Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
Department of Microbiology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
Int Immunol. 2018 Nov 14;30(12):591-606. doi: 10.1093/intimm/dxy057.
Dopamine (DA) is synthesized by various immune cells. DA receptors (DARs), which comprise five isoforms, are expressed on the surface of these cells. Therefore, it is likely that DA plays a role in regulating innate and adaptive responses. However, the underlying molecular mechanism(s) is largely unknown. Here, we found that, during innate immune responses, DA suppressed secretion of IFN-γ, TNF-α and IL-1β, but promoted secretion of IL-10 and CXCL1 by lipopolysaccharide (LPS)-stimulated mouse splenocytes, suggesting that DA regulates cytokine secretion. Immune subset studies indicated that DA suppressed secretion of IFN-γ, TNF-α and IL-1β by NK cells, as well as secretion of TNF-α by neutrophils and monocytes; however, DA up-regulated IL-10 secretion by neutrophils, monocytes, B cells, macrophages (Mφs) and dendritic cells within the splenocyte population. In addition, DA up-regulated secretion of CXCL1 by LPS-stimulated NK cells and Mφs. Meanwhile, treatment with DAR agonists or antagonists suppressed secretion of inflammatory cytokines from LPS-stimulated splenocytes. Pre-treatment of LPS-stimulated splenocytes with the PI3K inhibitor wortmannin reversed DA-mediated suppression of IFN-γ secretion, indicating that DA regulates IFN-γ secretion via the inositol 1,4,5-trisphosphate signaling pathway in these cells. Administration of DA and LPS to mice immunized with chicken ovalbumin (OVA) increased secretion of IL-5 by mouse lung lymphocytes, suggesting that DA promotes OVA-specific Th2-mediated immune responses by these cells. Taken together, these findings indicate that DA regulates cytokine secretion during innate and adaptive immune responses.
多巴胺 (DA) 由各种免疫细胞合成。DA 受体 (DAR) 有五个亚型，表达在这些细胞的表面。因此，DA 很可能在调节先天和适应性免疫反应中发挥作用。然而，其潜在的分子机制在很大程度上尚不清楚。在这里，我们发现，在先天免疫反应中，DA 抑制脂多糖 (LPS) 刺激的小鼠脾细胞分泌 IFN-γ、TNF-α 和 IL-1β，但促进 IL-10 和 CXCL1 的分泌，表明 DA 调节细胞因子的分泌。免疫亚群研究表明，DA 抑制 NK 细胞分泌 IFN-γ、TNF-α 和 IL-1β，以及中性粒细胞和单核细胞分泌 TNF-α；然而，DA 上调中性粒细胞、单核细胞、B 细胞、巨噬细胞 (Mφ) 和树突状细胞分泌 IL-10。此外，DA 上调 LPS 刺激的 NK 细胞和 Mφ 分泌 CXCL1。同时，DAR 激动剂或拮抗剂的处理抑制 LPS 刺激的脾细胞分泌炎症细胞因子。用 PI3K 抑制剂wortmannin预处理 LPS 刺激的脾细胞可逆转 DA 介导的 IFN-γ 分泌抑制，表明 DA 通过这些细胞中的肌醇 1,4,5-三磷酸信号通路调节 IFN-γ 的分泌。给予 DA 和 LPS 免疫鸡卵清蛋白 (OVA) 的小鼠，增加了小鼠肺淋巴细胞分泌的 IL-5，表明 DA 通过这些细胞促进 OVA 特异性 Th2 介导的免疫反应。总之，这些发现表明 DA 调节先天和适应性免疫反应期间的细胞因子分泌。
