Institut de Recherche en Santé Environnement Travail, EA-4427 Signalisation et Réponses aux Agents Infectieux et Chimiques, Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes, France.
Mol Immunol. 2011 Mar;48(6-7):956-65. doi: 10.1016/j.molimm.2011.01.005. Epub 2011 Feb 1.
Inorganic arsenic, a carcinogenic environmental contaminant, exerts immunosuppressive effects on human T lymphocytes. In particular, interleukin-2 (IL2) secretion and T cell proliferation are reduced when peripheral blood mononuclear cells (PBMC) from individuals chronically exposed to arsenic are stimulated ex vivo with lectins such as phytohemaglutinin (PHA). However, it is not clear whether the metalloid directly acts on T cells or blocks monocyte-dependent accessory signals activated by PHA. We report that in vitro pre-treatment of PBMC with sodium arsenite (NaAs) reduces IL2 secretion and T cell proliferation induced by PHA, but does not prevent expression of monocyte-derived cytokines (IL1, IL6, TNFα) functioning as lymphocyte-activating factors. In addition, we found that NaAs delays induction of IL2 and IL2 receptor α chain (IL2RA) mRNA levels in human primary isolated T cells activated by PHA. Kinetic analysis showed that NaAs pre-treatment first inhibits, but thereafter markedly increases, induction of IL2 and IL2RA mRNA when T cells are stimulated with PHA for 8 h and 72 h, respectively. We conducted whole genome microarray-based analysis of gene expression in primary T cell cultures derived from independent donors. NaAs systematically and significantly up-regulated a set of 35 genes, including several immune and stress genes, such as IL13, granulocyte-macrophage colony stimulating factor, lymphotoxin α and heme oxygenase-1 (HO-1). Up-regulation of HO-1, a stress and immunosuppressive protein, was rapidly detectable, both in T cells and in PBMC treated with NaAs. Inhibition of the immunosuppressive activity of HO-1 in PBMC however failed to prevent NaAs-dependent inhibition of T cell proliferation induced by PHA. Our findings demonstrate that, at least in vitro, inorganic arsenic acts directly on human T cells and impairs their activity, probably independently of HO-1 expression and monocyte-related accessory signals.
无机砷是一种致癌的环境污染物，对人类 T 淋巴细胞具有免疫抑制作用。特别是当个体长期暴露于砷环境中时，其外周血单核细胞（PBMC）在体外受到植物血凝素（PHA）等凝集素刺激后，IL-2（白细胞介素 2）分泌和 T 细胞增殖会减少。然而，目前尚不清楚该类金属元素是否直接作用于 T 细胞，还是阻断了 PHA 激活的单核细胞相关辅助信号。我们的研究结果表明，体外用亚砷酸钠（NaAs）预处理 PBMC 可降低 PHA 诱导的 IL-2 分泌和 T 细胞增殖，但不会阻止单核细胞衍生的细胞因子（IL1、IL6、TNFα）作为淋巴细胞激活因子的表达。此外，我们发现 NaAs 延迟了 PHA 激活的人原代 T 细胞中 IL2 和 IL2 受体 α 链（IL2RA）mRNA 水平的诱导。动力学分析显示，当 T 细胞分别在刺激 8 小时和 72 小时后用 PHA 刺激时，NaAs 预处理会首先抑制，但随后显著增加 IL2 和 IL2RA mRNA 的诱导。我们对来自不同供体的原代 T 细胞培养物进行了全基因组微阵列分析。NaAs 系统地显著上调了一组 35 个基因，包括几个免疫和应激基因，如 IL13、粒细胞-巨噬细胞集落刺激因子、淋巴毒素α和血红素加氧酶-1（HO-1）。HO-1 是一种应激和免疫抑制蛋白，在 NaAs 处理的 T 细胞和 PBMC 中都能快速检测到其表达上调。然而，在 PBMC 中抑制 HO-1 的免疫抑制活性并不能防止 NaAs 依赖的 PHA 诱导的 T 细胞增殖抑制。我们的研究结果表明，至少在体外，无机砷直接作用于人类 T 细胞并损害其活性，这可能与 HO-1 表达和单核细胞相关辅助信号无关。
