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Abstract
To elucidate the roles of metalloproteinases and the Bcl-2 family of proteins in Trichovaginalis. vaginalis-induced apoptosis in human cervical cancer cells (SiHa cells) and vaginal epithelial cells (MS74 cells), SiHa cells and MS74 cells were incubated with live T. vaginalis, T. vaginalis excretory and secretory products (ESP), and T. vaginalis lysates, either with or without the specific metalloproteinase inhibitor 1,10-phenanthroline (1,10-PT), and examined apoptotic events and Bcl-2 signaling. The live T. vaginalis and the T. vaginalis ESP induced the release of cytochrome c into the cytosol, the activation of caspase-3 and caspase-9, and the cleavage of PARP. Additionally, the live T. vaginalis, but not the T. vaginalis lysate, induced the cleavage of the proapoptotic Bim protein. The live T. vaginalis and the T. vaginalis ESP, but not the T. vaginalis lysate, induced the dose-dependent cleavage of the antiapoptotic Bcl-xL and Mcl-1 proteins and decreased the association levels of Bcl-xL/Bim and Mcl-1/Bim complexes. We performed gelatin zymography and casein-hydrolysis assays on the live T. vaginalis and the T. vaginalis ESP to identify the apoptosis-inducing factor. Both the live T. vaginalis and the ESP contained high levels of metalloproteinases, of which activities were significantly inhibited by 1,10-PT treatment. Furthermore, the 1,10-PT blocked the cleavage of Bcl-xL, Mcl-1, PARP, caspase-3, and caspase-9, as well as the release of cytochrome c into the cytosol, and it significantly increased the association levels of the Bcl-xL/Bim and Mcl-1/Bim protein complexes, returning them to normal levels. Our results demonstrate that T. vaginalis induces mitochondria-dependent apoptosis in SiHa cells through the dissociation of Bcl-xL/Bim and Mcl-1/Bim complexes and that the apoptosis is blocked by the metalloproteinase inhibitor 1,10-PT. These results expand our understanding of the role of metalloproteinases in T. vaginalis-induced apoptosis and the signaling pathway in trichomoniasis of the cervicovaginal epithelial cells.
Highlights
The protozoan parasite Trichomonas vaginalis infects the urogenital tract of humans
Each assay was carried out in triplicate, and the results shown are the relative percentages of protease activities in the cells infected with the pretreated parasites compared with those in the T. vaginalis-infected cells, which were set as 100%. * P,0.05. (F) The cytosolic fraction or protein extracts of the SiHa cells were isolated, and western blotting was performed with using indicated antibodies
The results suggest that live T. vaginalis induced cell death in the SiHa cells and excretory and secretory products (ESP) from T. vaginalis produced the similar effects on the cells
Summary
The protozoan parasite Trichomonas vaginalis infects the urogenital tract of humans. It is one of the most common nonviral sexually transmitted diseases [1]. Females infected with T. vaginalis develop vaginitis, but they have an increased risk of premature delivery, low birth weight, atypical pelvic inflammatory disease, infertility, a predisposition to developing invasive cervical cancer, and an increased susceptibility to HIV infection. T. vaginalis can cause nongonococcal urethritis and chronic prostatitis [1,2]. A highly regulated process that is essential for cell development and tissue homeostasis in eukaryotes, modulates pathogenesis in a variety of diseases [3,4].
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