Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Department of Medical Biochemistry and Molecular Biology, University of Seville School of Medicine, Seville, Spain.
J Pineal Res. 2011 Nov;51(4):454-62. doi: 10.1111/j.1600-079X.2011.00909.x. Epub 2011 Jul 7.
Melatonin modulates a wide array of physiological events with pleiotropic effects on the immune system. While the relevance of specific melatonin membrane receptors has been well established for several biological functions, retinoic acid-related orphan receptor alpha (RORα) has been suggested as a mediator of nuclear melatonin signalling by results obtained from pharmacological approaches. However, a melatonin-mediated downstream effect cannot be ruled out, and further evidence is needed to support a direct interaction between melatonin and RORα. Here, we show that RORα is mainly located in human Jurkat T-cell nucleus, and it is co-immunoprecipitated with melatonin. Moreover, immunocytochemistry studies confirmed the co-localization of melatonin and RORα. Melatonin promoted a time-dependent decrease in nuclear RORα levels, suggesting a role in the RORα transcriptional activity. Interestingly, RORα acts as a molecular switch implicated in the mutually exclusive generation of Th17 and Treg cells, both involved in the harm/protection balance of immune conditions such as autoimmunity or acute transplant rejection. Therefore, the identification of melatonin as a natural modulator of RORα gives it a tremendous therapeutic potential for a variety of clinical disorders.
褪黑素调节着广泛的生理事件，对免疫系统具有多种作用。虽然特定的褪黑素膜受体在几种生物学功能中已经得到很好的确立，但视黄酸相关孤儿受体 alpha（RORα）已被认为是核褪黑素信号转导的介导物，这是通过药理学方法获得的结果。然而，不能排除褪黑素介导的下游效应，并且需要进一步的证据来支持褪黑素与 RORα 之间的直接相互作用。在这里，我们表明 RORα 主要位于人 Jurkat T 细胞的核内，并且与褪黑素共免疫沉淀。此外，免疫细胞化学研究证实了褪黑素和 RORα 的共定位。褪黑素促进核 RORα 水平的时间依赖性下降，表明其在 RORα 转录活性中的作用。有趣的是，RORα 作为一种分子开关，参与 Th17 和 Treg 细胞的相互排斥产生，这两种细胞都参与自身免疫或急性移植排斥等免疫状况的伤害/保护平衡。因此，鉴定褪黑素作为 RORα 的天然调节剂赋予其在多种临床疾病中巨大的治疗潜力。
