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Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 2/2013

01-02-2013 | Original Research

Glucocorticoid Receptor-Beta Up-Regulation and Steroid Resistance Induction by IL-17 and IL-23 Cytokine Stimulation in Peripheral Mononuclear Cells

Authors: Alejandro Vazquez-Tello, Rabih Halwani, Qutayba Hamid, Saleh Al-Muhsen

Published in: Journal of Clinical Immunology | Issue 2/2013

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Abstract

Purpose

Most asthmatic patients have well controlled symptoms with regular treatment, but some require much higher doses of inhaled and oral corticosteroids, or in rare cases fail to respond; these patients may present Th-17 cell infiltration and associated cytokines (IL-17A and -F) in the airways, sputum and peripheral blood. Because glucocorticoid receptor-beta (GR-beta) is associated with corticosteroid resistance, we investigated whether Th-17 associated cytokines induce steroid insensitivity in PBMCs via GR-beta up-regulation.

Methods

GR-alpha, GR-beta, GILZ and IL-6 expression were analyzed in PBMCs stimulated with IL-2/IL-4, IL-17A/IL-17F and IL-23 cytokines by quantitative RT-PCR. Dexamethasone-inhibition of PHA-induced proliferation and Dexamethasone-induced apoptosis were determined by either 3H-thymidine or CFSE-labelled cells and by Annexin-V staining and flow cytometry.

Results

IL-17 and IL-23 cytokines significantly increased GR-beta expression. IL-2/IL-4 significantly decreased GR-alpha expression without affecting GR-beta. IL17, IL-23 and IL2 + 4 stimulations significantly hampered Dexamethasone-inhibition of proliferation (Dex EC50 for: IL-17A + F = 251 nM; IL-23 = 435 nM; IL2 + 4 = 950 nM; Medium = 90 nM). IL2 + 4 and IL17A + F but not IL-23, significantly hampered Dexamethasone-induced apoptosis (1400 and 320 nM Dex, respectively). Dexamethasone’s trans-activation of GILZ and trans-repression of NF-kB-driven IL-6 expression were both inhibited by IL2 + 4; IL17 + IL23 antagonized Dex trans-repression in PBMC from asthmatics.

Conclusions

GR-beta up-regulation by IL-17/IL-23 cytokines is associated with induced steroid insensitivity in PBMCs, observed as diminished Dexamethasone’s effects on cell proliferation, apoptosis and gene regulation. Steroid resistance induced by IL-2/IL-4 was associated with decreased GR-alpha expression. This study supports the possibility that Th-17 lymphocytes and associated cytokines play a role in the mechanism of steroid hypo-responsiveness in severe asthmatics.
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Metadata
Title
Glucocorticoid Receptor-Beta Up-Regulation and Steroid Resistance Induction by IL-17 and IL-23 Cytokine Stimulation in Peripheral Mononuclear Cells
Authors
Alejandro Vazquez-Tello
Rabih Halwani
Qutayba Hamid
Saleh Al-Muhsen
Publication date
01-02-2013
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 2/2013
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-012-9828-3

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