Departamento de Análises Clínica e Toxicológica, Faculdade de Ciências Farmacêuticas, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo Brazil.
J Immunol. 2010 Apr 1;184(7):3487-94. doi: 10.4049/jimmunol.0902961. Epub 2010 Feb 24.
Over the past 20 y, the hormone melatonin was found to be produced in extrapineal sites, including cells of the immune system. Despite the increasing data regarding the biological effects of melatonin on the regulation of the immune system, the effect of this molecule on T cell survival remains largely unknown. Activation-induced cell death plays a critical role in the maintenance of the homeostasis of the immune system by eliminating self-reactive or chronically stimulated T cells. Because activated T cells not only synthesize melatonin but also respond to it, we investigated whether melatonin could modulate activation-induced cell death. We found that melatonin protects human and murine CD4(+) T cells from apoptosis by inhibiting CD95 ligand mRNA and protein upregulation in response to TCR/CD3 stimulation. This inhibition is a result of the interference with calmodulin/calcineurin activation of NFAT that prevents the translocation of NFAT to the nucleus. Accordingly, melatonin has no effect on T cells transfected with a constitutively active form of NFAT capable of migrating to the nucleus and transactivating target genes in the absence of calcineurin activity. Our results revealed a novel biochemical pathway that regulates the expression of CD95 ligand and potentially other downstream targets of NFAT activation.
在过去的 20 年中，人们发现褪黑素不仅在松果体外的组织中产生，也存在于免疫系统的细胞中。尽管关于褪黑素对免疫系统调节的生物学作用的数据不断增加，但这种分子对 T 细胞存活的影响在很大程度上仍然未知。激活诱导的细胞死亡通过消除自身反应性或慢性刺激的 T 细胞，在维持免疫系统的动态平衡中起着关键作用。因为激活的 T 细胞不仅合成褪黑素，而且对其有反应，所以我们研究了褪黑素是否可以调节激活诱导的细胞死亡。我们发现，褪黑素通过抑制 TCR/CD3 刺激后 CD95 配体 mRNA 和蛋白的上调，来保护人源和鼠源 CD4(+)T 细胞免于凋亡。这种抑制是由于钙调蛋白/钙调磷酸酶激活 NFAT 受到干扰，从而阻止 NFAT 向核内转移的结果。因此，褪黑素对转染了组成型激活形式的 NFAT 的 T 细胞没有影响，这种形式的 NFAT 能够在没有钙调磷酸酶活性的情况下迁移到核内并转激活靶基因。我们的研究结果揭示了一条调节 CD95 配体表达和潜在的其他 NFAT 激活下游靶基因的新的生化途径。
