Palin K, McCusker R H, Strle K, Moos F, Dantzer R, Kelley K W
Laboratory of Integrative Immunophysiology, Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES, Urbana, IL 61801, USA.
Psychopharmacology (Berl). 2008 May;197(4):629-35. doi: 10.1007/s00213-008-1086-y. Epub 2008 Feb 12.
Tumor necrosis factor-alpha (TNFalpha) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFalpha binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors.
We hypothesized that TNFalpha-induced sickness behavior can be blocked by a novel JNK inhibitor.
To test this idea, we used a bipartite protein consisting of a ten-amino-acid sequence of the trans-activating domain of the viral TAT protein (D-TAT) linked to a 19-amino-acid peptide that specifically inhibits JNK activation (D-JNKI-1). C57BL/6J mice were pre-treated intracerebroventricularly (i.c.v.) with D-JNKI-1 or the control peptide containing only the protein transduction domain, D-TAT. Mice were then injected centrally with an optimal amount of TNFalpha (50 ng/mouse) to induce sickness behavior. Sickness was assessed as a decrease in social exploration of a novel juvenile, an increase in duration of immobility and loss of body weight.
Pre-treatment with D-JNKI-1 (10 ng/mouse), but not D-TAT, significantly inhibited all three indices of sickness induced by central TNFalpha.
These findings demonstrate that D-JNKI-1 can abrogate TNFalpha-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced sickness behavior.
肿瘤坏死因子-α（TNFα）在脑内发挥作用以诱导疾病行为，但其分子机制仍不清楚。TNFα结合可诱导受体三聚化、c-Jun氨基末端激酶（JNK）激活以及下游转录因子的诱导。
我们假设TNFα诱导的疾病行为可被一种新型JNK抑制剂阻断。
为验证这一想法，我们使用了一种双体蛋白，其由病毒TAT蛋白反式激活结构域的一个十肽序列（D-TAT）与一个特异性抑制JNK激活的19肽（D-JNKI-1）相连组成。C57BL/6J小鼠经脑室内（i.c.v.）给予D-JNKI-1或仅含蛋白转导结构域的对照肽D-TAT进行预处理。然后向小鼠中枢注射适量的TNFα（50 ng/小鼠）以诱导疾病行为。通过对陌生幼鼠社交探索的减少、不动时间的增加和体重减轻来评估疾病状态。
用D-JNKI-1（10 ng/小鼠）预处理可显著抑制中枢TNFα诱导的所有三项疾病指标，而D-TAT则无此作用。
这些发现表明D-JNKI-1可消除TNFα诱导的疾病行为，并提示在细胞因子诱导的疾病行为背景下发生的重度抑郁症可能有一个潜在的治疗靶点。
