Progesterone rapidly down-regulates the biosynthesis of 5-lipoxygenase products in human primary monocytes.
Progesterone rapidly down-regulates the biosynthesis of 5-lipoxygenase products in human primary monocytes.
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DOI：
10.1016/j.phrs.2015.01.007
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发表时间：
2015-04
影响因子：
9.3
通讯作者：
C. Pergola;A. M. Schaible;Felix Nikels;G. Dodt;H. Northoff;O. Werz
中科院分区：
文献类型：
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作者：
C. Pergola;A. M. Schaible;Felix Nikels;G. Dodt;H. Northoff;O. Werz
5-脂氧合酶(5-LO)是花生四烯酸生物合成促炎性白三烯(LTS)的关键酶，在中性粒细胞和单核细胞中受雄激素的调节，导致了LT形成的性别差异。在这里，我们发现黄体酮抑制人原代单核细胞5-LO代谢物的合成。10-100nM孕酮和1nMμ孕酮均能抑制钙离子载体A23187或脂多糖/甲酰肽刺激单核细胞产生5-LO产物。孕酮以快速和可逆的方式下调5-LO产物的形成，但在使用单核细胞匀浆的无细胞检测中并不显著抑制5-LO的活性。黄体酮对单核细胞花生四烯酸的释放及其对其他二十烷类化合物的代谢也没有明显的抑制作用。药物阻断丝裂原活化蛋白激酶、外源性补充刺激性1-油酰-2-乙酰-sn-甘油或通过络合清除细胞外钙离子时，仍可观察到孕酮对LTS的抑制作用。相反，通过两种不同的药理途径(即H89和细胞通透性PKA抑制肽)抑制PKA，可以阻止孕酮抑制5-LO产物的产生，其程度与PKA激活剂前列腺素E2和8-溴-cAMP相似，表明PKA参与了这一过程。总而言之，孕酮影响人类原代单核细胞产生5-LO产物的能力，除了雄激素外，可能还解释了促炎症LT的性别特异性影响。
5-Lipoxygenase (5-LO), the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) from arachidonic acid, is regulated by androgens in human neutrophils and monocytes accounting for sex differences in LT formation. Here we show that progesterone suppresses the synthesis of 5-LO metabolites in human primary monocytes. 5-LO product formation in monocytes stimulated with Ca2+-ionophore A23187 or with lipopolysaccharide/formyl peptide was suppressed by progesterone at concentrations of 10–100 nM in cells from females and at 1 μM in cells from males. Progesterone down-regulated 5-LO product formation in a rapid and reversible manner, but did not significantly inhibit 5-LO activity in cell-free assays using monocyte homogenates. Also, arachidonic acid release and its metabolism to other eicosanoids in monocytes were not significantly reduced by progesterone. The inhibitory effect of progesterone on LTs was still observed when mitogen-activated protein kinases were pharmacologically blocked, stimulatory 1-oleoyl-2-acetyl-sn-glycerol was exogenously supplied, or extracellular Ca2+was removed by chelation. Instead, suppression of PKA by means of two different pharmacological approaches (i.e. H89 and a cell-permeable PKA inhibitor peptide) prevented inhibition of 5-LO product generation by progesterone, to a similar extent as observed for the PKA activators prostaglandin E2and 8-Br-cAMP, suggesting the involvement of PKA. In summary, progesterone affects the capacity of human primary monocytes to generate 5-LO products and, in addition to androgens, may account for sex-specific effects on pro-inflammatory LTs.