Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21 - 05/01/22
Abstract |
Background |
Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin–producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity.
Objective |
We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells.
Methods |
Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients’ and in vitro glucocorticoid treated cells.
Results |
Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway–dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well.
Conclusions |
We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : NF-κB, PI3K, BCL2, cytokines, interleukins, infections
Abbreviations used : ACTH, BCL, eCs, GRE, HC, IκBα, iBCL, IL21R or IL-21R, Iono, LTHD, NF-κB, PBMC, PI3K, PMA, pS6, RTE, TcR, Tfh
Plan
| Supported by the Intramural Research Program at the NIH Clinical Center, US, National Institutes of Health (NIH), and the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. |
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| Disclosure of potential conflict of interest: W. J. Leonard and R. Spolski are inventors on NIH patents related to IL-21. The rest of the authors declare that they have no relevant conflicts of interest. |
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| The first 3 authors contributed equally to this article, and all should be considered first author. |
Vol 149 - N° 1
P. 302-314 - janvier 2022 Retour au numéro
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