Glucocorticoid dysregulation of natural killer cell function through epigenetic modification☆

Krukowski, Karen; Eddy, Justin L.; Kosik, Kelly Loster; Konley, Teresa; Janusek, Linda Witek; Mathews, Herbert L.

doi:10.1016/j.bbi.2010.07.244

Cited by 60 publications

(69 citation statements)

References 87 publications

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“…In contrast, a recent study demonstrated GR-mediated inhibition of NK cell activity [18]. Moreover, it has been shown that GCs disregulate NK cell functions through epigenetic modification [19]. These data suggest that NK cells respond differently to GC compared to T cells.…”

Section: Introductionmentioning

confidence: 86%

The selective impact of transgenically expressed glucocorticoid receptor on T cells

et al. 2014

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Glucocorticoids (GCs) strongly impact on different T cell subsets inducing generally immunosuppressive effects, whereas much less is known about the effect of GC on natural killer (NK) cells. The aims of this study were to investigate the effects of GC on T cell functions, including T cell-mediated anti-tumor immune response, and on NK cells. We have used lck-GR mice, which overexpress a transgenic rat GR in both T and NK cells. These mice were found to have decreased both CD4(+) and CD8(+) T cell populations in the periphery. In contrast, both NK and NKT cells were found in normal numbers in lck-GR mice. To identify genes and pathways affected by GR overexpression in our system in T cells, we have compared gene expression profiles in wild-type and lck-GR T cells. Among the genes upregulated in T cells from lck-GR mice, the microarray analysis has identified genes regulating expansion of regulatory T cells. The analysis of genes downregulated in lck-GR mice has identified genes and gene associated with the regulation of immune response. With regard to the effects on T cell functions in lck-GR mice, transgenic expression of GR had a suppressive effect on killer cell activity in vitro. In addition, lck-GR mice showed an increased tumor growth in murine tumor model in vivo, which may be a possible consequence of reduced T cell numbers and activity. We conclude that an increased expression of the GR strongly affects numbers and possibly functions of T cell subsets, but has little effect on NK cells.

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Section: Introductionmentioning

confidence: 86%

The selective impact of transgenically expressed glucocorticoid receptor on T cells

et al. 2014

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“…One potential hypothesis for the long-term suppression of relapse by initial use of mPSL may be epigenetic modification (26). Because corticosteroid induces epigenetic changes (32,33) and because DNA methylation in PBMCs is modified in MCD patients (34), altering between remission and relapse (35), the higher initial dose of corticosteroid administered in the mPSL+PSL group may possibly induce long-term epigenetic changes, leading to a long-term suppression of relapse compared with the PSL group. Additional study is essential to clarify the various long-term impacts of different corticosteroid doses on podocytes and immune cells.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Methylprednisolone Plus Prednisolone with Prednisolone Alone as Initial Treatment in Adult-Onset Minimal Change Disease

Shinzawa¹,

Yamamoto²,

Nagasawa³

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown.Design, setting, participants, & measurements This multicenter retrospective cohort study included 125 adultonset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models.Results During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P,0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant difference was observed in incidence of adverse events, including infection, aseptic osteonecrosis, cataract, diabetes, and gastrointestinal bleeding.Conclusions Initial use of methylprednisolone was associated with earlier remission and lower incidence of relapse in adult-onset minimal change disease patients. Efficacy of methylprednisolone should be evaluated in randomized controlled trials.

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“…The GC can inhibit natural killer cell function by global inhibition of histone acetylation. 52 Our own recent studies suggest that GC can inhibit angiogenesis indirectly through a micro RNA (miRNA)-mediated pathway whose targets are angiogenic factors. 23 In these studies, we identified a vascular miRNA (miR29c) whose expression was inhibited by in utero undernutrition.…”

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confidence: 99%

Excess Maternal Glucocorticoids in Response to In Utero Undernutrition Inhibit Offspring Angiogenesis

et al. 2014

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To test the hypothesis that inhibition of offspring angiogenesis by maternal undernutrition (MUN) is mediated by maternal glucocorticoids, 3 groups of dams were studied: controls received ad libitum food; MUN dams were food restricted by 50% from day 10 of gestation; and metyrapone (MET) dams were food restricted and treated with 0.5 mg/mL of MET, a glucocorticoid synthesis inhibitor. The MUN reduced birth weights, reduced vascular endothelial growth factor (VEGF) abundance in P1 aortas, reduced VEGF and VEGF-R2 abundances in P1 mesenteric arterioles, reduced arteriolar endothelial nitric oxide synthase abundance, reduced microvessel density in the anterior tibialis, reduced endothelial cell branching in culture, reduced arteriolar immunoreactivity for proliferating cell nuclear antigen (PCNA), increased active caspase 3 in P1 mesenteric arterioles, and decreased matrix metalloproteinase (MMP)-2 and MMP-9 abundances in lysates of P1 aortas. All of these effects were prevented by treatment with metyrapone. Collectively, these findings suggest that reduced angiogenesis in MUN offspring involves direct inhibitory effects of maternal glucorticoid on fetal VEGF and its receptors.

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Glucocorticoid dysregulation of natural killer cell function through epigenetic modification☆

Cited by 60 publications

References 87 publications

The selective impact of transgenically expressed glucocorticoid receptor on T cells

The selective impact of transgenically expressed glucocorticoid receptor on T cells

Comparison of Methylprednisolone Plus Prednisolone with Prednisolone Alone as Initial Treatment in Adult-Onset Minimal Change Disease

Excess Maternal Glucocorticoids in Response to In Utero Undernutrition Inhibit Offspring Angiogenesis

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