Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound—particularly for interleukin 6 (IL-6)—possibly due to differences in sex, species/strain, and/or the brain regions studied. As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1β in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1β. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

中文翻译：

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衰老会引发雄性，尤其是雌性啮齿动物海马体中多种细胞因子的上调，但其他大脑区域的变化更为离散

尽管人们普遍认为神经炎症会导致与年龄相关的认知能力下降，但比较年轻和老年大脑中细胞因子蛋白质表达的研究在细胞因子数量和所研究的大脑区域方面却出人意料地受到限制。使问题复杂化的是，差异比比皆是——尤其是白细胞介素 6 (IL-6)——可能是由于性别、物种/菌株和/或所研究的大脑区域的差异。因此，我们通过使用 Bioplex 和蛋白质印迹来测量两种性别的多个大脑区域的多种细胞因子，使用内部培育的 2 种小鼠品系以及从 NIA 获得的大鼠，阐明了细胞因子表达如何随年龄变化。酌情使用参数和非参数统计检验。在 C57BL/6J 小鼠的腹侧海马中，我们发现 IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-6、IL-9、IL-10、IL-12p40、IL-12p70、IL-13、IL-17、eotaxin、G-CSF、干扰素 δ、KC、MIP-1a、MIP-1b 、咆哮和 TNFα 通常在女性中更明显，但 IL-5、MCP-1 或 GM-CSF 没有与年龄相关的变化。我们还发现，衰老与 11 种强烈相关的细胞因子的模块（又名网络）的出现以及腹侧海马中 IL-10 和 IL-1β 的糖基化同工型向非糖基化亚型的年龄相关转变具有独特的相关性。有趣的是，与年龄相关的海马外细胞因子表达的增加更为谨慎，雄性和雌性 C57BL/6J 小鼠的前额叶皮层、纹状体和小脑表现出与年龄相关的 IL-6 表达的强烈增加，但不是 IL-1β。重要的是，我们发现这种与年龄相关的 IL-6 普遍增加也发生在 BALB/cJ 小鼠和 Brown Norway 大鼠中，展示跨物种和饲养环境的保护。因此，与其他大脑区域相比，与年龄相关的细胞因子在海马体中的增加更为明显，并且在女性与男性中更为明显，这取决于大脑区域、遗传背景和所检查的细胞因子。