Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells

Suzuki, Tomoko; Suzuki, Noboru; Daynes, Raymond A.; Engleman, Edgar G.

doi:10.1016/s0090-1229(05)80024-8

Cited by 273 publications

(137 citation statements)

References 21 publications

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“…Prior studies of DHEA on T cell function have shown conflicting results. It has been reported that DHEA enhances IL-2 production and, consequently, T cell proliferation in murine and human T cells (34,35), whereas others have noted an inhibition of lymphocyte proliferation and IL-2 production in the presence of DHEA (36 -38). Our previous work also has demonstrated that the addition of DHEA in vitro inhibits T lymphocyte proliferation stimulated by ligation of TCR complex and favors the induction of a Th2 immune response to Ag (24).…”

Section: Discussionmentioning

confidence: 99%

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice

Khalil

Subramaniam

2001

The Journal of Immunology

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Experimental allergic encephalomyelitis (EAE) is a Th1-mediated inflammatory demyelinating disease in the CNS, an animal model of multiple sclerosis. We have examined the effect of dehydroepiandrosterone (DHEA) on the development of EAE in mice. The addition of DHEA to cultures of myelin basic protein-primed splenocytes resulted in a significant decrease in T cell proliferation and secretion of (pro)inflammatory cytokines (IFN-γ, IL-12 p40, and TNF-α) and NO in response to myelin basic protein. These effects were associated with a decrease in activation and translocation of NF-κB. In vivo administration of DHEA significantly reduced the severity and incidence of acute EAE, along with a decrease in demyelination/inflammation and expressions of (pro)inflammatory cytokines in the CNS. These studies suggest that DHEA has potent anti-inflammatory properties, which at least are in part mediated by its inhibition of NF-κB activation.

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Section: Discussionmentioning

confidence: 99%

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice

Khalil

Subramaniam

2001

The Journal of Immunology

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“…DHEA is a naturally occurring steroid for which both immunosuppressive and immunostimulatory effects have been described in vitro and in vivo (27)(28)(29)(30)(31). The immunosuppressive effects may be due to the conversion of DHEA into androgens and estrogens (26).…”

Section: Discussionmentioning

confidence: 99%

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

Dulos¹,

Vleuten²,

Kavelaars³

et al. 2005

Arthritis & Rheumatism

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Objective. The cytochrome P450 enzyme CYP7B catalyzes the conversion of dehydroepiandrosterone (DHEA) into 7␣-hydroxy-DHEA (7␣-OH-DHEA). This metabolite can stimulate the immune response. We previously reported that the severity of murine collageninduced arthritis is correlated with CYP7B messenger RNA (mRNA) expression and activity in the arthritic joint. The purpose of this study was to investigate the presence of 7␣-OH-DHEA in synovial samples and the cytokine regulation of CYP7B activity in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Methods. The presence of 7␣-OH-DHEA was examined in synovial biopsy tissues, synovial fluid, and serum by radioimmunoassay. The effect of cytokines on CYP7B mRNA expression and CYP7B activity in FLS was examined by determining the formation of the CYP7B enzyme product 7␣-OH-DHEA with the use of high-performance liquid chromatography.Results. The CYP7B enzyme product 7␣-OH-DHEA was found in synovial biopsy tissues, synovial fluid, and serum from RA patients. The proinflammatory cytokines tumor necrosis factor ␣ (TNF␣), interleukin-1␣ (IL-1␣), IL-1␤, and IL-17 up-regulated CYP7B activity in an FLS cell line 2-10-fold. Enhanced CYP7B activity was correlated with an increase in CYP7B mRNA. The cytokine transforming growth factor ␤ inhibited CYP7B activity. Moreover, CYP7B activity was detected in 10 of 13 unstimulated synovial fibroblast cell lines. Stimulation with TNF␣ increased CYP7B activity in all cell lines tested.Conclusion. Exposure to the proinflammatory cytokines TNF␣, IL-1␣, IL-1␤, and IL-17 increases CYP7B activity in synovial tissue. Increased CYP7B activity leads to higher levels of the DHEA metabolite 7␣-OH-DHEA in synovial fluid, which may contribute to the maintenance of the chronic inflammation observed in RA patients.

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“…On these grounds, important studies indicate the role of dehydroepiandrosterone (DHEA) and its conjugate ester DHEA-sulfate (DHEAS) in the positive regulation of T/B immune cells and of NK cell activity (52,53), the latter by means of IL-2 modulation (6, 53). Furthermore, our previous investigation demonstrated an excitatory dose-related mechanism of DHEAS on NKCC of healthy subjects in young and old age (36).…”

Section: Discussionmentioning

confidence: 99%

Defect of a subpopulation of natural killer immune cells in Graves’ disease and Hashimoto’s thyroiditis: normalizing effect of dehydroepiandrosterone sulfate

Solerte

Precerutti²,

Gazzaruso³

et al. 2005

eur j endocrinol

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Background: The study of the natural killer (NK) immune compartment could provide important findings to help in the understanding of some of the pathogenetic mechanisms related to autoimmune thyroid diseases (Graves' disease (GD) and Hashimoto's thyroiditis (HT)). Within this context, it was suggested that alterations in NK cell cytotoxicity (NKCC) and NK production of cytokines might occur in subjects with GD and HT, whereas the normalization of NK functions could potentially contribute to the prevention of the onset or the progression of both diseases. Objective: Due to the hypothesis of alterations in NK in autoimmune thyroid diseases, we were interested to evaluate NKCC in GD and HT patients and to modulate NK function and secretory activity with cytokines and dehydroepiandrosterone sulfate (DHEAS) in an attempt to normalize NK cell defect. Design: We studied 13 patients with recent onset Graves' disease, 11 patients with Hashimoto's thyroiditis at first diagnosis and 15 age-matched healthy subjects. Methods: NK cells were concentrated at a density of 7.75 £ 10 6 cells/ml by negative immunomagnetic cell separation and validated by FACScan as CD16 þ /CD56 þ cells. NK cells were incubated with interleukin-2 (IL-2) and interferon-b (IFN-b) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor-a (TNF-a) from NK cells. Results: Lower spontaneous, IL-2-and IFN-b-modulated NKCC was demonstrated in GD and HT patients compared with healthy subjects (P , 0.001). A decrease in spontaneous and IL-2-modulated TNF-a release from NK cells was also found in both groups of patients (P , 0.001). The co-incubation of NK cells with IL-2/IFN-b þ DHEAS at different molar concentrations (from 10 28 to 10 25 M/ml/NK cells) promptly normalized NKCC and TNF-a secretion in GD and HT patients. Conclusions: A functional defect of a subpopulation of NK immune cells, involving both NKCC and the secretory activity, was demonstrated in newly-diagnosed GD and HT patients. This defect can be reversed by a dose-dependent treatment with DHEAS. The impairment of NK cell activity in autoimmune thyroid diseases could potentially determine a critical expansion of T/B-cell immune compartments leading to the generation of autoantibodies and to the pathogenesis of thyroid autoimmunity.

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Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells

Cited by 273 publications

References 21 publications

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

Defect of a subpopulation of natural killer immune cells in Graves’ disease and Hashimoto’s thyroiditis: normalizing effect of dehydroepiandrosterone sulfate

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