Low and nontoxic levels of ionic mercury interfere with the regulation of cell growth in the WEHI-231 B-cell lymphoma.
WEHI-231 is a mouse B-cell line, which is a well-established model for studying signal transduction in B lymphocytes, normally responding to cross-linking of the B-cell receptor (BCR) complex by the rapid upregulation of protein tyrosine kinase activity, followed by increased intracellular calcium and activation of protein kinase C. In WEHI-231, activation of protein kinase C is functionally associated with downregulation of DNA synthesis, followed by the induction of apoptosis. We have found in WEHI-231, that at low and environmentally relevant exposure levels (0.1 microM) mercury is not toxic, but still interferes with signal transduction in that it attenuates the growth inhibitory effects of BCR cross-linking. The molecular target for mercury resulting in attenuation of the BCR-mediated growth inhibitory signal is likely proximal to activation of the BCR complex, as HgCl2 had no effect on the negative growth signal generated downstream by direct activation of protein kinase C with phorbol 12-myristate 13-acetate. Treatment of WEHI-231 cells with high and toxic concentrations of Hg results in a marked increase in protein tyrosine phosphorylation in a great many proteins; whereas treatment of WEHI-231 cells with 0.1 microM mercury is not toxic. Under these conditions mercury selectively perturbed BCR-mediated protein tyrosine phosphorylation of a 75 kDa protein, without grossly affecting tyrosine phosphorylation levels of most other proteins. These data suggest that low levels of mercury, which are not toxic, may still contribute to immune dysfunction by interfering with antigen-receptor-mediated and protein-kinase-dependent signal transduction in lymphocytes.
McCabe
M J
MJ
Institute of Chemical Toxicology, Wayne State University, Detroit, USA.
Santini
R P
RP
Rosenspire
A J
AJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D007075:Immunoglobulin M / Q000494:pharmacology; D007477:Ions; D016393:Lymphoma, B-Cell; D008623:Mercaptoethanol / Q000378:metabolism / Q000494:pharmacology; D008627:Mercuric Chloride / Q000378:metabolism / Q000494:pharmacology; D008628:Mercury / Q000378:metabolism*; D051379:Mice; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D007075:Immunoglobulin M; D007477:Ions; D008934:Mitogens; D011947:Receptors, Antigen, B-Cell; D008627:Mercuric Chloride; D008623:Mercaptoethanol; D004247:DNA; D008628:Mercury; D013755:Tetradecanoylphorbol Acetate