Glucocorticoid Hormones Upregulate Interleukin 2 Receptor α Gene Expression

doi:10.1006/cimm.1993.1252

Cellular Immunology

Volume 151, Issue 2, 15 October 1993, Pages 437-450

https://doi.org/10.1006/cimm.1993.1252 Get rights and content

Abstract

We present evidence that glucocorticoid hormones increase expression of IL-2Rec α chain on T cells by regulating IL-2Rec α gene transcription. We have previously reported that glucocorticoids can upregulate IL-2Rec α mRNA and protein expression in some T cell hybrids. In the present study we show that the glucocorticoid analogue dexamethasone increases mRNA levels of the endogenous IL-2Rec α gene and the expression of plasmids containing 5′-flanking sequences of the IL-2Rec α gene linked to CAT reporter genes transiently transfected into different cell lines. We show that the dexamethasone effect depends on cis-acting regulatory elements in a segment (-1835/-802) of the mouse gene that also contains cytokine response elements and a inducible DNase I-hypersensitive site. Dexamethasone responses of IL-2Rec α-CAT reporter gene constructs were observed in a CTL line, in an IL-3-dependent bone marrow-derived cell line, and in COS7 monkey kidney cells. In the latter the response depended on cotransfection of a glucocorticoid receptor expression yector. The biological relevance of the glucocorticoid-mediated upregulation of the IL-2Rec α gene is discussed.

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Circulating microparticle subpopulations in systemic lupus erythematosus are affected by disease activity
2017, International Journal of Cardiology
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Finally, an outstanding point of the findings herein presented is the role of glucocorticoids in the generation of circulating MPs, which in turn could influence lymphocyte activation. Thus, patients under this treatment presented a higher amount of circulating CD25pos-TMPs and increased T cell CD25 expression, consistent with previous data about the role of glucocorticoids upregulating the expression of this molecule [53,54]. Moreover, glucocorticoid-treated patients displayed higher serum levels of IL-10 that were positively correlated with CD25pos-TMPs.
Immune cells under chronic inflammation shed microparticles (MPs) that could fuel the inflammatory responses and atherosclerosis typically presented in systemic lupus erythematosus (SLE). This study analyzes total and subset-specific MPs from SLE patients and their possible influence on clinical features, leukocyte activation and serum cytokines.
Total MPs and those derived from platelets, endothelial cells, monocytes, granulocytes and T-cells were quantified in plasma of 106 SLE patients and 33 healthy controls by flow cytometry. MP amounts were analyzed according to clinical manifestations, blood leukocyte populations and circulating cytokines (IFNα, TNFα, IL-10, BLyS, IL-17, IL-1β, CXCL10, CCL-2, CCL3, leptin). Finally, the in vitro effect of SLE-isolated MPs on the leukocyte activation status was analyzed.
Total circulating MPs in SLE patients were related to increased disease duration and the presence of cardiovascular disease. Furthermore, patients displayed increased counts of MPs from platelets, monocytes and T-lymphocytes, especially in SLE patients with disease activity or with TNFα^high-profile. Accordingly, MPs were associated with increased expression of activation markers in blood T-cells and monocytes. Finally, analyses propose a role of glucocorticoids in MPs generation and leukocyte activation since both fresh and cultured T-cells under this treatment presented higher IL-10 and CD25 production.
The altered profile of subset-specific SLE-MPs was influenced by the disease activity and altered status of leukocyte native cells, also associated with a TNFα^high-profile.
SLE patients, especially those with disease activity, displayed increased counts of MPs derived from platelets, monocytes and T-lymphocytes, which were more frequently found in TNFα^high-type patients. The origin of such SLE-MP subsets seems to be related to the over-activated status of T-cells and monocytes characteristic of these patients. Ex vivo and in vitro analyses propose a role of glucocorticoids in the generation of circulating MPs and leukocyte activation in SLE patients.
Effect of dexamethasone and meloxicam on counts of selected T lymphocyte subpopulations and NK cells in cattle - In vivo investigations
2014, Research in Veterinary Science
Citation Excerpt :
The drug may induce the expression of CD25 directly, in a manner not associated with T-cell activation. This hypothesis is supported by results of investigations which proved that glucocorticosteroids enhance CD25 expression on different mouse T cell lines, by specifically inducing transcription of the IL-2Rα gene (Lamas et al., 1993). The available literature contains a few reports on the effect of administration of SAIDs on percentages of CD4+, CD8+ and WC1+ T cells in cattle.
The purpose of these investigations has been to assess the in vivo effect of dexamethasone (DEX) and meloxicam (MEL) on percentages and absolute counts of cells within selected T lymphocyte subsets and NK cells in cattle. DEX application caused substantial loss of NK, CD4⁺, CD8⁺ and WC1⁺ T cells, but the drug’s influence on T-cell count was selective, that is it varied according to the presence and intensity of CD25 expression. Reduced counts of T lymphocytes were due to the depletion of CD25⁻CD4⁺, CD25⁻CD8⁺ and CD25⁻WC1⁺ T cells. The loss of CD25⁻CD8⁺ and CD25⁻WC1⁺ T cells was a deep and lasting disorder, whereas the depletion of CD25⁻CD4⁺ T cells was manifested less strongly and regressed promptly. The administration of DEX did not affect absolute counts of CD25^lowCD4⁺ and CD25^lowCD8⁺ T cells, but induced an increase in percentages and absolute counts of CD25^highCD4⁺, CD25^highCD8⁺, CD25^lowWC1⁺ and CD25^highWC1⁺ T cells. In respect of the effect on counts of CD4⁺, CD8⁺ and WC1⁺ T cells, MEL proved to be a safe medication, because it did not alter counts of these lymphocytes. The administration of MEL led to an increase in the absolute count of NK cells, but the effect did not appear quickly and its development required time.
In vitro effects of dexamethasone on bovine CD25+CD4+ and CD25-CD4+ cells
2012, Research in Veterinary Science
Citation Excerpt :
Thus, dexamethasone and IL-7 did not induce additional Tregs cells, but additively induced the expression of the activation marker CD25 by CD4+CD25− T cells (Chung et al., 2004). Moreover, it has been shown that glucocorticosteroids enhance the expression of high-affinity IL-2 receptors (CD25) in different mouse T cell lines, by specifically inducing transcription of the IL-2Rα gene (Lamas et al., 1993). However, later, and especially in recent years, opinions about the nature of human and mouse CD4+CD25+ generated with the use of glucocorticosteroids have changed, because the findings of a number of studies have shown or implied (Karagiannidis et al., 2004; Braitch et al., 2009; Provoost et al., 2009; Xie et al., 2009) that those are regulatory cells rather than activated lymphocytes.
This paper investigates the in vitro effect of dexamethasone on bovine CD25^highCD4⁺, CD25^lowCD4⁺ and CD25⁻CD4⁺ T cells. Only a small percentage of bovine CD25^highCD4⁺ (2–4%) and CD25^lowCD4⁺ (1–2%) cells expressed Foxp3. Dexamethasone caused considerable loss of CD25⁻CD4⁺ cells, but it increased the relative and absolute numbers of CD25^highCD4⁺ and CD25^lowCD4⁺ lymphocytes, while at the same time reducing the percentage of Foxp3⁺ cells within the latter subpopulations. Considering all these, as well as the intrinsically poor Foxp3 expression in bovine CD25⁺CD4⁺, it can be concluded that the drug most probably increased the number of activated non-regulatory CD4⁺ lymphocytes. It has been found that changes in cell number were at least partly caused by proapoptotic effect of the drug on CD25⁻CD4⁺ cells and antiapoptotic effect on CD25^highCD4⁺ and CD25^lowCD4⁺ cells. The results obtained from this study indicate that the involvement of CD4⁺ lymphocytes in producing the anti-inflammatory and immunosuppressive effect of dexamethasone in cattle results from the fact that the drug had a depressive effect on the production of IFN-γ by CD25⁻CD4⁺ cells. Secretion of TGF-β and IL-10 by CD4⁺ lymphocytes was not involved in producing these pharmacological effects, because the drug did not affect production of TGF-β and, paradoxically, it reduced the percentage of IL-10⁺CD4⁺ cells.
Bi-directional effects of stress on immune function: Possible explanations for salubrious as well as harmful effects
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A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival
2005, Blood
Citation Excerpt :
A similar GC-mediated enhancing effect on the expression of IL-2Rα21,22 supports the positive modulatory role of GCs on the immune system's function. Given the accumulating evidence of a stress-induced enhancement of immune function,23-29 some direct immune stimulatory effects of GCs have been interpreted in the context of their adoptive actions in the acute phase of a stress response.30 A typical example for the dual action of GCs on the immune system is GC–induced leucine zipper protein (GILZ).
Although glucocorticoids (GCs) have been described as acting mainly as anti-inflammatory and immunosuppressive drugs, they may also positively influence the immune system. In the present study, we demonstrate for the first time that hydrocortisone (HC), in synergy with interleukin-15 (IL-15), induces a dramatic increase in the expansion of peripheral blood–derived CD56⁺ cells, favoring the preferential outgrowth of classical natural killer (CD56⁺CD3^– NK) over CD56⁺CD3⁺ natural killer T (NKT) cells. HC plus IL-15–driven CD56⁺ cells exhibited an increased potential for cytokine production with no impairment in their NK- and lymphokine-activated killer (LAK) activities. Elevated levels of GC-induced leucine zipper protein (GILZ) messenger RNA (mRNA) were detected in both NK and NKT cells cultured with HC and IL-15, in comparison to IL-15 alone. Phosphorylation status of signal transducer and activator of transcription 5 (STAT5) was not affected by the presence of HC in either of the populations. On the contrary, HC differentially affected the IL-2/IL-15R β- and γ-chain surface expression and the phosphorylation levels of extracellular signal-regulated kinases 1/2 (ERK1/2) in IL-15–activated NK and NKT cells. Our data ascribe a novel role to GCs on mature NK-cell expansion and function and open new perspectives for their use in cellular adoptive cancer immunotherapy.

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Cellular Immunology

Abstract

References (0)

Cited by (37)

Circulating microparticle subpopulations in systemic lupus erythematosus are affected by disease activity

Effect of dexamethasone and meloxicam on counts of selected T lymphocyte subpopulations and NK cells in cattle - In vivo investigations

In vitro effects of dexamethasone on bovine CD25<sup>+</sup>CD4<sup>+</sup> and CD25<sup>-</sup>CD4<sup>+</sup> cells

Bi-directional effects of stress on immune function: Possible explanations for salubrious as well as harmful effects

Bi-directional Effects of Stress on Immune Function: Possible Explanations for Salubrious as well as Harmful Effects

A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival

Regular ArticleGlucocorticoid Hormones Upregulate Interleukin 2 Receptor α Gene Expression

Abstract

Regular Article
Glucocorticoid Hormones Upregulate Interleukin 2 Receptor α Gene Expression