Pharmazentrum Frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Faculty of Medicine, Goethe-University Frankfurt, D-60590 Frankfurt am Main, Germany.
Int J Mol Sci. 2021 Sep 30;22(19):10623. doi: 10.3390/ijms221910623.
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
深入了解与性别相关的免疫调节仍然是开发适当疾病模型和治疗策略以实现个体化医学的关键前提。在这里，研究了介导疾病缓解的细胞因子产生的关键参数。在这些细胞因子中，STAT3 激活的白细胞介素 (IL)-22 主要与组织损伤的恢复有关。通过研究典型的对乙酰氨基酚诱导的肝损伤，我们证明了雌性小鼠中 IL-22 的表达增强。使用脂多糖或 αCD3/CD28 刺激的鼠脾细胞在细胞水平上证实了增加的雌性 IL-22，以模拟先天或适应性免疫激活。有趣的是，睾酮或二氢睾酮降低了雌性而非雄性脾细胞中 IL-22 的产生。使用 PMA/PHA 刺激的 T 细胞淋巴瘤 EL-4 细胞进行的机制研究证实了睾酮/二氢睾酮降低 IL-22 产生的能力。此外，我们通过染色质免疫沉淀证明，睾酮会损害雄性激素受体与 IL-22 启动子中异源反应元件的结合。总体而言，经历急性肝损伤的雌性小鼠和经炎症激活的培养雌性脾细胞显示出增加的 IL-22。这一观察结果可能与雄性中雄激素的免疫抑制作用有关。所呈现的数据与女性中表现出的更明显的免疫警觉性一致，这可能与某些免疫性疾病的性别特异性病程有关。
