Regulation of cyclooxygenase-2 expression in human T cells by glucocorticoid receptor-mediated transrepression of nuclear factor of activated T cells
Entity
UAM. Departamento de Biología MolecularPublisher
MDPIDate
2022-11-01Citation
10.3390/ijms232113275
International Journal of Molecular Sciences 23.21 (2022): 13275
ISSN
1661-6596 (print); 1422-0067 (online)DOI
10.3390/ijms232113275Funded by
This research was funded by grants SAF2015-69396-R (MICINN/FEDER), RTI2018-100815-B-I00 (MICIU/FEDER), and the accompanying 2021 CSIC Exceptional Grant to M.A.I. and J.M.S. The Centro de Biología Molecular Severo Ochoa receives an institutional grant from the Fundación Ramón ArecesProject
Gobierno de España. SAF2015-69396-R; Gobierno de España. RTI2018-100815-B-I00Editor's Version
https://doi.org/10.3390/ijms232113275Subjects
Animals; Humans; Mammals; T-Lymphocytes; Metabolism; Dexamethasone; Biología y Biomedicina / BiologíaRights
© 2022 by the authorsAbstract
Cyclooxygenase (COX) is the key enzyme in prostanoid synthesis from arachidonic acid (AA). Two isoforms, named COX-1 and COX-2, are expressed in mammalian tissues. The expression of COX-2 isoform is induced by several stimuli including cytokines and mitogens, and this induction is inhibited by glucocorticoids (GCs). We have previously shown that the transcriptional induction of COX-2 occurs early after T cell receptor (TCR) triggering, suggesting functional implications of this enzyme in T cell activation. Here, we show that dexamethasone (Dex) inhibits nuclear factor of activated T cells (NFAT)-mediated COX-2 transcriptional induction upon T cell activation. This effect is dependent on the presence of the GC receptor (GR), but independent of a functional DNA binding domain, as the activation-deficient GRLS7 mutant was as effective as the wild-type GR in the repression of NFAT-dependent transcription. Dex treatment did not disturb NFAT dephosphorylation, but interfered with activation mediated by the N-terminal transactivation domain (TAD) of NFAT, thus pointing to a negative cross-talk between GR and NFAT at the nuclear level. These results unveil the ability of GCs to interfere with NFAT activation and the induction of pro-inflammatory genes such as COX-2, and explain some of their immunomodulatory properties in activated human T cells
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Google Scholar:Cacheiro-Llaguno, Cristina
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Hernández-Subirá, Elena
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Díaz-Muñoz, Manuel D.
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Fresno Escudero, Manuel
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Serrador Peiró, Juan Manuel
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Íñiguez Peña, Miguel Ángel
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