Oxidant stress mechanism of homocysteine potentiating Con A-induced proliferation in murine splenic T lymphocytes.
OBJECTIVE
An elevated plasma homocysteine (Hcy) level is considered an independent risk factor for atherosclerosis. However, the mechanisms by which hyperhomocysteinemia induces atherosclerosis are only partially understood. The effect of Hcy 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 Hcy, 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
Hcy (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 Hcy was 20.3+/-2.9 vs. 2.6+/-0.6 microM in control group, P<0.05) had a significant promotion of T-cell proliferation in response to Con A. Hcy (0.3-3.0 mM) also increased the intracellular ROS. Radical scavengers reduced Hcy effect.


CONCLUSIONS
These data indicate that ROS generated by thiol (-SH) of Hcy auto-oxidation are involved in Hcy 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.
Zhang
Qin
Q
Institute of Vascular Medicine, Third Hospital, Beijing, PR China. zqcua@yahoo.com
Zeng
Xiaokun
X
Guo
Jingxuan
J
Wang
Xian
X
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003208:Concanavalin A / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006710:Homocysteine / Q000097:blood / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000975:Antioxidants; D001057:Apolipoproteins E; D007376:Interleukin-2; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D006710:Homocysteine; D003208:Concanavalin A; D007770:L-Lactate Dehydrogenase