Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Immunol. 2011 Oct;49(1-2):311-6. doi: 10.1016/j.molimm.2011.09.001. Epub 2011 Sep 22.
Macrophages exposed to lipopolysaccharide (LPS) exhibit radical changes in mRNA and protein profiles. This shift in gene expression is geared not only to activate immune effector and regulatory mechanisms, but also to adjust the immune cell's metabolism to new physiological demands. However, it remains largely unknown whether immune function and metabolic state are mutually regulatory and, if so, how they are mechanistically interrelated in macrophages. Selenium, a dietary trace element exerting pleiotropic effects on immune homeostasis, and selenium-containing proteins (selenoproteins) may play a role in such coordination. We examined the incorporation of radiolabeled selenium into protein during LPS stimulation, and identified thioredoxin reductase 1 (TR1) as the only LPS-inducible selenoprotein in macrophages. TR1 induction occurred at the transcriptional level and depended on the intracellular signaling pathways mediated by p38 MAP kinase and IκB kinase. Macrophage-specific ablation of TR1 in mice resulted in a drastic decrease in the expression of VSIG4, a B7 family protein known to suppress T cell activation. These results reveal TR1 as both a regulator and a regulated target in the macrophage gene expression network, and suggest a link between selenium metabolism and immune signaling.
巨噬细胞暴露于脂多糖 (LPS) 后，其 mRNA 和蛋白质谱发生剧烈变化。这种基因表达的转变不仅旨在激活免疫效应和调节机制，还调整免疫细胞的代谢以适应新的生理需求。然而，免疫功能和代谢状态是否相互调节，以及它们在巨噬细胞中是如何通过机制相互关联的，在很大程度上仍然未知。硒是一种对免疫稳态发挥多种作用的膳食微量元素，含硒蛋白（硒蛋白）可能在这种协调中发挥作用。我们检查了 LPS 刺激期间放射性标记硒掺入蛋白质的情况，并鉴定出硫氧还蛋白还原酶 1 (TR1) 是巨噬细胞中唯一受 LPS 诱导的硒蛋白。TR1 的诱导发生在转录水平上，并取决于由 p38 MAP 激酶和 IκB 激酶介导的细胞内信号通路。在小鼠中特异性敲除巨噬细胞中的 TR1 会导致 B7 家族蛋白 VSIG4 的表达急剧下降，该蛋白已知可抑制 T 细胞激活。这些结果揭示了 TR1 既是巨噬细胞基因表达网络中的调节剂又是受调控的靶标，并提示硒代谢与免疫信号之间存在联系。
