Macrophage-activating lipopeptide-2 (MALP-2) induces a localized inflammatory response in rats resulting in activation of brain sites implicated in fever
Macrophage-activating lipopeptide-2 (MALP-2) induces a localized inflammatory response in rats resulting in activation of brain sites implicated in fever
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DOI：
10.1016/j.brainres.2008.02.021
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发表时间：
2008-04-18
期刊：
影响因子：
2.9
通讯作者：
Roth, Joachim
中科院分区：
文献类型：
--
作者：
Knorr, Carolin;Huebschle, Thomas;Roth, Joachim
巨噬细胞活化脂肽-2（MALP-2）已被鉴定为发酵支原体的病原体相关分子模式，其通过激活异二聚体Toll样受体（TLR）2和6刺激先天免疫系统。基于所报道的MALP-2对皮肤伤口愈合的保护作用，本研究的中心目标是评估MALP-2在皮下气囊的已建立模型中诱导局部炎症反应的能力。将MALP-2注射到袋中引起大鼠发热和某些疾病行为。在局部炎症的皮下部位，注射MALP-2后，可以证明肿瘤坏死因子-α（TNF）、白细胞介素-6（IL-6）和前列腺素E-2（PGE（2））大量形成。中等量的IL-6和PGE 2似乎进入MALP-2处理的大鼠的体循环。在将MALP-2注射到气囊中后出现在血液中的IL-6足以引起缺乏完全血脑屏障的区域中的脑细胞的直接激活，即在感觉脑室周围器官（sCVO）、终板血管器（OVLT）、皮下器官（SFO）和最后区（AP）中。通过证明转录因子STAT 3（信号转导子和转录激活子3）的核转位，揭示了这些脑部位的细胞刺激。对应于IL-6的循环水平，与用MALP-2全身治疗相比，在局部皮下后，sCVO内细胞的核STAT 3活化不太明显。总之，皮下隔室内的细胞被TLR 2/6激动剂MALP-2激活。通过将MALP-2注射到皮下组织中诱导的发热和疾病行为可能部分地由IL-6从炎症的皮下部位溢出到血液中以引起与这些疾病反应的表现有关的脑部位的激活来介导。(C)2008 Elsevier B. V.保留所有权利。
Macrophage-activating lipopeptide-2 (MALP-2) has been identified as the pathogen-associated molecular pattern of Mycoplasma fermentans, which causes stimulation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs) 2 and 6. Based on the reported protective effects of MALP-2 on healing of skin wounds, the central goal of this study was to evaluate the capacity of MALP-2 to induce a localized inflammatory response in an established model of a subcutaneous air pouch. injections of MALP-2 into the pouch caused fever and some components of sickness behavior in rats. At the subcutaneous site of localized inflammation, a massive formation of tumor necrosis factor-alpha (TNF), interleukin-6 (IL-6), and prostaglandin E-2 (PGE(2)) could be demonstrated in response to injections of MALP-2. Moderate amounts of IL-6 and PGE2 seemed to enter the systemic circulation of MALP-2-treated rats. The IL-6, which appeared in the blood after injection of MALP-2 into the air pouch was sufficient to cause a direct activation of brain cells in areas which lack a complete blood-brain barrier, namely in the sensory circumventricular organs (sCVOs), the organum Vasculosum laminae terminalis (OVLT), the subfomical organ (SFO), and the area postrema (AP). The stimulation of cells at these brain sites was revealed by demonstration of a nuclear translocation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Corresponding to the circulating levels of IL-6, the nuclear STAT3 activation of cells within the sCVOs was much less pronounced after local subcutaneous when compared to systemic treatment with MALP-2. In conclusion, cells within the subcutaneous compartment are activated by the TLR2/6 agonist MALP-2. Fever and sickness behavior induced by injection of MALP-2 into subcutaneous tissue may, in part, be mediated by a spillover of IL-6 from the subcutaneous site of inflammation into the blood to cause activation of brain sites which are implicated in the manifestation of these illness responses. (C) 2008 Elsevier B.V. All rights reserved.