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 μM) 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 IFNγ) 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 IFNγ, 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 IFNγ than IL-4 and hence, the study unravels to some extend, the underlying events involved in Cd immunotoxicity.
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References
Achanzar WE, Achanzar KB, Lewis JG, Webber MM, Waalkes MP (2000) Cadmium induces c-myc, p53 and c-jun expression in normal human prostate epithelial cell as a prelude to apoptosis. Toxicol Appl Pharmacol 164:291–300
Aukrust P, Svardal AM, Muller F, Lunden B, Berge RK, Froland SS (1995) Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress. Blood 86:1383–1391
Baumann CA, Badamchian M, Goldstein AL (1997) Thymosin α 1 antagonizes dexamethasone and CD3-induced apoptosis of CD4+CD8+ thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways. Mech Ageing Dev 94:85–101
Conroy A, Alexander DR (1996) The role of intracellular signaling pathways regulating thymocytes and leukemic T cell apoptosis. Leukemia 10:1422–1435
Dan G, Lall SB, Rao DN (2000) Humoral and cell mediated immune response to cadmium in mice. Drug Chem Toxicol 23:349–360
Descotes J (1992) Immunotoxicology of cadmium. IARC Sci Publ 118:385–390
Dong SY, Shen HM, Ong CN (2001) Cadmium-induced apoptosis and phenotypic changes in mouse thymocytes. Mol Cell Biochem 222:11–20
Gupta S (2003) Molecular signaling in death receptor and mitochondrial pathways of apoptosis. Int J Oncol 22:15–20
Gupta S, Yel L, Kim D, Kim C, Chiplunkar S, Gollapudi S (2003) Arsenic trioxide induces apoptosis in peripheral blood T lymphocyte subsets by inducing oxidative stress: a role of Bcl-2. Mol Cancer Ther 2: 711–719
Harring AC, Xu Z, Andersson G, Hedlund G (1997) Linomide enhances apoptosis in CD4+CD8+ thymocytes. Scand J Immunol 46:488–494
Harstad EB, Klaassen CD (2002) Tumor necrosis factor-α-null mice are not resistant to cadmium chloride-induced hepatotoxicity. Toxicol Appl Pharmacol 179:155–162
Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776
Kamath AB, Nagarkatti PS, Nagarkatti M (1998) Characterization of phenotypic alterations induced by 2,3,7,9-tetrachlorodibenzo-p-dioxin on thymocytes in vivo and its effect on apoptosis. Toxicol Appl Pharmacol 150:117–124
Kisiclow P (1995) Apoptosis in intrathymic T-cell development. In: Gregory CD (ed), Apoptosis and the immune response. Wiley-Liss Inc, New York, pp 13–53
Koller LD (1998) Immunotoxicology of environmental and occupational metals. In: Zelikoff JT, Thomas PT (eds) Cadmium. Taylor and Francis, London, pp 41–61
Lafuente A, Gonzalez-Carracedo A, Esquifino AI (2004) Differential effects of cadmium on blood lymphocyte subsets. Biometals 17:451–456
Lai ZW, Fiore NC, Gasiewick TA, Silverstone AE (1998) 2,3,7,8 tetra chlorodibenzo p dioxin and diethylstilbestrol affect thymocytes at different stages of development in fetal thymus organ culture. Toxicol Appl Pharmacol 149:167–177
Liu J, Liu Y, Habeebu SS, Klaassen CD (1999) Metallothionein-null mice are highly susceptible to the hematotoxic and immunotoxic effects of chronic CdCl2 exposure. Toxicol Appl Pharmacol 159:98–108
Mackova NO, Lenikova S, Fedorocko P, Brezani P, Fedorockovo A (1996) Effects of cadmium on haemopoiesis in irradiated and non-irradiated mice: 2. Relationship to the number of circulating blood cells and haemopoiesis. Physiol Res 45:101–106
Miua K, Nakajima Y, Yamanaka N, Terao K, Shibato T, Ishino S (1998) Induction of apoptosis with fusarenon-X in mouse thymocytes. Toxicology 127:195–206
Morselt AF, Leene W, De Groot C et al (1988) Differences in immunological susceptibility to cadmium toxicity between two rat strains as demonstrated with cell biological methods. Effect of cadmium on DNA synthesis of thymus lymphocytes. Toxicology 48:127–139
Ohsawa M, Sato K, Takahashi K, Ochi T (1983) Modified distribution of lymphocyte subpopulation in blood and spleen from mice exposed to cadmium. Toxicol Lett 19:29–35
Pathak N, Khandelwal S (2006a) Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium. Toxicology 220:26–36
Pathak N, Khandelwal S (2006b) Influence of cadmium on murine thymocytes: potentiation of apoptosis and oxidative stress. Toxicol Lett 165:121–132
Pathak N, Khandelwal S (2007) Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice. Toxicol Lett 169:95–108
Pieters RH, Bol M, Penninks AH (1994) Immunotoxic organotins as possible model compounds in studying apoptosis and thymocyte differentiation. Toxicology 91:189–202
Ram MS, Neetu D, Yogesh B et al (2002) Cyto- protective and immunomodulating properties of Amla (Emlica officinalis) on lymphocytes: an in vitro study. J Ethanopharmacol 81:5–10
Rothenberg EV (1992) The development of functionally responsive T cells. Adv Immunol 51:85–214
Shen HM, Dong SY, Ong CN (2001) Critical role of calcium overloading in cadmium induced apoptosis in mouse thymocytes. Toxicol Appl Pharmacol 171:12–19
Suzuki KT, Yamada YK, Shimizu F (1981) Essential metals and metallothionein in cadmium induced thymic atrophy and splenomegaly. Biochem Pharmacol 30:1217–1222
Zamzani N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2:67–71
Acknowledgements
Authors are grateful to Director, ITRC for his keen interest in this work and to Dr. Y. Shukla for providing flow cytometer facility. The secretarial assistance of Mr. R.S. Verma is acknowledged.
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Pathak, N., Khandelwal, S. Impact of cadmium in T lymphocyte subsets and cytokine expression: differential regulation by oxidative stress and apoptosis. Biometals 21, 179–187 (2008). https://doi.org/10.1007/s10534-007-9106-7
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DOI: https://doi.org/10.1007/s10534-007-9106-7