AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages
AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages
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DOI：
10.1074/jbc.m115.678243
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发表时间：
2015-10-02
影响因子：
4.8
通讯作者：
Bruene, Bernhard
中科院分区：
文献类型：
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作者：
Namgaladze, Dmitry;Snodgrass, Ryan G.;Bruene, Bernhard
巨噬细胞响应 Th2 细胞因子 11,-4，花生四烯酸 15-脂氧合酶 (ALOX15) 表达升高。尽管 IL-4 信号传导会引发抗炎反应，但 15-脂氧合酶可能以上下文依赖性方式支持或抑制炎症过程。 AMP 激活蛋白激酶 (AMPK) 是一种支持抗炎巨噬细胞表型的代谢传感器/调节器。 AMPK 激活如何与 IL-4 引发的基因特征联系起来仍有待探索。使用 IL-4 刺激的原代人巨噬细胞，我们观察到 ALOX15 mRNA 和蛋白表达升高，但 AMPK 激活会减弱这种表达。 AMPK 激活剂，例如苯乙双胍和氨基咪唑-4-甲酰胺 1-0D-呋喃核糖苷抑制 IL-4 诱发的 STAT3 激活，同时完整保留 STAT6 激活和典型 IL-4 响应基因的诱导。此外，苯乙双胍还可阻止 IL-4 诱导的 AL0X15 启动子处组蛋白 H3 的 STAT6 和 Lys-9 乙酰化关联。激活 AMPK 会消除 IL-4 刺激的巨噬细胞中 15-脂氧合酶花生四烯酸代谢物的产生，这可以通过 AI,OX15 敲低来模拟。最后，用 IL-4 预处理巨噬细胞 48 小时，增加了随后用脂多糖刺激诱导的促炎细胞因子 IL-6、IL-12、CXCL9 和 CXCI,10 的 mRNA 表达。在与 IL-4 孵育期间抑制 AI、OX15 或激活 AMPK 会减弱这种反应。总之，通过 AMPK 限制 ALOX15 表达可能会促进 IL-4 刺激的人巨噬细胞的抗炎表型。
Macrophages respond to the Th2 cytokine 11,-4 with elevated expression of arachidonate 15-lipoxygenase (ALOX15). Although IL-4 signaling elicits anti-inflammatory responses, 15-lipoxygenase may either support or inhibit inflammatory processes in a context-dependent manner. AMP-activated protein kinase (AMPK) is a metabolic sensor/regulator that supports an anti-inflammatory macrophage phenotype. How AMPK activation is linked to IL-4-elicited gene signatures remains unexplored. Using primary human macrophages stimulated with IL-4, we observed elevated ALOX15 mRNA and protein expression, which was attenuated by AMPK activation. AMPK activators, e.g. phenformin and aminoimidazole-4-carboxamide 1-0D-ribofuranoside inhibited IL-4-evoked activation of STAT3 while leaving activation of STAT6 and induction of typical IL-4responsive genes intact. In addition, phenformin prevented IL-4-induced association of STAT6 and Lys-9 acetylation of histone H3 at the AL0X15 promoter. Activating AMPK abolished cellular production of 15-lipoxygenase arachidonic acid metabolites in IL-4-stimulated macrophages, which was mimicked by AI,OX15 knockdown. Finally, pretreatment of macrophages with IL-4 for 48 h increased the mRNA expression of the proinflammatory cytokines IL-6, IL-12, CXCL9, and CXCI,10 induced by subsequent stimulation with lipopolysaccharide. This response was attenuated by inhibition of AI,OX15 or activation of AMPK during incubation with IL-4. In conclusion, limiting ALOX15 expression by AMPK may promote an anti-inflammatory phenotype of IL-4-stimulated human macrophages.