Oxidant stress mechanism of homocysteine potentiating Con A-induced proliferation in murine splenic T lymphocytes

Objective: An elevated plasma homocysteine (Hey) level is considered an independent risk factor for atherosclerosis. However, the mechanisms by which hyperhomocysteinemia induces atherosclerosis are only partially understood. The effect of Hey on T lymphocyte proliferation and its mechanisms were examined in normal and hyperhomocysteinemia ApoE-knockout mice. Methods: The mouse splenic T-cells were treated with Hey, related compounds and/or antioxidants in the presence or absence of Concanavalin A (Con A). DNA synthesis, cell apoptosis, interleukin-2 level and production of reactive oxygen species (ROS) were measured. Results: Hey (0.3-3.0 mM) and related compounds with thiol (-SH), such as cysteine and glutathione significantly potentiated Con A-induced proliferation and partially inhibited apoptosis in T lymphocytes, but it had no direct effect on resting T lymphocyte. ApoE-knockout mice with hyperhomocysteinemia (the level of plasma Hey was 20.3+/-2.9 vs. 2.6+/-0.6 muM in control group, P<0.05) had a significant promotion of T-cell proliferation in response to Con A. Hey (0.3-3.0 mM) also increased the intracellular ROS. Radical scavengers reduced Hey effect. Conclusions: These data indicate that ROS generated by thiol (-SH) of Hey auto-oxidation are involved in Hey effect on Con A-induced T lymphocyte proliferation. These findings suggest a novel mechanism may be involved in chronic inflammatory progression of atherosclerosis with hyperhomocysteinemia. (C) 2002 Elsevier Science BY All rights reserved.