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Citations to this article

Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells
Daphne C. Tsitoura, Paul B. Rothman
Daphne C. Tsitoura, Paul B. Rothman
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):619-627. https://doi.org/10.1172/JCI18975.
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Article Immunology

Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells

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Abstract

Glucocorticoids have potent immunosuppressive properties, but their effects are often modulated by the conditions prevailing in the local immune milieu. In this study we determined whether the action of glucocorticoids is influenced by the degree of signaling during T cell activation. We found that dexamethasone (Dex) effectively suppressed T cell receptor–induced (TCR-induced) proliferation of naive CD4+ T cells, through a mechanism involving downregulation of c-Fos expression and inhibition of activator protein-1 (AP-1), nuclear factor of activated T cells (NF-AT), and NF-κB transcriptional activity. However, enhancement of TCR signaling by CD28- or IL-2–mediated costimulation abrogated the suppressive effect of Dex on c-Fos expression and AP-1 function and restored cellular proliferation. The amount of signaling through the MAPK pathway was critical in determining the effect of Dex on T cell activation. In particular, costimulatory signaling via MAPK kinase (MEK) and extracellular signal–regulated kinase (ERK) was essential for the development of T cell resistance to Dex. Selective blockade of MEK/ERK signal transduction abolished the costimulation-induced resistance. In contrast, transmission of IL-2 signals via STAT5 and CD28 signals via NF-κB remained inhibited by Dex. These results imply that the immune system, by regulating the degree of local costimulation through MEK/ERK, can modify the effect of glucocorticoids on T cells. Moreover, these findings suggest that MAPK inhibitors may offer a therapeutic solution for glucocorticoid resistance.

Authors

Daphne C. Tsitoura, Paul B. Rothman

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2014 2012 2010 2009 2007 2006 2005 Total
Citations: 1 2 3 3 1 3 1 2 2 1 2 6 6 3 2 3 1 42
Citation information
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Citations to this article in year 2012 (6)

Title and authors Publication Year
Dynamic development of glucocorticoid resistance during autoimmune neuroinflammation
SM Gold, MV Sasidhar, V Lagishetty, RD Spence, E Umeda, MO Ziehn, T Krieger, KH Schulz, C Heesen, M Hewison, RR Voskuhl
The Journal of clinical endocrinology and metabolism 2012
End-point effector stress mediators in neuroimmune interactions: their role in immune system homeostasis and autoimmune pathology
M Dimitrijevic, S Stanojevic, N Kustrimovic, G Leposavic
Immunologic Research 2012
TEC and MAPK Kinase Signalling Pathways in T helper (TH) cell Development, TH2 Differentiation and Allergic Asthma
Y Kannan, MS Wilson
Journal of clinical & cellular immunology 2012
Heparanase Enhances the Insulin Receptor Signaling Pathway to Activate Extracellular Signal-regulated Kinase in Multiple Myeloma
A Purushothaman, SK Babitz, RD Sanderson
2012
Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma
PJ Chang, PK Bhavsar, C Michaeloudes, N Khorasani, KF Chung
Journal of Allergy and Clinical Immunology 2012
Post-Translational Modifications of Nuclear Receptors and Human Disease
M Anbalagan, B Huderson, L Murphy, BG Rowan
Nuclear receptor signaling 2012

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