In Vitro Immune Toxicity of Depleted Uranium: Effects on Murine
Macrophages, CD4+ T Cells, and Gene Expression Profiles|
In summary we have demonstrated DU-induced apoptosis and necrosis in both peritoneal macrophages and splenic CD4^+ T cells in a cell-specific and concentration-dependent manner. Short-term DU exposure (> 200 µM) to macrophages interferes with the interplay between macrophages and CD4^+ T cells, resulting in an enhanced T-cell proliferation response. At lower (noncytotoxic) concentrations, DU has the potential to influence immune function by modulating cytokine gene expression mainly involved in signal transductions, interleukin
production, chemokine and chemokine receptors, and neurotrophic factors. Array analyses have successfully identified differentially regulated genes implicating DU in carcinogenesis and the development of autoimmune diseases. The up-regulation of /IL-5/ and /IL-10/ genes in CD4^+ T cells and macrophages, respectively, strongly suggests a DU-induced Th2 shift during naive T-cell differentiation. Considering the substantial sequence homology between the mouse and human genome and the conserved expression patterns of orthologs reflecting common physiologic functions in these two organisms (Su et al. 2002), the
alteration in immune functions and cytokine gene expression in murine immune cells demonstrated in this study identify putative molecular targets for the toxic actions of DU and suggest molecular mechanisms for the development of DU-related diseases in humans.