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首页> 外文期刊>Cytokine >An intracellular adrenomedullin system reduces IL-6 release via a NF-kB-mediated, cAMP-independent transcriptional mechanism in rat thymic epithelial cells
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An intracellular adrenomedullin system reduces IL-6 release via a NF-kB-mediated, cAMP-independent transcriptional mechanism in rat thymic epithelial cells

机译：细胞内肾上腺髓质素系统通过大鼠胸腺上皮细胞中的NF-kB介导的cAMP依赖性转录机制减少IL-6释放

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Thymic epithelial cells (TECs) play a key role in the regulation of central immune tolerance by expressing autoantigens and eliminating self-reactive T cells. In a previous paper we reported that adrenomedullin (ADM) and its co-receptor protein RAMP2 are located intracellularly in newborn human thymic epithelial cells (TECs). This work has two main aims: (1) to examine the cellular localization of ADM and its receptor in TECs of adult Wistar rats to validate this animal model for the study of the ADM system and its function(s) in thymus; (2) to investigate the potential modulating effect of ADM on the NF-kB pathway, which is involved through the production of cytokines such as IL-6, in the maturation of T-lymphocytes and immunological tolerance. Our results show that, similarly to human newborn TECs, ADM is localized to the cytoplasm of adult rat TECs, and RAMP2 is expressed in the nucleus but not in the plasma membrane. Pretreatment of TECs for 4 h with ADM significantly reduced lipopolysaccharide (LPS)-induced release of IL-6 (P < 0.001) and expression of the p65 subunit of NF-kB, while doubled the expression of IkBce (P < 0.001), the physiological inhibitor of NF-kB nuclear translocation. These effects were not mediated by activation of the cAMP pathway, a signalling cascade that is rapidly activated by ADM in cells that express plasma membrane RAMP2, but were the consequence of a reduction in the transcription of p65 (P < 0.001) and an increase in the transcription of IkB alpha (P < 0.05). On the basis of these findings we propose that in rat TECs ADM reduces IL-6 secretion by modulating NF-kB genes transcription through an interaction with a receptor localized to the nucleus. This may partly explain the protective effects of ADM in autoimmune diseases and points to the ADM system of TECs as a novel potential target for immunomodulating drugs. (C) 2016 Elsevier Ltd. All rights reserved.
机译：胸腺上皮细胞（TECs）通过表达自身抗原并消除自身反应性T细胞，在调节中枢免疫耐受中起关键作用。在以前的论文中，我们报道了肾上腺髓质素（ADM）及其共受体蛋白RAMP2位于新生的人胸腺上皮细胞（TECs）的细胞内。这项工作有两个主要目标：（1）检查成年Wistar大鼠TEC中ADM及其受体的细胞定位，以验证该动物模型用于研究ADM系统及其在胸腺中的功能; （2）研究ADM对NF-kB通路的潜在调节作用，该通路涉及细胞因子（如IL-6）的产生，参与T淋巴细胞的成熟和免疫耐受。我们的结果表明，与人类新生TEC相似，ADM定位于成年大鼠TEC的细胞质，RAMP2在细胞核中表达，但不在质膜中表达。用ADM预处理TECs 4小时可显着降低脂多糖（LPS）诱导的IL-6释放（P <0.001）和NF-kB p65亚基的表达，而IkBce的表达则翻倍（P <0.001）， NF-kB核易位的生理抑制剂。这些作用不是由cAMP通路的激活介导的，cAMP通路的激活是由ADM在表达质膜RAMP2的细胞中迅速激活的，但它是p65转录减少（P <0.001）的结果。 IkB alpha的转录（P <0.05）。基于这些发现，我们提出在大鼠TECs中，ADM通过与位于细胞核内的受体相互作用来调节NF-kB基因转录，从而减少IL-6分泌。这可能部分解释了ADM在自身免疫性疾病中的保护作用，并指出TECs的ADM系统是免疫调节药物的新型潜在靶标。 （C）2016 Elsevier Ltd.保留所有权利。

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