Immunosuppression with tacrolimus improved implantation and rescued expression of uterine progesterone receptor and its co-regulators FKBP52 and PIASy at nidation in the obese and diabetic mice: Comparative studies with metformin

Albaghdadi, Ahmad J.H.; Kan, Frederick W. K.

doi:10.1016/j.mce.2017.07.007

Cited by 12 publications

(24 citation statements)

References 61 publications

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“…High-fat fed diabetic NONcNZO mice exhibited higher rates of peri- and post-implantation resorption, and had aberrant expression of uterine interferon-γ and progesterone receptor (PGR) and its immunophilin co-chaperone FKBP52 at nidation (30). The aberrant PGR-targeted gene expression in PCOS-like rats pre- and post-implantation overlapped with dysregulated expression of FKBP52, which was linked to endometrial dysfunction and infertility (31).…”

Section: Discussionmentioning

confidence: 99%

Expression of FKBP52 in the ovaries of PCOS rats

Song

Tan

2018

Int J Mol Med

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The present study aimed to examine the expression of FK-506 binding protein 52 (FKBP52) in the ovary tissues of rats with polycystic ovarian syndrome (PCOS) and its action on mediating androgen receptor (AR) through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. PCOS model rats were established by dehydroepiandrosterone injection. Enzyme-linked immunosorbent assay (ELISA) measured serum sex hormones. Hematoxylin and eosin (H&E) staining was used to examine histological changes of the ovarian tissues. The expression levels of FKBP52 were detected by immunohistochemical (IHC) staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting (WB). In addition, RT-qPCR analysis was used to detect the mRNA expression of AR, and WB was used to detect the protein expression levels of AR, ERK1/2 and phosphorylated (p-) ERK1/2. In granulosa cell (GC) experiments, primary GCs were extracted and cultured. FKBP4 is the FKBP52-encoding gene, therefore, adenovirus vectors Ad-Oe-FKBP4-EGFP and Ad-siRNA-FKBP4-EGFP were constructed to examine the association among the above factors using the RT-qPCR and WB methods. In the animal experiment, the vaginal smear, H&E staining and ELISA results showed that the PCOS model was successfully established. The IHC staining revealed that the expression of FKBP52 in the GCs of the PCOS model group was higher than the remaining groups (P<0.01). The mRNA and expression levels of FKBP52 and AR in the PCOS model rats were significantly increased, when compared with levels in the other rats (P<0.05). The expression level of p-ERK1/2 was also higher (P<0.05). In the GC experiment, following overexpression of the FKBP4 gene, the mRNA and expression levels of FKBP52 and AR were increased (P<0.05). The expression level of p-ERK1/2 was also increased (P<0.05). Following FKBP4 gene silencing, the mRNA and expression levels of FKBP52 and AR were decreased (P<0.05). The expression level of ERK1/2 was also decreased (P<0.05). However, the expression level of p-ERK1/2 was increased (P<0.05). In conclusion, the upregulation of co-chaperone FKBP52 may mediate the activation of AR through the MAPK/ERK pathway.

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Section: Discussionmentioning

confidence: 99%

Expression of FKBP52 in the ovaries of PCOS rats

Song

Tan

2018

Int J Mol Med

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“…In high-fat-fed diabetic (HFD) NON-cNZO mice, which have higher rates of peri-and post-implantation fetal resorption, tacrolimus and metformin normalized decidual IFN-γ and progesterone receptor (PGR) expressions. In addition, these drugs increased immunophilin co-chaperone FKBP52, and colocalization of STATy and PGR, resulting in up-regulated uterine IL-11 and LIF at nidation (171). In abortion prone mice model, blocking of IL-7/IL-7R pathway by IL-7R antagonist significantly down-regulated Th17 immune responses while upregulating Treg immunity in the decidua, and consequently, increased successful pregnancy outcome (111).…”

Section: Therapeutic Approaches To Modulate T Helper Cell Responsesmentioning

confidence: 99%

T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells

et al. 2020

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During pregnancy, various immune effectors and molecules participating in the immunemicroenvironment establish specific maternal tolerance toward the semi-allogeneic fetus. Activated maternal immune effectors by the trophoblast antigens, such as T helper (Th), T cytotoxic (Tc), T regulatory (Treg), and B cells, are involved in the regulation of adaptive immunity. Recognition of active signal through the T cell receptors stimulate the differentiation of naive CD3 + CD4 + T cells into specific T cell subsets, such as Th1, Th2, Th9, Th17, Th22, and follicular Th cells (Tfh). Each of these subsets has a significant and distinct role in human pregnancy. Th1 immunity, characterized by immune-inflammatory responses, becomes dominant during the peri-implantation period, and the "controlled" Th1 immunity benefits the invading trophoblasts rather than harm. Quickly after the placental implantation, the early inflammatory Th1 immunity is shifted to the Th2 antiinflammatory immune responses. The predominant Th2 immunity, which overrules the Th1 immunity at the placental implantation site, protects a fetus by balancing Th1 immunity and accommodate fetal and placental development. Moreover, Treg and Th9 cells regulate local inflammatory immune responses, potentially detrimental to the fetus. Th17 cells induce protective immunity against extracellular microbes during pregnancy. However, excessive Th17 immunity may induce uncontrolled neutrophil infiltration at the maternal-fetal interface. Other Th cell subsets such as Tfh cells, also contribute to pregnancy by setting up favorable humoral immunity during pregnancy. However, dysregulation of Th cell immunity during pregnancy may result in obstetrical complications, such as recurrent pregnancy losses (RPL) and preeclampsia (PE). With this review, we intend to deliver a comprehensive overview of CD4 + Th cell subsets, including Th1, Th2, Th9, Th17, Th22, and Tfh cells, in human pregnancy by reviewing their roles in normal and pathological pregnancies.

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“…6D). We have also found that in restoring fertility in the HFD-dNONcNZO mice 29 , the use of metformin was also effective in favorably altering the Th1:Th2 cell ratios among treated mice compared to the untreated (mean difference = 0.473, t = 3.944, p < 0.001). A statistical trend ( p = 0.066) was observed between treatment with tacrolimus vs that of metformin (mean difference = 0.495, t = 2.781; 95% confidence interval = −0.0160–1.006).…”

Section: Resultsmentioning

confidence: 63%

“…Importantly, emerging evidence revealed significant immunosuppressive properties of metformin when used at high dosage in the treatment of immune-mediated reproductive disorders and in cancer immunotherapy when used in combination with macrolide immunosuppressants such as tacrolimus and/or sirolimus 27,28 . Tacrolimus (FK506) is a 822 kDa lipophilic macrolide lactone antibiotic with potent immune suppressive activity which has recently been used to treat female infertility in obese and diabetic mice 29 and women with recurrent implantation failure with elevated systemic Th1 (CD4 + IFNγ + ): Th2 (CD4 + IL4 + ) cell ratios 30 . Tacrolimus inhibits Ca ++ dependent activation of NFκB and the nuclear factor of activated T cells (NFAT) in T lymphocytes blocking T-cell receptor-mediated lymphokine gene transcription, degranulation, exocytosis and apoptosis 31,32 .…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Tacrolimus Prevents Dysregulated Peri-Conceptional Ovarian and Systemic Immune Cellular Homeostasis in Subjects with PCOS

Albaghdadi

Feeley

Kan

2019

Sci Rep

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Polycystic ovary syndrome (PCOS) is characterized by failure of ovulation and is associated with obesity and chronic inflammation. Recent evidence suggests that anomalous activation of ovarian macrophages and numerical and functional deficits in the Th17 (CD4+IL17A+) and the CD4+CD25+CD127 low Tregs plays crucial role in PCOS. We have shown that the pre-pregnancy use of tacrolimus prevents adverse reproductive outcomes in a mouse model of PCOS. Here we used the HFD-NONcNZO mice to test a hypothesized beneficial use of tacrolimus relative to metformin in favorably influencing the ovarian and systemic immune milieux conducive to gestational success in subjects with PCOS. Compared to normative controls, our data revealed an aberrant peri-conceptional suppression of the CD4 + CD25 + CD127 low Tregs together with an overexpression of the Th17 T cells and lack of coordinated activation of ovarian macrophages in untreated HFD-dNONcNZO mice. Significant variances in treatment outcomes favoured the use of tacrolimus over metformin in treated mice. Consistent with the human fertility studies, this investigation reveals a beneficial systemic use of tacrolimus (0.1 mg/kg) in promoting early pregnancy in individuals with PCOS and suggests the need for further research into the selective inhibition of IL17A as a plausibly alternative immunotherapeutic approach in the clinical management of infertile individuals with PCOS.

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Immunosuppression with tacrolimus improved implantation and rescued expression of uterine progesterone receptor and its co-regulators FKBP52 and PIASy at nidation in the obese and diabetic mice: Comparative studies with metformin

Cited by 12 publications

References 61 publications

Expression of FKBP52 in the ovaries of PCOS rats

Expression of FKBP52 in the ovaries of PCOS rats

T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells

Low-Dose Tacrolimus Prevents Dysregulated Peri-Conceptional Ovarian and Systemic Immune Cellular Homeostasis in Subjects with PCOS

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