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Gene expression changes induced by bismuth in a macrophage cell line

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Abstract

We have investigated the effect of bismuth by autometallography, cell viability, TUNEL assay and microarray analysis of a macrophage cell line. The cells accumulate bismuth in their lysosomes in a time- and dose-dependent manner. Cell viability assays show a significant decrease in the number of viable cells related to both bismuth concentrations and exposure time. TUNEL assays after 12 h and 24 h at a bismuth-citrate concentration of 50 μM revealed the presence of 30% and 70% TUNEL-positive cells, respectively, compared with 8% in the controls. We have analysed gene expression profiles for cells exposed to 50 μM bismuth-citrate and for untreated controls at 12 h and 24 h by microarray analysis, which confirmed that bismuth is a powerful metallothionein inducer. A number of glycolytic enzymes are induced by bismuth, suggesting that bismuth is able to induce “hypoxia-like” stress. BCL2/adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) has been suggested as a regulator of hypoxia-induced cell death independent of caspase-3 activation and cytochrome c release. Bnip3 is up-regulated indicating the involvement of Bnip3 as a possible mechanism for bismuth-induced cell death. Differences have been noticed in cell viability and in the modification of the mRNA expression levels at 12 and 24 h. Only 13 genes are modified at both these times, suggesting a time-dependent molecular cascade in which bismuth-exposed cells enter a dormant stage with mRNA down-regulation being followed by cell death of susceptible cells.

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Acknowledgements

We thank Ms. L. Munkøe, Ms. D. Jensen, Ms. M. Sand, Ms. K. Wiedemann and Mr. A. Meier at the Institute of Anatomy, University of Aarhus, and Ms. G. Høj, Ms. Susanne Bruun and Ms. H. Steen at the Molecular Diagnostic Laboratory, University Hospital of Aarhus, for excellent technical assistance.

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Authors and Affiliations

  1. Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

    Nils E. Magnusson, Mogens Kruhøffer & Torben F. Ørntoft

  2. Department of Neurobiology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark

    Agnete Larsen, Jørgen Rungby & Meredin Stoltenberg

  3. Department of Pharmacology, University of Aarhus, 8000, Aarhus C, Denmark

    Jørgen Rungby

  4. Department of Endocrinology C, Aarhus University Hospital, 8000, Aarhus C, Denmark

    Jørgen Rungby

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  1. Nils E. Magnusson
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Correspondence to Jørgen Rungby.

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This study was supported by the Aarhus University Research Foundation, “Aase og Ejnar Danielsens Fond” and “Direktør Jacob Madsen og Hustrus Fond”.

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Magnusson, N.E., Larsen, A., Rungby, J. et al. Gene expression changes induced by bismuth in a macrophage cell line. Cell Tissue Res 321, 195–210 (2005). https://doi.org/10.1007/s00441-005-1103-y

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