Inorganic arsenic impairs proliferation and cytokine expression in human primary T lymphocytes.
Inorganic arsenic is a toxic environmental contaminant to which humans are mainly exposed through drinking water. This metalloid impairs functions of several key immune cells. Particularly, it reduces IL-2 secretion and proliferation of blood peripheral mononuclear cells stimulated by lectins that, however, do not mimic physiological T cell activation. The present study used isolated human T cells activated, in a more physiological manner, through stimulation with CD3/CD28 antibodies, to carefully analyze the impact of arsenic on T cell proliferation and cytokine expression. We demonstrate that non cytotoxic concentrations of sodium arsenite (As(III), 0.25-2μM) significantly reduce T cell proliferation by increasing the percentage of non dividing cells blocked in G1 phase and by preventing cyclin D3 and CDC25A expression. They also markedly, although not totally, reduces IL-2 expression at both mRNA and protein levels; however, metalloid-dependent inhibition of T cells could not be reversed by addition of recombinant IL-2. In addition, As(III) markedly reduces secretion of interferon-γ without impairing that of IL-4 and IL-13; it also decreases interferon-γ mRNA levels but increases those of IL-13. Finally, simultaneously to its immune effects, As(III) rapidly and potently increases expression of the redox-sensitive genes HMOX1, NQO1 and GCLM in activated T cells without altering the levels of reactive oxygen species. In conclusion, our results demonstrate that As(III) inhibits T cell proliferation, independently of IL-2, and alters the Th balance of cytokines secreted by co-stimulated T cells which thus constitute direct targets of this major environmental contaminant.
UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes, France.
Claudie
C
Morzadec
Fidaa
F
Bouezzedine
Mélinda
M
Macoch
Olivier
O
Fardel
Laurent
L
Vernhet
D001152:Arsenicals / Q000009:adverse effects*; D018053:Arsenites / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects*; D056743:Cyclin D3 / Q000032:analysis / Q000096:biosynthesis; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis*; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D018793:Interleukin-13 / Q000032:analysis / Q000096:biosynthesis; D007376:Interleukin-2 / Q000032:analysis / Q000096:biosynthesis; D015847:Interleukin-4 / Q000032:analysis / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D017670:Sodium Compounds / Q000009:adverse effects; D013601:T-Lymphocytes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D001152:Arsenicals; D018053:Arsenites; D056743:Cyclin D3; D016207:Cytokines; D018793:Interleukin-13; D007376:Interleukin-2; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D015847:Interleukin-4; C017947:sodium arsenite; D007371:Interferon-gamma