Immune-pineal axis activation is part of the assembly of immune responses. Proinflammatory cytokines inhibit the pineal synthesis of melatonin while inducing it in macrophages by mechanisms dependent on nuclear factor-κB (NF-κB) activation. Cytokines activating the Janus kinase/signal transducer and activator of transcription (STAT) pathways, such as interferon-gamma (IFN-γ) and interleukin-10 (IL-10), modulate melatonin synthesis in the pineal, bone marrow (BM), and spleen. The stimulatory effect of IFN-γ upon the pineal gland depends on STAT1/NF-κB interaction, but the mechanisms controlling IL-10 effects on melatonin synthesis remain unclear. Here, we evaluated the role of STAT3 and NF-κB activation by IL-10 upon the melatonin synthesis of rats' pineal gland, BM, spleen, and peritoneal cells. The results show that IL-10-induced interaction of (p)STAT3 with specific NF-κB dimmers leads to different cell effects. IL-10 increases the pineal's acetylserotonin O-methyltransferase (ASMT), N-acetylserotonin, and melatonin content via nuclear translocation of NF-κB/STAT3. In BM, the nuclear translocation of STAT3/p65-NF-κB complexes increases ASMT expression and melatonin content. Increased pSTAT3/p65-NF-κB nuclear translocation in the spleen enhances phosphorylated serotonin N-acetyltransferase ((p)SNAT) expression and melatonin content. Conversely, in peritoneal cells, IL-10 leads to NF-κB p50/p50 inhibitory dimmer nuclear translocation, decreasing (p)SNAT expression and melatonin content. In conclusion, IL-10's effects on melatonin production depend on the NF-κB subunits interacting with (p)STAT3. Thus, variations of IL-10 levels and downstream pathways during immune responses might be critical regulatory factors adjusting pineal and extra-pineal synthesis of melatonin.

中文翻译：

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IL-10诱导的STAT3/NF-κB串扰调节松果体和松果体外褪黑素合成

免疫松果体轴激活是免疫反应集合的一部分。促炎细胞因子抑制松果​​体合成褪黑素，同时通过依赖于核因子-κB (NF-κB) 激活的机制在巨噬细胞中诱导褪黑素。激活 Janus 激酶/信号转导器和转录激活剂 (STAT) 途径的细胞因子，例如干扰素-γ (IFN-γ) 和白细胞介素-10 (IL-10)，可调节松果体、骨髓 (BM)、和脾。IFN-γ对松果体的刺激作用取决于STAT1/NF-κB相互作用，但控制IL-10对褪黑激素合成的影响的机制仍不清楚。在这里，我们评估了 IL-10 激活 STAT3 和 NF-κB 对大鼠松果体、骨髓、脾脏和腹膜细胞褪黑激素合成的作用。结果表明，IL-10 诱导的 (p)STAT3 与特定 NF-κB 二聚体的相互作用会导致不同的细胞效应。IL-10通过 NF-κB/STAT3 的核易位增加松果体的乙酰血清素 O-甲基转移酶 (ASMT)、N-乙酰血清素和褪黑激素含量。在 BM 中，STAT3/p65-NF-κB 复合物的核转位增加了 ASMT 表达和褪黑激素含量。脾脏中 pSTAT3/p65-NF-κB 核转位的增加可增强磷酸化血清素N-乙酰转移酶 ((p)SNAT) 的表达和褪黑激素含量。相反，在腹膜细胞中，IL-10 会导致 NF-κB p50/p50 抑制性二聚体核易位，从而降低 (p)SNAT 表达和褪黑激素含量。总之，IL-10 对褪黑激素产生的影响取决于 NF-κB 亚基与 (p)STAT3 的相互作用。因此，免疫反应过程中IL-10水平和下游途径的变化可能是调节松果体和松果体外褪黑激素合成的关键调节因素。