ERK-mediated regulation of leukotriene biosynthesis by androgens: A molecular basis for gender differences in inflammation and asthma
ERK-mediated regulation of leukotriene biosynthesis by androgens: A molecular basis for gender differences in inflammation and asthma
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DOI：
10.1073/pnas.0809120105
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发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Werz, Oliver
中科院分区：
文献类型：
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作者：
Pergola, Carlo;Dodt, Gabriele;Werz, Oliver
5-脂氧合酶启动白三烯的生物合成，白三烯是参与正常宿主防御以及炎症和过敏性疾病的脂质介质。尽管在白三烯相关疾病中存在明显的性别偏见（例如，哮喘），在关于白三烯和5-脂氧合酶的研究中，性别方面被忽视。在这里，我们表明，白三烯形成刺激的全血或中性粒细胞从男性是大大低于女性相比，伴随着改变5-脂氧合酶贩运。这是由于细胞外信号调节激酶（ERK）的性别特异性差异激活。这些差异与不同的男性/女性睾酮加5 α-二氢睾酮水平直接相关，向女性血液或中性粒细胞中添加5 α-二氢睾酮将高（女性）LT生物合成能力降低至低（男性）水平。总之，雄激素对ERK和白三烯形成的调节构成了炎症反应和炎症性疾病（如哮喘）中性别差异的分子基础。
5-Lipoxygenase initiates the biosynthesis of leukotrienes, lipid mediators involved in normal host defense and in inflammatory and allergic disorders. Despite an obvious gender bias in leukotriene-related diseases (e.g., asthma), gender aspects have been neglected in studies on leukotrienes and 5-lipoxygenase. Here, we show that leukotriene formation in stimulated whole blood or neutrophils from males is substantially lower compared with females, accompanied by changed 5-lipoxygenase trafficking. This is due to gender-specific differential activation of extracellular signal-regulated kinases (ERKs). The differences are directly related to variant male/female testosterone plus 5 alpha-dihydrotestosterone levels, and addition of 5 alpha-dihydrotestosterone to female blood or neutrophils reduced the high (female) LT biosynthesis capacity to low (male) levels. In conclusion, regulation of ERKs and leukotriene formation by androgens constitutes a molecular basis for gender differences in the inflammatory response, and in inflammatory diseases such as asthma.