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

Petrillo, Maria Grazia; Fettucciari, Katia; Montuschi, Paolo; Ronchetti, Simona; Cari, Luigi; Migliorati, Graziella; Mazzon, Emanuela; Bereshchenko, Oxana; Bruscoli, Stefano; Nocentini, Giuseppe; Riccardi, Carlo
March 2014
BMC Pharmacology & Toxicology;2014, Vol. 15 Issue 1, p35
Academic Journal
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.


Related Articles

  • Glucocorticoid-induced alternative promoter usage for a novel 5′ variant of granzyme A. Ruike, Yoshinao; Katsuma, Susumu; Hirasawa, Akira; Tsujimoto, Gozoh // Journal of Human Genetics;Feb2007, Vol. 52 Issue 2, p172 

    Glucocorticoids exert diverse physiological functions through transcriptional regulation of genes including granzyme A (GZMA). GZMA is one of the apoptotic effectors localized in cytotoxic T lymphocytes and is considered to mediate glucocorticoid-induced apoptosis of human leukemia 697 cells. In...

  • STAT5 in hematopoietic stem cell biology and transplantation. Zhengqi Wang; Bunting, Kevin D. // JAK-STAT;Oct2013, Vol. 2 Issue 4, pe27159-1 

    Signal transducer and activator of transcription 5 (STAT5) regulates normal lympho-myeloid development through activation downstream of early-acting cytokines, their receptors, and Janus kinases (JAKs). Despite a general understanding of the role of STAT5 in hematopoietic stem cell (HSC)...

  • A ROLE OF TEC, A NON RECEPTOR TYROSINE KINASE AS APOPTOTIC REGULATOR. Patel, Khushbu; Patel, Jayvadan K.; Patel, Anita; Deshmukh, Aaishwarya; Mishra, Bharat // International Journal of Pharmaceutical Sciences Review & Resear;Jul/Aug2011, Vol. 9 Issue 2, p58 

    There are many types of tyrosine kinase involved in intracellular mitogenic mechanism, particularly, Tec tyrosine kinase are involved in apoptosis pathway. Tec tyrosine kinases do not have any transmembrane domain so it is known as non receptor tyrosine kinase. There are various types of Tec...

  • Glucocorticoids: mechanisms of action and anti-inflammatory potential in asthma. Velden, V. H. J. Van Der // Mediators of Inflammation;Aug98, Vol. 7 Issue 4, p229 

    GLUCOCORTICOIDS are potent inhibitors of inflammatory processes and are widely used in the treatment of asthma. The anti-inflammatory effects are mediated either by direct binding of the glucocorticoid/glucocorticoid receptor complex to glucocorticoid responsive elements in the promoter region...

  • Steroids, Pregnancy and Fetal Development. Solano, Maria Emilia; Arck, Petra Clara // Frontiers in Immunology;1/22/2020, Vol. 10, p1 

    Maternal glucocorticoids critically rise during pregnancy reaching up to a 20-fold increase of mid-pregnancy concentrations. Concurrently, another steroid hormone, progesterone, increases. Progesterone, which shows structural similarities to glucocorticoids, can bind the intracellular...

  • The Glucocorticoid Receptor as Target for Classic and Novel Anti- Inflammatory Therapy. Cato, Andrew C. B.; Schäcke, Heike; Sterry, Wolfram; Asadullah, Khusru // Current Drug Targets - Inflammation & Allergy;Dec2004, Vol. 3 Issue 4, p347 

    Glucocorticoids are well known for their potent anti-inflammatory and immune-suppressive actions. Their clinical usefulness remains limited due to serious side effects that have necessitated a search for ways of improving their benefit-risk ratios. Mechanistically, glucocorticoids function by...

  • A Unique Mechanism of Chaperone Action: Heme Regulation of Hap1 Activity Involves Separate Control of Repression and Activation. Hee Chul Lee; Li Zhang // Protein & Peptide Letters;Jun2009, Vol. 16 Issue 6, p642 

    The Hsp90 and Hsp70 molecular chaperones play important roles in the folding and proper functioning of diverse cellular proteins, including transcriptional regulators and protein kinases. In yeast, several transcriptional regulators and protein kinases are known to be substrates for Hsp90 and...

  • Phorbol esters inhibit the Hedgehog signalling pathway downstream of Suppressor of Fused, but upstream of Gli. Lauth, M.; Bergström, Å.; Toftgård, R. // Oncogene;8/2/2007, Vol. 26 Issue 35, p5163 

    The developmentally important Hedgehog (Hh) signal transduction pathway, which has recently been implicated in several forms of cancer, is subject to regulation by several protein kinases. Here, we address the role of protein kinase Cδ in pathway inhibition and show that cellular depletion or...

  • Mineralocorticoid receptor interaction with SP1 generates a new response element for pathophysiologically relevant gene expression. Meinel, Sandra; Ruhs, Stefanie; Schumann, Katja; Strätz, Nicole; Trenkmann, Kay; Schreier, Barbara; Grosse, Ivo; Keilwagen, Jens; Gekle, Michael; Grossmann, Claudia // Nucleic Acids Research;Sep2013, Vol. 41 Issue 17, p8045 

    The mineralocorticoid receptor (MR) is a ligand-induced transcription factor belonging to the steroid receptor family and involved in water-electrolyte homeostasis, blood pressure regulation, inflammation and fibrosis in the renocardiovascular system. The MR shares a common...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics