Impact of cadmium in T lymphocyte subsets and cytokine expression: differential regulation by oxidative stress and apoptosis.
Cadmium (Cd), a possible human carcinogen is a potent immunotoxicant. In rodents it causes thymic atrophy and splenomegaly, in addition to immuno-suppression and modulation of humoral and/or cellular immune response. Oxidative stress and apoptosis appear to be underlying mechanism of Cd induced thymic injury. To understand the involvement of reactive oxygen species (ROS), intracellular glutathione (GSH) and apoptosis in modulation of T-cell repertoire, we studied the effect of Cd (10, 25 and 50 microM) on primary T lymphocytes of BALB/c mice at different time intervals (6, 12 and 18 h). We observed a dose and time dependent decline in CD4(+)/CD8(+) ratio (a bio-indicator of immunotoxicity) as a result of significant suppression of CD4(+)subsets (helper T-cells) and enhancement in CD8(+) cells (cytotoxic T-cells) At the same time, the CD4(+)CD8(+) (DP) cell population was lowered while the CD4(-)CD8(-) (DN) cells were increased. The oxidative stress and apoptotic data revealed almost similar ROS generation in both CD4(+) and CD8(+) cells, but relatively more marked GSH depletion and apoptosis in CD4(+) than in CD8(+) population. On further analysis of CD4(+) T-subsets, cytokine release (IL-2 and IFNgamma) by Th 1 cells and IL-4 by Th 2 cells were shown to be significantly suppressed in a dose responsive manner. The highest inhibition was observed in IFNgamma, then IL-2 followed by IL-4. In conclusion, our data demonstrates that T-cell apoptosis by Cd, more in CD4(+)than in CD8(+)cells appear related to higher depletion of intracellular glutathione. Th 1 cells of CD4(+) sub-population are more responsive to Cd than Th 2, leading to higher suppression of IL-2 and IFNgamma than IL-4 and hence, the study unravels to some extend, the underlying events involved in Cd immunotoxicity.
Pathak
Neelima
N
Industrial Toxicology Research Centre, Mahatma Gandhi Marg, Lucknow, India.
Khandelwal
Shashi
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D017382:Reactive Oxygen Species; D002104:Cadmium