Mécanisme d'action de l'immunotoxicité induite par les hydrocarbures polycycliques aromatiques

Abstract : Polycyclic aromatic hydrocarbons (PAH) are ubiquitus environmental contaminants know to be carcinogenic as well as immunosuppressive. Using as PAH the synthetic compound 7.12-dimetthylbenz(a)anthracene (DMBA) that is well characterised for its immunotoxicity in mice, we study DMBA interaction with T lymphocyte activation focusing mainly on calcium homeostasis. DMBA induces an increase in intracellular calcium (Ca2+ic) in murine T lymphocytes and also human T lymphocytes. This Ca2+ic elevation is detected early in murine T cells whereas this augmentation is observed later in human T cells. In murine T lymphocytes, DMBA induced calcium elevation follows tyrosine kinase activation and inositol-1,4,5-triphosphate production. This leads to calcium depletion of the endoplasmic reticulum. Furthermore, DMBA also blocks extracellular calcium entry. Thus, reduction of calcium mobilisation by DMBA is responsible to altered T cell proliferation in response to mitogens. In the second part of this study, we have defined the structural requirements for suppression of murine T lymphocyte activation by DMBA using two benz(a)anthracene monomethylated derivatives, 7-methylbenz(a)anthracene (7MBA) and 12-methylbenz(a)anthracene (12MBA). We show that DMBA is the more active for suppressing T cell activation. Like its two derivatives, DMBA inhibits molecular events that lead to G0 toG1 transition of the cell cycle (il-2 production, high affinity il-2 receptor expression). However, only DMBA interferes with G1 to S transition by inhibiting il-2 dependent proliferation. The methyl in position 12 is necessary to modify calcium homeostasis in murine T lymphocytes, since 12 MBA acts in the same way as DMBA unlike 7MBA which does not increase Ca2+ic. Finally, immunosuppression of human peripheral blood lymphocytes and murine splenocytes is compared following DMBA in vitro exposure. NK cytotoxicity, T cell proliferation, cytotoxic T lymphocyte induction and function are affected by DMBA whatever the origin of the cells (human or murine) despite a different mechanism of DMBA with calcium homeostasis in murine and human cells
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Philippe Saas. Mécanisme d'action de l'immunotoxicité induite par les hydrocarbures polycycliques aromatiques. Sciences agricoles. Université Paul Verlaine - Metz, 1997. Français. ⟨NNT : 1997METZ036S⟩. ⟨tel-01777219⟩

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