|LATORRE, ANDREIA - Universidad De Sao Paulo|
|CANICEIRO, BEATRIZ - Universidad De Sao Paulo|
|FUKUMASU, HEIDGE - Universidad De Sao Paulo|
|LOPES, FABRICIO - Federal University Of Parana Polytechnic Center|
|WYOSPCHI JR, HARRY - Institute Of Biology - Brazil|
|DA SILVA, TEREZA - Universidad De Sao Paulo|
|HARAGUCHI, MITSUE - Institute Of Biology - Brazil|
|BRESSAN, FABIANA - Universidad De Sao Paulo|
|GORNIAK, SILVANA - Universidad De Sao Paulo|
Submitted to: Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/11/2012
Publication Date: 2/8/2013
Citation: Latorre, A.O., Caniceiro, B.D., Fukumasu, H., Gardner, D.R., Lopes, F.M., Wyospchi Jr, H.L., Da Silva, T.C., Haraguchi, M., Bressan, F.F., Gorniak, S.L. 2013. Ptaquiloside reduces NK cell activities by enhancing metallothionein expression, which is prevented by selenium. Toxicology. 304:100-108.
Interpretive Summary: Pteridium aquilinum, also known as bracken fern, is one of the most common plants in the world and can be poisonous to livestock and humans. The toxic compound in bracken fern is considered to be the terpene glycoside known as ptaquiloside. Most recently bracken fern was shown to be immunotoxic in a mouse model system and these effects could be reversed by selenium supplementation. Reported here are the results of gene expression microarray analysis to identify gene transcripts altered by ptaquiloside that could be linked to the immunosupression. It was confirmed that two genes, metallothinonein 1 (Mt1) and metallathinonein (2) are responsible for zinc homeostatsis and a reduction of free intracellular zinc impairs NK functions and such action could be prevented by selenium co-treatment. These findings could help understand the higher susceptibility to cancer that is induced by the bracken fern-mediated immunosuppressive effects.
Technical Abstract: Pteridium aquilinum, one of the most important poisonous plants in the world, is known to be carcinogenic to animals and humans. Moreover, our previous studies showed that the immunosuppressive effects of ptaquiloside, its main toxic agent, were prevented by selenium in mouse natural killer (NK) cells. We also verified that this immunosuppression facilitated development of cancer. Here, we performed gene expression microarray analysis in splenic NK cells from mice treated for 14 days with ptaquiloside (5.3 mg/kg) and/or selenium (1.3 mg/kg) to identify gene transcripts altered by ptaquiloside that could be linked to the immunosuppression and that would be prevented by selenium. Transcriptome analysis of ptaquiloside samples revealed that 872 transcripts were expressed differentially (fold change>2 and p<0.05), including 77 up-regulated and 795 down-regulated transcripts. Gene ontology analysis mapped these up-regulated transcripts to three main biological processes (cellular ion homeostasis, negative regulation of apoptosis and regulation of transcription). Considering the immunosuppressive effect of ptaquiloside, we hypothesized that two genes involved in cellular ion homeostasis, metallothionein 1 (Mt1) and metallothionein 2 (Mt2), could be implicated because Mt1 and Mt2 are responsible for zinc homeostasis, and a reduction of free intracellular zinc impairs NK functions. We confirm these hypotheses and show increased expression of metallothionein in splenic NK cells and reduction in free intracellular zinc following treatment with ptaquiloside that were completely prevented by selenium co-treatment. These findings could help avoid the higher susceptibility to cancer that is induced by P. aquilinum-mediated immunosuppressive effects.