title: Inorganic arsenic alters expression of immune and stress response genes in activated primary human T lymphocytes.
abstract: 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.
authors.affiliation: 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.
authors.forename: Corinne
authors.initials: C
authors.lastname: Martin-Chouly
authors.forename: Claudie
authors.initials: C
authors.lastname: Morzadec
authors.forename: Mélodie
authors.initials: M
authors.lastname: Bonvalet
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Galibert
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernhet
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D002469:Cell Separation; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010835:Phytohemagglutinins / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D013997:Time Factors; D014019:Tissue Donors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D018053:Arsenites; D007376:Interleukin-2; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2; D017670:Sodium Compounds; C017947:sodium arsenite; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1