Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release
Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release
复制标题
DOI：
10.4049/jimmunol.1400974
复制
发表时间：
2015-09-01
影响因子：
4.4
通讯作者：
Grau, Veronika
中科院分区：
文献类型：
--
作者：
Hecker, Andreas;Kuellmar, Mira;Grau, Veronika
IL-1 β是先天免疫系统的一种有效的促炎细胞因子，参与宿主防御感染。然而，IL-1 β的增加在各种炎症性疾病中起致病作用，如类风湿关节炎、痛风、败血症、中风和移植排斥反应。为了防止有害的附带损害，IL-1 β的释放受到严格控制，通常需要两个连续的危险信号。来自革兰氏阴性菌的LPS是诱导pro-IL-1 β合成的典型第一信号，而细胞外ATP是ATP受体P2X7感知的典型第二信号，它触发含有nlrp3的炎性体的激活，caspase-1对pro-IL-1 β的蛋白水解裂解，并释放成熟的IL-1 β。控制IL-1 β释放的机制，即使在存在这两种危险信号的情况下，也需要保护免受附带损害，并且具有治疗意义。在这篇文章中，我们发现乙酰胆碱、胆碱、磷胆碱、来自流感嗜血杆菌的磷胆碱修饰LPS和磷胆碱修饰蛋白通过含有α 7、α 9和/或α 10亚基的烟碱乙酰胆碱受体有效抑制atp介导的IL-1 β在人和大鼠单核细胞中的释放。值得注意的是，我们确定了由微生物和真核寄生虫合成的磷酸胆碱修饰大分子的受体，这些大分子是众所周知的免疫系统调节剂。我们的数据表明，内源性抗炎胆碱能控制机制有效地控制atp介导的IL-1 β的释放，并且共生体和寄生虫滥用相同的机制来逃避宿主的先天免疫反应。
IL-1 beta is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1 beta plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1 beta release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1 beta synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1 beta by caspase-1, and release of mature IL-1 beta. Mechanisms controlling IL-1 beta release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1 beta release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits alpha 7, alpha 9, and/or alpha 10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1 beta and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.