Interferon Signaling in the Endometrium and in Endometriosis

Park, Yuri; Han, Sang Jun

doi:10.3390/biom12111554

Cited by 13 publications

(8 citation statements)

References 115 publications

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“…The observed downregulation of IFNs and related genes during the LP phase aligns with prior observations, indicating a transient increase in certain IFNs (e.g., IFNA) within the WOI in human endometrium [41]. Interferons exert significant regulatory effects on cell growth, viability, and immune responses [42], with crucial roles documented in the implantation process within normal endometrium [43].…”

Section: Discussionsupporting

confidence: 85%

Endometrial Proliferative Phase-Centered View on the Transcriptome Dynamics Across the Menstrual Cycle

Apostolov,

Naydenov,

Kalinina

et al. 2024

Preprint

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The endometrium, the inner mucosal lining of the uterus, undergoes complex molecular and cellular changes across the menstrual cycle in preparation for embryo implantation. Transcrip-tome-wide analyses have mainly been utilized to study the endometrial receptivity, the prerequisite for successful implantation, with most of the studies, so far, comparing the endometrial transcriptomes between (i) secretory versus proliferative endometrium or (ii) mid-secretory versus early-secretory endometrium. In the current study, we provide the complete transcriptome description of the endometrium across the entire menstrual cycle and, for the first time, comprehensively characterize the proliferative phase of the endometrium. Our temporal transcriptome analysis includes five time points: mid-proliferative, late-proliferative (peri-ovulatory phase), early-secretory, mid-secretory, and late-secretory phases. Thus, we exhaustively unveil the transitions between the consecutive proliferative and secretory phases, highlighting their unique gene expression profiles and possible distinct biological functions. Transcriptome analysis reveals many differentially expressed genes (DEGs) across the menstrual cycle, most of which are phase-specific. As an example of the coordinated gene activity, the expression profile of his-tone-encoding genes within the HIST cluster on chromosome 6 showed an increase in cluster activity during the late-proliferative and a decline during the mid-secretory phase. Moreover, numerous DEGs are shared among all phases. In conclusion, in the current study, we delineate the endometrial proliferative phase-centered view of transcriptome dynamics across the menstrual cycle. Data analysis highlights significant transcriptomic and functional changes occurring during the late-proliferative phase – an essential transition point from the proliferative to the secretory phase. Future studies should explore how the biology of the late-proliferative phase endometrium impacts the achievement of mid-secretory endometrial receptivity or contributes to molecular aberrations leading to embryo implantation failure.

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Section: Discussionsupporting

confidence: 85%

Endometrial Proliferative Phase-Centered View on the Transcriptome Dynamics Across the Menstrual Cycle

Apostolov,

Naydenov,

Kalinina

et al. 2024

Preprint

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“…IFNA levels are elevated in patients with endometriosis (Park & Han, 2022), and the elevated IFNA causes apoptosis in various cells, including cancer cells (Herzer et al, 2009, Shi et al, 2022). Compared to normal endometrium, a distinctive molecular phenotype of endometriotic cells is their resistance to apoptosis in response to cell-death signaling, including IFNA (Sugihara, Kobayashi et al, 2014).…”

Section: The Erβ/hdac8 Axis Leads To the Reduction Of Nmi Expression ...mentioning

confidence: 99%

“…This suggests that the IFNA/IFNAR2/JAK1 signaling pathway is essential in endometriosis progression. (Matsuzaki, Canis et al, 2006, Park & Han, 2022). However, the transition from IFNA-mediated cell death signaling to IFNA-mediated growth stimulation signaling in endometriotic lesions, as opposed to the normal endometrium, remains unclear in the context of endometriosis progression.…”

Section: Introductionmentioning

confidence: 98%

“…These phosphorylated forms subsequently dimerize and, in collaboration with Interferon Regulatory Factor 9 (IRF9), bind to the Interferon-Stimulated Response Element (ISRE) (Mazewski, Perez et al, 2020). In endometriosis, type I IFN (including IFNA and IFNB) is dysregulated (Park & Han, 2022, Pia, Anna et al, 2012). The mRNA levels of IFNα and its receptor 2 (IFNAR2) are elevated in the eutopic endometrium of endometriosis patients compared to healthy women (Kao, Germeyer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…During retrograde menstruation, refluxed endometrial fragments activate host immune surveillance systems and elevate proinflammatory cytokines (such as TNFα and IFNs) in the pelvic area (Park & Han, 2022). IFNA induces cell death in malignant cells through various mechanisms (Shi, Yao et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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N-Myc and STAT Interactor is an endometriosis suppressor

Park,

Guan,

Han

2024

Preprint

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In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3, and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including β-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions' growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure.

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