In Vitro Immune Toxicity of Depleted Uranium: Effects on Murine Macrophages, CD4+ T Cells, and Gene Expression Profiles

http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1289%2Fehp.8085

Depleted Uranium: Effects on Murine Macrophages, CD4+ T Cells, and Gene Expression Profiles
Bin Wan1,2, James T. Fleming1,3, Terry W. Schultz1,2,4, Gary S. Sayler1,2,3

1 Center for Environmental Biotechnology, , 2 Department of Ecology and Evolutionary Biology, , 3 Department of Microbiology, and , 4 Department of Comparative Medicine, University of Tennessee, Knoxville, Tennessee, USA

Abstract Top

Depleted uranium (DU) is a by-product of the uranium enrichment process and shares chemical properties with natural and enriched uranium. To investigate the toxic effects of environmental DU exposure on the immune system, we examined the influences of DU (in the form of uranyl nitrate) on viability and immune function as well as cytokine gene expression in murine peritoneal macrophages and splenic CD4+ T cells. Macrophages and CD4+ T cells were exposed to various concentrations of DU, and cell death via apoptosis and necrosis was analyzed using annexin-V/propidium iodide assay. DU cytotoxicity in both cell types was concentration dependent, with macrophage apoptosis and necrosis occurring within 24 hr at 100 μM DU exposure, whereas CD4+ T cells underwent cell death at 500 μM DU exposure. Noncytotoxic concentrations for macrophages and CD4+ T cells were determined as 50 and 100 μM, respectively. Lymphoproliferation analysis indicated that macrophage accessory cell function was altered with 200 μM DU after exposure times as short as 2 hr. Microarray and real-time reverse-transcriptase polymerase chain reaction analyses revealed that DU alters gene expression patterns in both cell types. The most differentially expressed genes were related to signal transduction, such as c-jun, NF-κ Bp65, neurotrophic factors (e.g., Mdk), chemokine and chemokine receptors (e.g., TECK/CCL25), and interleukins such as IL-10 and IL-5, indicating a possible involvement of DU in cancer development, autoimmune diseases, and T helper 2 polarization of T cells. The results are a first step in identifying molecular targets for the toxicity of DU and the elucidation of the molecular mechanisms for the immune modulation ability of DU.
Keywords: apoptosis, CD4+ T cell, cytokine gene expression, depleted uranium, macrophage function, necrosis.

Citation: Wan B, Fleming JT, Schultz TW, Sayler GS 2006. In Vitro Immune Toxicity of Depleted Uranium: Effects on Murine Macrophages, CD4+ T Cells, and Gene Expression Profiles. Environ Health Perspect 114:85-91. http://dx.doi.org/10.1289/ehp.8085

Received: 2 March 2005; Accepted: 17 August 2005; Online: 17 JanuaryAugust 2006 2005

Address correspondence to G.S. Sayler, Center for Environmental Biotechnology, University of Tennessee, Knoxville, 676 Dabney Hall, Knoxville, TN 37996-1605 USA. Telephone: (865) 974-8080. Fax: (865) 974-8086. E-mail: sayler@utk.edu

Conclusions Top

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.

One Response to “In Vitro Immune Toxicity of Depleted Uranium: Effects on Murine Macrophages, CD4+ T Cells, and Gene Expression Profiles”

  1. CaptD Says:

    Wonder who funded this study, probably the pro nuclear industry through a grant…

    Notice this:
    Received: 2 March 2005; Accepted: 17 August 2005; Online: 17 JanuaryAugust 2006 2005

    Liked and Tweeted…

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