Regulatory effect of daphnetin on the balance of Th17 and Treg cells in the peripheral blood mononuclear cells from patients with unexplained recurrent pregnancy loss

Zhang, Zhiqin; Long, Shenggen; Huang, Zhihui; Tan, Jun; Wu, Qiongfang; Huang, Ouping

doi:10.5114/ceji.2020.103414

“…According to our results, the expression of both miR-155 and miR-146a seems to be reduced in patients with recurrent EPL, which may be related to the reduced number of Treg cells in the patients. Studies have shown that the number of Treg cells decreased in both mouse pregnancy loss model and patients with unexplained recurrent pregnancy loss [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…According to our results, the expression of both miR-155 and miR-146a seems to be reduced in patients with recurrent EPL, which may be related to the reduced number of Treg cells in the patients. Studies have shown that the number of Treg cells decreased in both mouse pregnancy loss model and patients with unexplained recurrent pregnancy loss [28,29]. The miR-106b-93-25 cluster plays a crucial role in the regulation of the TGF-β signaling pathway, and it is an essential cytokine in the induction of Foxp3 production by Treg cells.…”

Section: Discussionmentioning

confidence: 99%

T Cell Subsets and the Expression of Related MicroRNAs in Patients with Recurrent Early Pregnancy Loss

Yan

¹

,

Jian

²

,

Yang

³

et al. 2023

Mediators of Inflammation

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This study explored the role of T cell subsets and the expression of related microRNAs in patients with recurrent early pregnancy loss (EPL). Fifty patients with EPL loss between May 2018 and May 2021 were randomly selected as the EPL group, and 50 pregnant women with normal pregnancies or normal delivery outcomes were randomly selected as the control group. The expression levels of T cell subset-related markers and T cell subset-related miRNAs, in addition to the frequencies of T cell subsets, in peripheral blood of the two groups were analyzed. In terms of T cell-related markers, the results showed that the expression levels of the transcriptional regulator TBX-21 (T-bet) and interferon regulatory factor 4 (IRF4) were significantly upregulated in peripheral blood of the patients in the EPL group ( P < 0.05 ), whereas the expression levels of GATA binding protein 3 (GATA3) and glucocorticoid-induced tumor necrosis factor receptor (GITR) were significantly downregulated ( P < 0.05 ). In the EPL group, the expression of mir-106b, mir-93, and mir-25 was upregulated ( 1.51 ± 0.129 , 1.43 ± 0.132 , and 1.73 ± 0.156 , respectively) in regulatory T (Treg) cell-related T cell subsets, whereas the expression of miR-146a and miR-155 was downregulated ( P < 0.05 ). The frequencies of Treg and exhausted T cells in the EPL group were significantly lower than those in the control group ( P < 0.05 ). The cell frequencies of T helper 17 (Th17) cells and exhausted Treg cells in the EPL group were significantly higher than those in the control group ( P < 0.05 ). In conclusion, immune cells and associated miRNA profiles can be used as prognostic biomarkers for the treatment of human reproductive disorders, such as EPL.

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“…Cai et al (2016) reported increased IL17 expression in the decidua and PB of idiopathic RM women [56]. Several studies found that RM patients exhibit a decline in Tregs and an elevation of IL17-generating cells in their PB and decidua [57,58]. Serum IL17 increases in women with healthy pregnancies toward the end of pregnancy but decreases after pregnancy loss, suggesting the important regulatory role of IL17 in the successful completion of pregnancy [59].…”

Section: Discussionmentioning

confidence: 99%

Immunogenetic Role of IL17A Polymorphism in the Pathogenesis of Recurrent Miscarriage

Ali

¹

,

Majid

²

,

Ali

³

et al. 2022

JCM

2

0

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Interleukin-17A (IL17A) is a proinflammatory cytokine and is assumed to play an important role in fetal rejection. In order to evaluate the potential role of IL17A polymorphism in the pathogenesis of recurrent miscarriage (RM), serum IL17A levels were estimated by ELISA. Single-nucleotide polymorphism was assessed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) using gene-specific primers and the EcoNI restriction enzyme. Serum IL17A levels were nonsignificantly (p > 0.5) low in RM patients compared with the control group. IL17A gene amplification by PCR yielded the undigested product of 815 bp, and its digestion with EcoNI enzyme produced 815, 529, 286, and 270 bp fragments for the GG genotype; 529, 286, and 270 bp fragments for the GA genotype; and 529 and 286 bp fragments for the AA genotype. The genotype frequency between the RM and control groups exhibited a significant difference (p = 0.001), whereas no significant difference was observed between allele frequencies in the two groups (p = 0.0954). These data suggest that the IL17A gene polymorphism exhibits no significant effect on IL17A gene expression. However, it significantly decreases and increases RM risk in the homozygous and recessive models, suggesting its potential pregnancy-protecting and -harming roles in the AA and GA + GG genotypes, respectively.

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“…For example, in the context of chronic inflammatory status, Daphnetin could inhibit the activation of T helper (Th) 1, 2, and 17 cells, but increase the ratio of regulatory T (Treg) cells. Daphnetin could regulate the balance of Th17 and Treg cells in the PMBCs from patients with unexplained recurrent pregnancy loss ( 35 ), in the intestine of dextran sodium sulfate-induced experimental colitis in mice ( 36 ) and also in collagen-induced arthritis in rats ( 37 , 38 ). Daphnetin also suppresses the production of inflammatory cytokines in experimental autoimmune encephalomyelitis mice ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity

Yao

¹

,

Yang

²

,

Yao

³

et al. 2021

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Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.

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Regulatory effect of daphnetin on the balance of Th17 and Treg cells in the peripheral blood mononuclear cells from patients with unexplained recurrent pregnancy loss

Cited by 7 publications

References 23 publications

T Cell Subsets and the Expression of Related MicroRNAs in Patients with Recurrent Early Pregnancy Loss

T Cell Subsets and the Expression of Related MicroRNAs in Patients with Recurrent Early Pregnancy Loss

Immunogenetic Role of IL17A Polymorphism in the Pathogenesis of Recurrent Miscarriage

Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity

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