IL-1β-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes
IL-1β-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes
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DOI：
10.4049/jimmunol.174.8.4991
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发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Freund, GG
中科院分区：
文献类型：
--
作者：
O'Connor, JC;Satpathy, A;Freund, GG
慢性炎症似乎在 2 型糖尿病及其并发症中发挥着关键作用。在这里，我们测试了这样的假设：这种炎症失调会影响 IL-1 β 系统并对大脑产生功能影响。糖尿病小鼠（db/db）和非糖尿病小鼠（db/+）通过腹腔注射给药。 LPS，一种有效的细胞因子诱导剂，剂量为 100 μg/kg/小鼠。 db/db 小鼠先天免疫相关疾病行为在 2、4、8 和 12 小时分别比 db/+ 小鼠高 14.8%、33%、44.7% 和 34%。当使用固定剂量的LPS（5μg/小鼠）时，与db/+小鼠相比，db/db小鼠的疾病在4、8和12小时时再次增强18.4%、22.2%和14.5%。在糖尿病小鼠中，腹膜巨噬细胞响应 LPS 产生更多的 IL-1β，并且 LPS 诱导的腹膜 IL-1β 水平增加。重要的是，在 db/db 小鼠中，IL-1R 拮抗剂和 2 型 IL-1 受体 (IL-1R2) 未能对 LPS 做出上调反应。最后，IL-1β的外周和中枢给药本身都会在db/db小鼠中诱发疾病，其模仿外周LPS的作用，并且明显大于在db/+小鼠中观察到的疾病。综上所述，这些结果表明，db/db 小鼠的外周和大脑中 IL-1 β 介导的先天免疫均增强，其机制是由于糖尿病相关的 IL-1 β 反调节作用丧失所致。
Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1 beta system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 mu g/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34 % greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 mu g/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5 % at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1 beta in response to LPS, and peritoneal levels of IL-1 beta induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1 beta, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1 beta-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1 beta counterregulation.