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Transcriptional regulation of kinases downstream of the T cell receptor: another immunomodulatory mechanism of glucocorticoids

TitoloTranscriptional regulation of kinases downstream of the T cell receptor: another immunomodulatory mechanism of glucocorticoids
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2014
AutoriPetrillo, Maria Grazia, Fettucciari Katia, Montuschi Paolo, Ronchetti Simona, Cari Luigi, Migliorati Graziella, Mazzon Emanuela, Bereshchenko Oxana, Bruscoli Stefano, Nocentini Giuseppe, and Riccardi Carlo
RivistaBMC pharmacology & toxicology
Volume15
Paginazione35
Type of ArticleArticle
ISSN20506511
Parole chiaveAdjuvants, animal, Animals, antigen, Bagg albino mouse, Base Sequence, C3H mouse, down regulation, Down-Regulation, drug effects, gene expression regulation, Genetic, genetic transcription, genetics, glucocorticoid, Glucocorticoids, Immunologic, immunological adjuvant, Inbred BALB C, Inbred C3H, Knockout, knockout mouse, Ltk protein, lymphocyte antigen receptor, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mice, molecular genetics, Molecular Sequence Data, mouse, nucleotide sequence, Polymerase Chain Reaction, protein kinase, protein kinase Lck, Protein Kinases, protein tyrosine kinase, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptors, T-Cell, Tec protein-tyrosine kinase, Transcription, Up-Regulation, upregulation
Abstract

BACKGROUND: Glucocorticoids affect peripheral immune responses, including modulation of T-cell activation, differentiation, and apoptosis. The quantity and quality of T-cell receptor (TCR)-triggered intracellular signals modulate T-cell function. Thus, glucocorticoids may affect T cells by interfering with the TCR signaling cascade. The purpose of the study was to search for glucocorticoid-modulated kinases downstream of the TCR.; METHODS: Gene modulation in lymphoid cells either treated with glucocorticoids or from glucocorticoid-treated mice was studied using a RNase protection assay, real-time PCR, and western blotting. The sensitivity of genetically modified thymocytes to glucocorticoid-induced apoptosis was studied by performing hypotonic propidium iodide staining and flow cytometry. The Student's t-test was employed for statistical evaluation.; RESULTS: We found that transcription of Itk, a non-receptor tyrosine kinase of the Tec family, was up-regulated in a mouse T-cell hybridoma by the synthetic glucocorticoid dexamethasone. In contrast, dexamethasone down-regulated the expression of Txk, a Tec kinase that functions redundantly with Itk, and Lck, the Src kinase immediately downstream of the TCR. We investigated the expression of Itk, Txk, and Lck in thymocytes and mature lymphocytes following in vitro and in vivo dexamethasone treatment at different time points and doses. Kinase expression was differentially modulated and followed distinct kinetics. Itk was up-regulated in all cell types and conditions tested. Txk was strongly up-regulated in mature lymphocytes but only weakly up-regulated or non-modulated in thymocytes in vitro or in vivo, respectively. Conversely, Lck was down-regulated in thymocytes, but not modulated or up-regulated in mature lymphocytes in the different experimental conditions. This complex behaviour correlates with the presence of both positive and negative glucocorticoid responsive elements (GRE and nGRE, respectively) in the Itk, Txk and Lck genes. To investigate the function associated with Itk up-regulation, dexamethasone-induced apoptosis of thymocytes from Itk-deficient mice was evaluated. Our results demonstrated that Itk deficiency causes increased sensitivity to dexamethasone but not to other pro-apoptotic stimuli.; CONCLUSIONS: Modulation of Itk, Txk, and Lck in thymocytes and mature lymphocytes is another mechanism by which glucocorticoids modulate T-cell activation and differentiation. Itk up-regulation plays a protective role in dexamethasone-treated thymocytes.

Note

Cited by: 22; All Open Access, Gold Open Access, Green Open Access

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84926102267&doi=10.1186%2f2050-6511-15-35&partnerID=40&md5=c0791ecb7a2d813e5214e1f3791a6d59
DOI10.1186/2050-6511-15-35
Citation KeyPetrillo201435
PubMed ID24993777