Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, MD F3-07, Research Triangle Park, NC 27709, USA.
Sci Signal. 2010 Oct 12;3(143):ra74. doi: 10.1126/scisignal.2001077.
Males and females show differences in the prevalence of many major diseases that have important inflammatory components to their etiology. These gender-specific diseases, which include autoimmune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, are largely considered to reflect the actions of sex hormones on the susceptibility to inflammatory stimuli. However, inflammation reflects a balance between pro- and anti-inflammatory signals, and investigation of gender-specific responses to the latter has been neglected. Glucocorticoids are the primary physiological anti-inflammatory hormones in mammals, and synthetic derivatives of these hormones are prescribed as anti-inflammatory agents, irrespective of patient gender. We explored the possibility that sexually dimorphic actions of glucocorticoid regulation of gene expression may contribute to the dimorphic basis of inflammatory disease by evaluating the rat liver, a classic glucocorticoid-responsive organ. Surprisingly, glucocorticoid administration expanded the set of hepatic sexually dimorphic genes. Eight distinct patterns of glucocorticoid-regulated gene expression were identified, which included sex-specific genes. Our experiments also defined specific genes with altered expression in response to glucocorticoid treatment in both sexes, but in opposite directions. Pathway analysis identified sex-specific glucocorticoid-regulated gene expression in several canonical pathways involved in susceptibility to and progression of diseases with gender differences in prevalence. Moreover, a comparison of the number of genes involved in inflammatory disorders between sexes revealed 84 additional glucocorticoid-responsive genes in the male, suggesting that the anti-inflammatory actions of glucocorticoids are more effective in males. These gender-specific actions of glucocorticoids in liver were substantiated in vivo with a sepsis model of systemic inflammation.
男性和女性在许多主要疾病的患病率上存在差异，这些疾病的病因都有重要的炎症成分。这些性别特异性疾病包括自身免疫性疾病、肝细胞癌、糖尿病和骨质疏松症，它们在很大程度上被认为反映了性激素对炎症刺激易感性的作用。然而，炎症反映了促炎和抗炎信号之间的平衡，而对后者的性别特异性反应的研究一直被忽视。糖皮质激素是哺乳动物中主要的生理性抗炎激素，这些激素的合成衍生物被作为抗炎剂开处方，而不论患者的性别如何。我们通过评估大鼠肝脏（一种经典的糖皮质激素反应器官），探讨了糖皮质激素调节基因表达的性别二态作用可能导致炎症性疾病的性别二态基础的可能性。令人惊讶的是，糖皮质激素给药扩大了肝脏性别二态基因的集合。确定了八种不同的糖皮质激素调节基因表达模式，其中包括性别特异性基因。我们的实验还定义了在两性中对糖皮质激素治疗有反应但表达方向相反的特定基因。途径分析确定了几个具有性别特异性的糖皮质激素调节基因表达的经典途径，这些途径涉及到与性别差异相关的疾病的易感性和进展。此外，比较两性中涉及炎症性疾病的基因数量，发现男性中额外有 84 个糖皮质激素反应基因，这表明糖皮质激素的抗炎作用在男性中更为有效。这些糖皮质激素在肝脏中的性别特异性作用在全身炎症的脓毒症模型中得到了体内证实。
