Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase
Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase
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DOI：
10.1038/22572
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发表时间：
1999-07-22
期刊：
影响因子：
64.8
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
Huang, JT;Welch, JS;Glass, CK
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）是一种配体依赖性核受体，参与调节发育和体内平衡的关键方面，包括脂肪细胞分化（1）、葡萄糖代谢（2，3）和巨噬细胞发育和功能（4-6）。PPAR-gamma被一系列合成和天然存在的物质激活，包括抗糖尿病噻唑烷二酮（2，3），多不饱和脂肪酸（7），15-脱氧-Delta（12，14）前列腺素J（2）（参考文献8，9）和氧化低密度脂蛋白的组分，如13-羟基十八碳二烯酸（13-HODE）和15-羟基二十碳四烯酸（15-HETE）（10），然而，还没有确定PPAR-γ的内源性配体及其体内产生方式。在单核细胞和巨噬细胞中，13-HODE和15-HETE可分别由亚油酸和花生四烯酸通过12/15-脂氧合酶生成，该酶可被T（H）2衍生的细胞因子白细胞介素-4上调（参考文献11）。在这里，我们表明，白细胞介素-4也诱导的PPAR-gamma的表达，并提供证据表明，协同诱导的PPAR-gamma和12/15-脂氧合酶介导的白细胞介素-4依赖的转录的CD 36基因在巨噬细胞。这些发现揭示了12/15-脂氧合酶在产生内源性PPAR-gamma配体中的生理作用，并提出了细胞因子调节核受体功能的范例。
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation(1), glucose metabolism(2,3) and macrophage development and function(4-6). PPAR-gamma is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones(2,3), polyunsaturated fatty acids(7), 15-deoxy-Delta(12,14)prostaglandin J(2) (refs 8, 9) and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE)(10), However, the identities of endogenous ligands for PPAR-gamma and their means of production in vivo have not been established. In monocytes and macrophages, 13-HODE and 15-HETE can be generated from linoleic and arachidonic acids, respectively, by a 12/15-lipoxygenase that is upregulated by the T(H)2-derived cytokine interleukin-4 (ref. 11). Here we show that interleukin-4 also induces the expression of PPAR-gamma and provide evidence that the coordinate induction of PPAR-gamma and 12/15-lipoxygenase mediates interleukin-4-dependent transcription of the CD36 gene in macrophages. These findings reveal a physiological role of 12/15-lipoxygenase in the generation of endogenous ligands for PPAR-gamma, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.