All-trans retinoic acid (ATRA) induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity

Diego Sanchez-Martínez, Ewelina Krzywinska, Moeez G. Rathore, Anne Saumet, Amelie Cornillon, Nuria Lopez-Royuela, Luis Martínez-Lostao, Ariel Ramirez-Labrada, Zhao Yang Lu, Jean François Rossi, Dietmar Fernández-Orth, Sergio Escorza, Alberto Anel, Charles Henri Lecellier, Julian Pardo, Martin Villalba

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

NK cell is an innate immune system lymphocyte lineage with natural cytotoxicity. Its optimal use in the clinic requires in vitro expansion and activation. Cytokines and encounter with target cells activate NK cells and induce proliferation, and this could depend on the presence of other immune cells. Here we activated PBMCs during 5 days with IL-2, with IL-2 plus the tumor cell line K562 and with the lymphoblastoid cell line R69 and perform integrated analyses of microRNA and mRNA expression profiles of purified NK cells. The samples cluster depending on the stimuli and not on the donor, indicating that the pattern of NK cell stimulation is acutely well conserved between individuals. Regulation of mRNA expression is tighter than that of miRNA expression. All stimuli induce a common preserved genetic remodeling. In addition, encounter with target cells mainly activates pathways related to metabolism. Different target cells induce different NK cell remodeling which affects cytokine response and cytotoxicity, supporting the notion that encounter with different target cells significantly changing the activation pattern. We validate our analysis by showing that activation down regulates miR-23a, which is a negative regulator of cathepsin C (CTSC) mRNA, a gene up regulated by all stimuli. The peptidase CTSC activates the granzymes, the main effector proteases involved in NK cell cytotoxicity. All-trans retinoic acid (ATRA), which induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity in an in vivo mouse model.

Original languageEnglish (US)
Pages (from-to)42-52
Number of pages11
JournalInternational Journal of Biochemistry and Cell Biology
Volume49
Issue number1
DOIs
StatePublished - Apr 2014

Bibliographical note

Funding Information:
This work was supported by the program “Chercheur d’avenir” from the Region Languedoc-Rousillon (MV), a scientific program from the “Communauté de Travail des Pyrénées” (CTPP10/09 to MV, SE and AA), the CliNK project (SOE2/P1/E341) from Sudoe/EU (AA, J-FR and MV), the Association pour la Recherche contre le Cancer (MV), the Fondation pour la Recherche Medicale (MV), a grant FEDER Objectif competitivite (MV), l’association CIEL, l’association L’Un pour l’Autre et la fédération Ensangble (MV), Fondo Social Europeo (FSE), grants SAF2010-15341 (AA) and SAF2011-25390 (JP) Ministerio de Economía y Competitividad , Spain and fellowships from Gobierno de Aragon (DS) the ARC (MGR and EK) and Higher Education Commission, Pakistan (MGR) and La Ligue contre le Cancer (NL-R).

Keywords

  • Cathepsin C
  • NK cells
  • Transcriptomics
  • miR-23a
  • miRNA

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