Protection against CD95-mediated apoptosis by inorganic mercury in Jurkat T cells.
Dysregulation of CD95/Fas-mediated apoptosis has been implicated as a contributing factor in autoimmune disorders. Animal studies clearly have established a connection between mercury exposure and autoimmune disease in rodents, while case reports have suggested a link between accidental mercury contamination and autoimmune disease in humans. The mechanism(s) for these associations are poorly understood. Using the Jurkat cell model, we have found that low levels (</=10 microM) of inorganic mercury (i.e., HgCl2) attenuated anti-CD95-mediated growth arrest and markedly enhanced cell survival. Several biochemical assays for apoptosis, including DNA degradation, poly(ADP-ribose) polymerase degradation, and phosphatidylserine externalization, directly verified that HgCl2 attenuated anti-CD95-mediated apoptosis. In an attempt to further characterize the effect of mercury on CD95-mediated apoptosis, several signaling components of the CD95 death pathway were analyzed to determine whether HgCl2 could modulate them. HgCl2 did not modulate CD95 expression; however, it did block CD95-induced caspase-3 activation. HgCl2 was not able to attenuate TNF-alpha-mediated apoptosis in U-937 cells, or ceramide-C6-mediated apoptosis in Jurkat cells, suggesting that mercury acts upstream of, or does not involve, these signals. Thus, inorganic mercury specifically attenuates CD95-mediated apoptosis likely by targeting a signaling component that is upstream of caspase-3 activation and downstream of CD95.
Whitekus
M J
MJ
Institute of Chemical Toxicology, Detroit, MI 48201, USA.
Santini
R P
RP
Rosenspire
A J
AJ
McCabe
M J
MJ
D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000187:drug effects / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002518:Ceramides / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008628:Mercury / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D000911:Antibodies, Monoclonal; D002518:Ceramides; D006131:Growth Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D008628:Mercury