FEVER, SICKNESS BEHAVIOR, AND EXPRESSION OF INFLAMMATORY GENES IN THE HYPOTHALAMUS AFTER SYSTEMIC AND LOCALIZED SUBCUTANEOUS STIMULATION OF RATS WITH THE TOLL-LIKE RECEPTOR 7 AGONIST IMIQUIMOD
FEVER, SICKNESS BEHAVIOR, AND EXPRESSION OF INFLAMMATORY GENES IN THE HYPOTHALAMUS AFTER SYSTEMIC AND LOCALIZED SUBCUTANEOUS STIMULATION OF RATS WITH THE TOLL-LIKE RECEPTOR 7 AGONIST IMIQUIMOD
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DOI：
10.1016/j.neuroscience.2011.11.013
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发表时间：
2012-01-10
期刊：
影响因子：
3.3
通讯作者：
Roth, J.
中科院分区：
文献类型：
--
作者：
Damm, J.;Wiegand, F.;Roth, J.
toll样受体7 （TLR7）激动剂咪喹莫特用于局部治疗皮肤癌。我们研究了咪喹莫特皮下（s.c）气囊注射或腹腔（i.p）注射对发热表现、疾病行为以及各种炎症分子的外周和脑内诱导的影响。大鼠给予咪齐莫特s.c或ig（1、5 mg/kg）。通过遥测设备记录体温、运动活动、食物和水的摄入量。通过实时聚合酶链反应（RT-PCR）、生物测定、酶联免疫吸附测定（elisa）和免疫组织化学分析炎症介质的外周和脑内诱导。米喹莫特是第一个在s.c.中产生比ip更有效的tlr激动剂。外周干扰素（ifn）的诱导和假定的循环热原与疾病反应的程度相对应。在大脑中，细胞因子（TNFoz， IL-1B和IL-6）和诱导形式的前列腺素E2合成酶（COX-2和mPGES）的表达发生，同时伴随着转录因子NFKB和STAT3的适度激活，转录因子NF-IL6的强烈激活，在开放的血脑屏障的特定区域的细胞中。这些炎症反应在s.c.给药后比口服咪喹莫特更明显。在5 mg/kg剂量下，咪喹莫特引起相当中度的脑炎症反应，这与外周ifn表达有关，可能是由NF-1L6的脑内激活和促炎鸡尾酒的诱导介导的。阿米喹莫德治疗的大鼠没有出现类似败血症的状态，这加强了这种药物的治疗作用。(c) 2011 ibro。Elsevier Ltd.出版。版权所有。
The Toll-like receptor 7 (TLR7) agonist imiquimod is used for topical treatment of skin cancers. We studied the consequences of injections of imiquimod into a subcutaneous (s.c.) air pouch or of intraperitoneal (i.p.) injections on the manifestation of fever, sickness behavior, and the peripheral and brain-intrinsic induction of a variety of inflammatory molecules. Rats were given imiqimod s.c. or i.p. (1 or 5 mg/kg). Body temperature, motor activity, and food and water intake were recorded by telemetric devices. Peripheral and brain-intrinsic induction of inflammatory mediators was analyzed by real-time polymerase chain reaction (RT-PCR), bioassays, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemistry. lmiquimod is the first TLR-agonist to produce more potent effects with s.c. than i.p. administration. Peripheral induction of interferons (IFNs) and putative circulating pyrogens corresponded to the magnitude of the illness responses. In the brain, an expression of cytokines (TNFoz, IL-1B, and IL-6) and inducible forms of enzymes for prostaglandin E2 synthesis (COX-2 and mPGES) occurred, which was accompanied by a moderate activation of the transcription factors NFKB and STAT3, and a strong activation of the transcription factor NF-IL6, in cells of specific areas with an open blood brain barrier. These inflammatory responses noted within the brain were more marked after s.c. administration, than i.p. administration of imiquimod. At a dose of 5 mg/kg, imiquimod causes rather moderate brain-inflammatory responses, which are related to peripheral IFN-expression and possibly mediated by brain-intrinsic activation of NF-1L6 and induction of a proinflammatory cocktail. The lack of a septic-like state in imiquimod-treated rats reinforces the therapeutic use of this drug. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.