Johnson Daniel R, O'Connor Jason C, Dantzer Robert, Freund Gregory G
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15184-9. doi: 10.1073/pnas.0507191102. Epub 2005 Oct 10.
To the ill patient with diabetes, the behavioral symptoms of sickness such as fatigue and apathy are debilitating and can prevent recuperation. Here we report that peripherally administered insulin-like growth factor 1 (IGF-1) attenuates LPS-dependent depression of social exploration (sickness) in nondiabetic (db/+) but not in diabetic (db/db) mice. We show that the insulin/IGF-1 mimetic vanadyl sulfate (VS) is effective at augmenting recovery from sickness in both db/+ and db/db mice. Specifically, peak illness was reached at 2 h for both VS and control animals injected with LPS, and VS mice recovered 50% faster than non-VS-treated animals. Examination of the mechanism of VS action in db/+ mice showed that VS paradoxically augmented peritoneal macrophage responsivity to LPS, increasing both peritoneal and ex vivo macrophage production of IL-1beta and IL-6 but not TNF-alpha. The effects of VS in promoting recovery from sickness were not restricted to LPS, because they were also observed after direct administration of IL-1beta. To explore the possibility that VS impairs immune-to-brain communication via vagal afferents, the vagally mediated satiety-inducing effects of cholecystokinin 8 were tested in db/+ mice. Cholecystokinin decreased food intake in saline-injected mice but not in VS-treated mice. VS also inhibited LPS-dependent up-regulation of IL-1beta and IL-6 mRNA in the brain, while increasing by 50% the cerebral expression of transcripts of the specific antagonist of IL-1 receptors IL-1RA and IL-1R2. Taken together, these data indicate that VS improves recovery from LPS-induced sickness by blocking vagally mediated immune-to-brain signaling and by up-regulating brain expression of IL-1beta antagonists.
对于患有糖尿病的患病患者而言，疾病的行为症状如疲劳和冷漠会使人虚弱，并可能妨碍康复。在此我们报告，外周给予胰岛素样生长因子1（IGF-1）可减轻非糖尿病（db/+）小鼠中脂多糖（LPS）依赖性的社交探索抑制（疾病状态），但对糖尿病（db/db）小鼠无效。我们发现胰岛素/IGF-1模拟物硫酸氧钒（VS）对促进db/+和db/db小鼠从疾病状态中恢复均有效。具体而言，注射LPS的VS组和对照组动物在2小时时均达到疾病峰值，且VS组小鼠的恢复速度比未用VS处理的动物快50%。对db/+小鼠中VS作用机制的研究表明，VS反常地增强了腹膜巨噬细胞对LPS的反应性，增加了腹膜和体外巨噬细胞IL-1β和IL-6的产生，但未增加TNF-α的产生。VS促进从疾病状态中恢复的作用并不局限于LPS，因为在直接给予IL-1β后也观察到了这种作用。为了探究VS是否通过迷走神经传入损害免疫与脑的通讯，在db/+小鼠中测试了胆囊收缩素8的迷走神经介导的饱腹感诱导作用。胆囊收缩素可减少注射生理盐水小鼠的食物摄入量，但对VS处理的小鼠无效。VS还抑制了LPS依赖性的脑中IL-1β和IL-6 mRNA的上调，同时使IL-1受体特异性拮抗剂IL-1RA和IL-1R2的转录本在脑中的表达增加了50%。综上所述，这些数据表明VS通过阻断迷走神经介导的免疫与脑信号传导以及上调脑中IL-1β拮抗剂的表达来改善从LPS诱导的疾病状态中的恢复。
