The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro- and anti-inflammatory genes in the rat brain
The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro- and anti-inflammatory genes in the rat brain
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DOI：
10.1016/j.neuropharm.2013.03.014
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发表时间：
2013-08-01
影响因子：
4.7
通讯作者：
Rummel, Christoph
中科院分区：
文献类型：
--
作者：
Damm, Jelena;Harden, Lois May;Rummel, Christoph
在感染和炎症过程中，炎性转录因子如信号转导和转录激活因子(STAT3)、核因子(NF)kappaB或核因子-IL(IL)6的激活及其在诱导脑控制疾病反应(如发热)中的作用尚不清楚。因此，我们利用AG490(先前被证明抑制STAT3和NF-IL6信号通路)，研究了这两个信号通路在介导外周脂多糖(LPS)刺激引起的疾病行为、发热和伴随的脑炎症中的中枢作用。大鼠经静脉注射预处理。在IP前1小时使用AG490。与脂多糖对照组相比，脂多糖组(100微克/公斤体重)表现出轻微的高热，脂肪减少，运动活动几乎未受影响。脂多糖诱导的大鼠食欲减退不受影响，AG490对PBS大鼠无明显影响。我们观察到AG490在4h对STAT3信号的影响，而AG490在8h对炎性转录因子脑活性的影响不明显。与溶剂组相比，AG490/LPS组大鼠下丘脑抗炎IL-10的表达显著降低，炎性微粒体前列腺素E合成酶(MPGES)的mRNA表达显著增加。综上所述，我们已经显示了中枢AG490治疗对发热的影响和疾病行为的组成部分之间的分离，这似乎与大脑中IL-10的减少和mPGES-表达的增加有关。因此，AG490可能具有减少疾病行为的治疗潜力。(C)2013爱思唯尔有限公司。保留所有权利。
The functional significance for activation of inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), nuclear factor (NF)kappa B or NF-interleukin (IL)6 and their contribution to the induction of brain controlled sickness responses, such as fever, during infection and inflammation is unknown. Using AG490, previously shown to inhibit the STAT3- and NF-IL6-signaling pathway, we therefore investigated the central involvement of these two signaling pathways in mediating sickness behavior, fever and accompanying brain inflammation induced by peripheral lipopolysaccharide (LPS)-stimulation. Rats pre-treated i.c.v. with AG490 1 h before the i.p. LPS-challenge (100 mu g/kg) showed a modestly exaggerated fever, attenuated adipsia and almost unimpaired locomotor activity compared to LPS-controls receiving vehicle (i.c.v.). The LPS-induced anorexia was not altered and AG490 did not have any effect on rats receiving PBS (i.p.). We did observe effects of AG490 on STAT3-signaling at 4 h, while AG490-mediated changes in brain activity of inflammatory transcription factors at 8 h were not significant. Increased NF-IL6 and suppressor of cytokines 3 mRNA-expression in AG490/LPS-treated rats were indicative of a compensative activation at 24 h. Moreover, a significant decrease in hypothalamic anti-inflammatory IL-10-expression and an increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA-expression 8 h after LPS-injection was revealed in AG490 pre-treated animals compared to solvent-treated LPS-controls. In summary, we have shown a dissociation between the effects of central AG490 treatment on fever and components of sickness behavior, which appears to be related to reduced IL-10 and increased mPGES-expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior. (C) 2013 Elsevier Ltd. All rights reserved.