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High-dose interferon-? promotes abortion in mice by suppressing Treg and Th17 polarization.

ABSTRACT: As a classic type I cytokine, interferon-gamma (IFN-?) is known to manifest a miscarriage-inducing effect, although the specific mechanism is still unclear. To determine whether immune cells such as regulatory T (Treg) and Th17 cells are involved in these abortions, syngeneically pregnant (BALB/c×BALB/c) mice were subjected to intravaginal IFN-? administration (5 × 10(3) IU/mouse on D3 of gestation). These mice experienced significant fetal loss on D7/D8 of pregnancy, and a remarkable drop in the Treg cell ratio was observed in the peripheral blood and the spleen by flow cytometry. In situ detection of the uterine tissue peri-implantation revealed that IFN-? treatment also caused statistically significant reductions in forkhead box P3, RAR-related orphan receptor gamma, and IL-17 levels, which indicated local decreases in Treg and Th17 cells at uterine implantation sites. The IFN-? receptor alpha (IFN-?R?) level was also lowered in the uterus. These results demonstrate that in murine pregnancy, a supraphysiological dose of IFN-? could induce peri-implantation failure. Moreover, in this study, the decreases in both Treg and Th17-type cells, which may be relevant to the role of IFN-?R?, may be one of the main reasons that IFN-? causes abortion.

SUBMITTER: Liu HY

PROVIDER: S-EPMC4015477 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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High-dose interferon-γ promotes abortion in mice by suppressing Treg and Th17 polarization.

Liu Hai-Yan HY Liu Zhen-Kun ZK Chao Huhe H Li Zhongyin Z Song Zhihui Z Yang Ying Y Peng Jing-Pian JP

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20131220 5

As a classic type I cytokine, interferon-gamma (IFN-γ) is known to manifest a miscarriage-inducing effect, although the specific mechanism is still unclear. To determine whether immune cells such as regulatory T (Treg) and Th17 cells are involved in these abortions, syngeneically pregnant (BALB/c×BALB/c) mice were subjected to intravaginal IFN-γ administration (5 × 10(3) IU/mouse on D3 of gestation). These mice experienced significant fetal loss on D7/D8 of pregnancy, and a remarkable drop in th ...[more]

PMID: 24359574

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Project description:Both interleukin (IL)-7 and human periodontal ligament cells (hPDLCs) have immunomodulatory properties. However, their combined effect on CD4+T cells has never been studied. In this study, we aimed to investigate the effect of conditioned medium of hPDLCs treated with rhIL-7 on the differentiation of CD4+T cells into regulatory T cells/T helper 17 cells (Treg/Th17 cells) and observe the effect of IL-7 on the immunomodulatory properties of PDLCs. After hPDLCs were treated with different concentrations of rhIL-7 for 24 h, the collected supernatants were used to incubate CD4+T cells for 3 days. A gamma-secretase inhibitor (DAPT) was used to suppress the activation of the Notch1 signaling pathway. Cell proliferation, apoptosis, and necrosis were determined using the cell counting kit-8 (CCK-8) and flow cytometry (FCM). The expressions of forkhead box P3 (Foxp3) in CD4+T cells and transforming growth factor (TGF-β) and IL-6 in the supernatants were determined by ELISA. Reverse transcription-quantitative PCR (RT-qPCR), and the Western blot (WB) determined the mRNA levels and protein expression of various target factors. FCM was used to detect the mean fluorescence intensity of PD-L1 in hPDLCs and to analyze the differentiation of Treg/Th17 cells. Our results showed that IL-7 promoted proliferation and inhibited apoptosis in hPDLCs, promoted the expression of TGF-β, PD-L1, Notch1, Jagged1, and Hes1, and inhibited the levels of hypoxia-inducible factor (HIF)-1α and TCF7, whereas the addition of DAPT effectively reversed these effects. Importantly, we found that the conditioned medium of hPDLCs treated with rhIL-7 promoted the polarization of CD4+T cells into Treg cells but had no significant effect on the differentiation of Th17 cells. Our study indicated that treatment of PDLCs with IL-7 can promote the polarization of CD4+T cells into Treg cells by modulating the expression of inflammatory factors and signaling molecules through activating the Notch1 signaling pathway, thus participating in the regulation of immune homeostasis in the periodontal microenvironment.

Project description:BackgroundSeveral types of T cells have been associated with the pathogenesis of unexplained recurrent spontaneous abortion (URSA), including Th1/Th2/Th17/Tregs cell. It has been appreciated that immunotherapy with paternal or third party lymphocytes is an effective method of treatment for URSA patients. The balance of Th1/Th2 cells could be maintained and an increase of Treg cells would be beneficial after immunotherapy; however, the mechanism by which the Th17/Treg balance affects URSA has not yet been fully elucidated.MethodsHere, we used flow cytometry, liquid chip technology and quantitative real-time PCR (qPCR) methods to characterize Th17/Treg cell populations after immunotherapy. We found that after immunotherapy in URSA patients, the percentage of Th17 cells decreased and the percentage of Treg cells in peripheral blood mononuclear cells (PBMC) increased, as detected by flow cytometry.ResultsImmunotherapy may induce a decrease in the Th17/Treg ratio and the Treg bias, which may be beneficial for the maintenance of pregnancy. The expression level of ROR gamma t, a transcription factor found in Th17 cells, decreased and the expression of the Treg-specific transcription factor Foxp3 increased in peripheral blood as detected by qPCR. Immunotherapy may induce a decrease in the ratio of ROR gamma t to Foxp3 and a Treg cell bias, which would be beneficial for pregnancy maintenance. The secretion of the Treg-associated cytokine TGF-beta, as well as Th2 cytokines, was increased in serum, while the secretion of Th17-associated cytokine IL-17A and Th1 cytokine production was decreased. The Th1/Th2 cytokine ratio significantly decreased. Similarly, the Th17/Treg ratio significantly decreased in the total patient after immunotherapy.ConclusionsThese results indicate that in patients with URSA, immunotherapy with mononuclear cells derived from the baby's father could affect both Th1/Th2 and Th17/Treg balance, and we found that the Th2 and Treg bias would be beneficial for pregnancy, which may lead to a balancing of the Th17/Treg ratio in URSA patients after immunotherapy.

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High-dose interferon-? promotes abortion in mice by suppressing Treg and Th17 polarization.

Publications

High-dose interferon-γ promotes abortion in mice by suppressing Treg and Th17 polarization.

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