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RESEARCH ARTICLE |
Department of Bacteriology, Georg-August-University Göttingen, Kreuzbergring 57, D-37075 Göttingen, Germany
*Author for correspondence (e-mail: clueder{at}gwdg.de)
Accepted July 2, 2001
The obligate intracellular protozoan parasite Toxoplasma gondii has been shown to protect different cell types from apoptosis induced by a variety of pro-apoptotic treatments. However, the precise cell biological mechanisms of this inhibition remained unknown. As shown in this study, apoptosis in human-derived HL-60 and U937 cells induced by treatment with actinomycin D or TNF-
in combination with cycloheximide, respectively, was indeed dose-dependently downregulated by prior infection with T. gondii, as determined by DNA fragmentation assays. Cleavage of caspase 3 and caspase 9 after treatment with pro-apoptotic stimuli was considerably diminished by T. gondii. Furthermore, release of mitochondrial cytochrome c during apoptosis in HL-60 cells was prevented by intracellular parasites and this was correlated with the absence of DNA strand breaks on the single cell level. Inhibition of cytochrome c release coincided with a twofold upregulation of Mcl-1 protein levels in HL-60 and U937 cells, while Bcl-2 expression did not increase after infection. Parasitic interference with the caspase cascade led to a reduced proteolytic cleavage of the nuclear target molecule protein kinase C
. In parallel, poly(ADP-ribose) polymerase protein levels were prominently downregulated by T. gondii, irrespective of whether HL-60 and U937 cells had been treated with pro-apototic stimuli or left untreated. However, poly(ADP-ribose) polymerase mRNA levels remained unchanged after infection as determined by RT-PCR analyses. These observations suggest that T. gondii has evolved different mechanisms that may contribute to downregulation of host cell apoptosis, namely inhibition of cytochrome c release and subsequent caspase activation as well as downregulation of poly(ADP-ribose) polymerase protein levels.
Key words: Apoptosis, Toxoplasma gondii, Poly(ADP-ribose) polymerase, Caspase, Mitochondria, Mcl-1
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