Impact of cadmium in T lymphocyte subsets and cytokine expression: differential regulation by oxidative stress and apoptosis

Abstract

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.

Cadmium Is a Novel and Independent Risk Factor for Early Atherosclerosis Mechanisms and In Vivo Relevance

“…Our in vitro data suggest that Cd, which is taken up by ECs via solute carriers or ion channels clustering on the luminal side of ECs (see Figure 2), causes DNA strand brakes. An involvement of oxidative stress, as has been suggested by others 27,28 seems unlikely in our model because we were not able to detect oxidative stress by various methods (eg, 123 Di-hydro-rhodamine, H2-DCF-DA staining, Oxyblotting, and no shift in the GSH:GSSG ratio toward GSSG; data not shown). The phosphorylation of ATM on serine 1981 clearly indicates that ECs sense DNA damage and react by upregulation and stabilization of p53 and its downstream target, cell cycle inhibitor p21/WAF1/Cip1 (note the drop in the number of viable cells in the absence of cell death after 24 and 48 hours in response to Cd treatment; Figure 3A and 3B).…”

Lymphocyte subpopulations in human exposure to metals (IUPAC Technical Report)

“…When primary mouse T lymphocytes were treated with cadmium, the CD4+/CD8+ ratio declined in a dose-and time-dependent manner, indicative of a greater susceptibility of CD4+ cells. Both populations were decreased in overall number [72].…”

Effects of Agaricus blazei Murill Polysaccharide on Cadmium Poisoning on the MDA5 Signaling Pathway and Antioxidant Function of Chicken Peripheral Blood Lymphocytes

“…Pathak [28] showed that Cd exposure reduced the cell viability of lymphocytes in rodents. In vivo and in vitro studies in mice also have indicated that splenocytes are very sensitive to Cd exposure [28,32,33]. The Fengping Xu [34] study showed that Cd can increase the mRNA expression of IL-1β in chicken spleens.…”