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L-Arginine-Dependent Epigenetic Regulation of Interleukin-10, but Not Transforming Growth Factor-?, Production by Neonatal Regulatory T Lymphocytes.

ABSTRACT: A growing number of diseases in humans, including trauma, certain cancers, and infection, are known to be associated with l-arginine deficiency. In addition, l-arginine must be supplemented by diet during pregnancy to aid fetal development. In conditions of l-arginine depletion, T cell proliferation is impaired. We have previously shown that neonatal blood has lower l-arginine levels than adult blood, which is associated with poor neonatal lymphocyte proliferation, and that l-arginine enhances neonatal lymphocyte proliferation through an interleukin (IL)-2-independent pathway. In this study, we have further investigated how exogenous l-arginine enhances neonatal regulatory T-cells (Tregs) function in relation to IL-10 production under epigenetic regulation. Results showed that cord blood mononuclear cells (CBMCs) produced higher levels of IL-10 than adult peripheral blood mononuclear cells (PBMCs) by phytohemagglutinin stimulation but not by anti-CD3/anti-CD28 stimulation. Addition of exogenous l-arginine had no effect on transforming growth factor-? production by PBMCs or CBMCs, but enhanced IL-10 production by neonatal CD4+CD25+FoxP3+ Tregs. Further studies showed that IL-10 promoter DNA hypomethylation, rather than histone modification, corresponded to the l-arginine-induced increase in IL-10 production by neonatal CD4+ T cells. These results suggest that l-arginine modulates neonatal Tregs through the regulation of IL-10 promoter DNA methylation. l-arginine supplementation may correct the Treg function in newborns with l-arginine deficiency.

SUBMITTER: Yu HR

PROVIDER: S-EPMC5403834 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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l-Arginine-Dependent Epigenetic Regulation of Interleukin-10, but Not Transforming Growth Factor-β, Production by Neonatal Regulatory T Lymphocytes.

Yu Hong-Ren HR Tsai Ching-Chang CC Chang Ling-Sai LS Huang Hsin-Chun HC Cheng Hsin-Hsin HH Wang Jiu-Yao JY Sheen Jiunn-Ming JM Kuo Ho-Chang HC Hsieh Kai-Sheng KS Huang Ying-Hsien YH Yang Kuender D KD Hsu Te-Yao TY

Frontiers in immunology 20170425

A growing number of diseases in humans, including trauma, certain cancers, and infection, are known to be associated with l-arginine deficiency. In addition, l-arginine must be supplemented by diet during pregnancy to aid fetal development. In conditions of l-arginine depletion, T cell proliferation is impaired. We have previously shown that neonatal blood has lower l-arginine levels than adult blood, which is associated with poor neonatal lymphocyte proliferation, and that l-arginine enhances n ...[more]

PMID: 28487700

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Project description:BACKGROUND:Regulatory T lymphocytes (Treg) are characterized by the presence of CD4+ surface antigen. Today the transcription factor FOXP3 is considered to be the most specific marker of Treg cells. The aim of the study was to estimate the percentage of Treg in peripheral blood and the tissue of the epithelial ovarian tumor and blood serum TGF-beta concentrations and relationships between them. Moreover, the aim of the study was to answer the question whether the percentage of Treg lymphocytes affects the time of survival in patients with ovarian cancer. METHODS:The patients were divided into four groups, depending on the histopathological examination result: I--a group without any pathology within the ovaries (C; n?=?20), II--a group with benign tumors (B; n?=?25), III - with borderline tumors (BR; n?=?11), IV--a group with cancer of the ovary (M; n?=?24). The percentage of Treg lymphocytes in peripheral blood and the tissue was assessed using the flow cytometry method. TGF-beta cytokine concentration was estimated with the ELISA immunoenzymatic test. Statistical analysis of the results was conducted using the computer program Statistica 10.0PL (StatSoft, Inc). RESULTS:No significant differences were found in percentages of Treg lymphocytes in peripheral blood between individual groups of patients (p?=?0.11). However, we observed marked differences in the tissue of malignant and non-malignant tumors between individual groups of patients (p?=?0.003). The analysis with the post hoc test revealed significantly higher TGF-beta concentration in the group of women with malignant tumors. Moreover, no relationship was found between TGF-beta concentration and the percentage of Treg cells in peripheral blood and tumors of the ovary. No correlation was found between the percentage of Treg lymphocytes in peripheral blood (p?=?0.4) and the tissue of ovarian tumors (p?=?0.3) and the time of survival of patients with ovarian cancer. CONCLUSIONS:The recruitment of Treg lymphocytes toward the tumor is one of the mechanisms of escape of neoplasm from the response of the immune system. The percentage of Treg lymphocytes in peripheral blood and the neoplastic tissue does not influence the time of survival of patients with ovarian cancer.

Project description:Functional cytokine networks have been poorly characterized in systemic sclerosis (SSc). While interleukin-17A (IL-17A) is increased in SSc skin and other organs, its role is still debated, particularly considering fibrogenesis. We uncover here a dual function of IL-17A in the presence of transforming growth factor-? 1 (TGF-?), the master pro-fibrotic cytokine. In the one hand, we report an unexpected synergic activity resulting in enhanced production of IL-6 by dermal fibroblasts; in the other hand, a substantial inhibition of type I collagen (col-I) production. IL-17A or TGF-? enhanced the production of IL-6 by 8- to 16-folds when compared to control in healthy donors (HD) and SSc cultures. However, the joint presence of IL-17A and TGF-? resulted in robustly exuberant responses with levels of IL-6 up to 100-folds higher than those observed in untreated cells. Inhibition of NF?B signaling pathway preferentially inhibited the production of IL-6 driven by IL-17A in HD fibroblasts, while inhibition of PI3K preferentially inhibited the production of IL-6 driven by TGF-?. Interestingly, when p38 MAPK was inhibited, substantial reduction of IL-6 production was observed for both IL-17A and TGF-?. Consistently with the inhibition experiments, the combined stimulation of fibroblasts by IL-17A and TGF-? resulted in 1.8-fold increase in p38 MAPK phosphorylation (P?=?0.025), when compared to levels of phosphorylated p38 MAPK induced by IL-17A alone. Furthermore, the enhanced phosphorylation of p38 MAPK in the joint presence of IL-17A and TGF-? was unique among the signaling molecules we examined. As expected, TGF-? induced SMAD2 phosphorylation and col-I production. However, in fibroblasts cultured in the joint presence of TGF-? and IL-17A, SMAD2 phosphorylation was decreased by 0.6-folds (P?=?0.022) when compared to that induced by TGF-? alone. Remarkably, in this condition, the production of col-I and fibronectin was significantly decreased in both HD and SSc. Thus, IL-17A and TGF-? reciprocally influence each other effector functions in fibroblasts. Intracellular molecular switches may favor synergic or antagonistic activities, which are revealed by specific readouts. The implications of these data in the context of SSc are far reaching, particularly in terms of therapeutic approaches since IL-6, IL-17A, and TGF-? are all putative targets of treatment.

Dataset Information

L-Arginine-Dependent Epigenetic Regulation of Interleukin-10, but Not Transforming Growth Factor-?, Production by Neonatal Regulatory T Lymphocytes.

Publications

l-Arginine-Dependent Epigenetic Regulation of Interleukin-10, but Not Transforming Growth Factor-β, Production by Neonatal Regulatory T Lymphocytes.

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