Antiinflammatory roles of peroxisome proliferator-activated receptor γ in human alveolar macrophages
Antiinflammatory roles of peroxisome proliferator-activated receptor γ in human alveolar macrophages
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DOI：
10.1164/rccm.200207-740oc
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发表时间：
2004-01-15
影响因子：
24.7
通讯作者：
Nakamura, H
中科院分区：
文献类型：
--
作者：
Asada, K;Sasaki, S;Nakamura, H
过氧化物酶体增殖物激活受体γ（PPARgamma）是一种配体激活的转录因子，属于核受体超家族。主要在脂肪组织中表达的PPARgamma在葡萄糖代谢和脂肪形成中起主要调节作用。有趣的是，最近的研究已经证明了PPARgamma在单核细胞/巨噬细胞中的表达及其抑制活性。然而，目前还不清楚肺泡巨噬细胞（AM）是否表达功能性PPARgamma。本研究旨在研究AM中PPARgamma的表达，并阐明其功能作用。利用逆转录-聚合酶链反应和蛋白质印迹，我们证明了PPARs信使RNA和蛋白质在新鲜分离的人AM中的强表达。PPARgamma、15-deoxy-Delta（12，14）前列腺素J（2）和曲格列酮的配体显著降低了LPS诱导的AM产生的肿瘤坏死因子-α。这些配体显著上调CD 36的表达，CD 36是介导凋亡中性粒细胞吞噬作用的清道夫受体。事实上，配体处理的AM摄取的凋亡中性粒细胞的数量比未处理的AM显著更高。这些数据表明，由AM表达的PPARgamma通过抑制细胞因子产生和增加其CD 36表达以及增强凋亡中性粒细胞的吞噬作用而发挥抗炎作用，这是解决炎症的必要过程。这表明PPARgamma配体在肺部炎性疾病中的潜在治疗应用。
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcriptional factor belonging to the nuclear receptor superfamily. PPARgamma, which is predominantly expressed in adipose tissue, plays a major regulatory role in glucose metabolism and adipogenesis. Interestingly, recent studies have demonstrated PPARgamma expression in monocytes/macrophages and its antiinflammatory activities. However, it is unclear whether alveolar macrophages (AMs) express functional PPARgamma. The present study was conducted to investigate the expression of PPARgamma by AMs and to elucidate its functional role. Using reverse transcription-polymerase chain reaction and Western blotting, we demonstrated the strong expression of PPARs messenger RNA and protein in freshly isolated human AMs. Ligands of PPARgamma, 15-deoxy-Delta(12,14)prostaglandin J(2), and troglitazone significantly decreased LIPS-induced tumor necrosis factor-alpha production by AMs. These ligands markedly upregulated the expression of CD36, a scavenger receptor that mediates the phagocytosis of apoptotic neutrophils. Indeed, ligand-treated AMs ingested a significantly higher number of apoptotic neutrophils than untreated AMs. These data indicate that PPARgamma expressed by AMs play an antiinflammatory role through inhibiting cytokine production and increasing their CD36 expression together with the enhanced phagocytosis of apoptotic neutrophils, which is an essential process for the resolution of inflammation. This suggests the potential therapeutic application of PPARgamma ligands in inflammatory disorders of the lung.