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Protection Against CD95-Mediated Apoptosis by Inorganic Mercury in Jurkat T Cells¹

Michael J. Whitekus^*, Ronald P. Santini^*, Allen J. Rosenspire and Michael J. McCabe, Jr.^2,*

^* Institute of Chemical Toxicology, Detroit, MI 48201; and Departments of Pediatrics and Biological Sciences, Wayne State University, Detroit, MI 48201

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 µM) 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--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.

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