Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Minato-ku, Tokyo, Japan; Dairy Science and Technology Institute, Kyodo Milk Industry Co Ltd., Hinode-machi, Tokyo, Japan.
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Minato-ku, Tokyo, Japan.
Arch Biochem Biophys. 2020 Oct 30;693:108587. doi: 10.1016/j.abb.2020.108587. Epub 2020 Sep 15.
Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4 T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4 T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4 T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4 T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9, Irf4, and Batf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4 T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4 T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.
多胺是原核生物和真核生物产生的生物活性物质，具有多种作用。越来越多的证据表明，多胺通过抑制单核细胞和巨噬细胞中促炎细胞因子的表达，有助于抗炎反应。然而，多胺对 CD4 T 细胞反应的影响仍有待阐明。在这里，我们研究了多胺对体外幼稚 CD4 T 细胞命运决定的影响。我们发现，内源性多胺对于辅助性 T 细胞 2（Th2）细胞的发育是必不可少的。在 Th2 偏向条件下，用多胺生物合成的抑制剂 DL-2-二氟甲基鸟氨酸（DFMO）处理会降低 CD4 T 细胞中的 GATA3 表达。在 CD4 T 细胞中补充外源性多胺可挽救 DFMO 处理引起的 GATA3 下调。转录组分析显示，即使在 Th2 偏向条件下，内源性多胺的剥夺也会导致 Th9 相关基因（如 Il9、Irf4 和 Batf3）的上调。细胞内多胺的耗竭会降低 GATA3 表达，但会增加 Th2 和 Th9 偏向条件下产生 IL-9 的 CD4 T 细胞。此外，DFMO 的口服给药会增加小鼠小肠中产生 IL-9 的 CD4 T 细胞。因此，我们的数据表明，多胺在调节 Th2/Th9 平衡中起关键作用。
