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Immunomodulatory actions and epigenetic alterations induced by proteases from Bothrops snake venoms in human immune cells.

Authors
  • Menaldo, Danilo L1
  • Costa, Tássia R2
  • Ribeiro, Diego L3
  • Zambuzi, Fabiana A2
  • Antunes, Lusânia M G2
  • Castro, Fabíola A2
  • Frantz, Fabiani G2
  • Sampaio, Suely V4
  • 1 Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: [email protected] , (Brazil)
  • 2 Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. , (Brazil)
  • 3 Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. , (Brazil)
  • 4 Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: [email protected] , (Brazil)
Type
Published Article
Journal
Toxicology in vitro : an international journal published in association with BIBRA
Publication Date
Jul 02, 2019
Volume
61
Pages
104586–104586
Identifiers
DOI: 10.1016/j.tiv.2019.06.020
PMID: 31271808
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The aim of this study was to evaluate the immunomodulatory effects of two toxins from Bothrops snake venoms (the P-I metalloprotease Batroxase and the thrombin-like serine protease Moojase) on human peripheral blood mononuclear cells (PBMC), also investigating changes in the expression of genes related to epigenetic alterations and their immunotherapeutic potential. After 24 h of PBMC stimulation, Batroxase (2 μg/mL) and Moojase (4 μg/mL) increased some cytokine levels (including IL-6 and IL-10), but did not promote cell death processes (apoptosis/necrosis) or alterations in the global DNA methylation levels. Gene expression experiments (RT-qPCR) showed that most of the genes with altered transcript levels encode enzymes that act on histones, such as acetyltransferases (HAT1), deacetylases (HDACs), methyltransferases (DOT1L) or demethylases (KDM5B), indicating that these toxins may alter gene regulation through epigenetic changes mainly related to histones and to methyl-CpG binding proteins (MECP2). Subsequently, the immunotherapeutic potential of these toxins was evaluated using in vitro cytotoxicity assays with NK cells and K562 leukemic cells. Both toxins were able to potentiate the NK cell cytotoxic effects against K562 tumor cells, and the effect of Batroxase was dependent on the concomitant stimulus with IL-2, whereas Moojase increased the NK cytotoxicity independently of IL-2. Thus, Batroxase and Moojase presented interesting immunomodulatory effects that could be explored for the development of new strategies in anticancer immunotherapies. Copyright © 2019 Elsevier Ltd. All rights reserved.

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