子启动子的结合，并诱导PPARgamma和GR与嗜酸细胞活化趋化因子启动子的结合，如通过染色质免疫沉淀测定分析的。我们的数据表明，HASM细胞中的趋化因子表达受PPARgamma激动剂的差异调节，PPARgamma和GR之间的相互作用可能是PPARgamma激动剂、糖皮质激素和β 2-激动剂对趋化因子表达的叠加和协同抑制的原因，特别是嗜酸细胞活化趋化因子基因转录的染色质依赖性抑制。这种相互作用可能具有广泛的应用，并可能为药理学和分子干预提供潜在的靶点。
Chemokine-mediated inflammatory cell infiltration is a hallmark of asthma. We recently demonstrated that glucocorticoids and beta(2)-agonists additively or synergistically suppress tumor necrosis factor-alpha (TNFalpha)-induced production of chemokines eotaxin and interleukin-8 (IL-8), respectively, in human airway smooth muscle (HASM) cells, which may partly explain their combined benefits in asthma. Peroxisome proliferator-activated receptors (PPARs) also modulate inflammatory gene expression. We reported here that the PPARgamma agonists 15-deoxy-Delta(12,14)- PGJ(2) (15d-PGJ(2)) and troglitazone, but not PPARalpha agonist VVY-14643, inhibited TNFalpha-induced production of eotaxiin and monocyte chemotactic protein-1 (MCP-1) but not IL-8. Eotaxin inhibition was transcriptional and additively enhanced by the glucocorticoid fluticasone and the beta(2)-agonist salmeterol, whereas MCP-1 inhibition was post-transcriptional and additively and synergistically enhanced by fluticasone and salmeterol, respectively. Coinununoprecipitation revealed that 15d-PGJ2 induced a protein-protein interaction between PPARgamma and the glucocorticoid receptor (GR) in TNFalpha-treated HASM cells, which was enhanced by fluticasone and salmeterol. 15d-PGJ2, fluticasone, and salmeterol all inhibited TNFalpha-induced histone H4 acetylation at the eotaxin promoter and NF-kappaB p65 binding to the eotaxin promoter and induced PPARgamma and GR association with the eotaxin promoter, as analyzed by chromatin immunoprecipitation assay. Our data suggest that chemokine expression in HASM cells is differentially regulated by PPARgamma agonists and that the interaction between PPARgamma and GR may be responsible for the additive and synergistic inhibition of chemokine expression by PPARgamma agonists, glucocorticoids, and beta(2)-agonists, particularly the chromatin-dependent suppression of eotaxin gene transcription. The interaction may have wide applications and may provide a potential target for pharmacological and molecular intervention.