30 March 2024, Volume 44 Issue 2

    

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  IRF4: a key molecule regulating the differentiation and fate determination of multiple immune cell lineages

  WANG Xue, LU Li-ming

  Current Immunology. 2024, 44(2): 89-95.

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  Interferon regulatory factor 4 (IRF4) is an evolutionarily conserved regulatory molecule that is expressed in varying levels at key stages of differentiation of many immune cells. In terms of its role in the differentiation of innate immune cell lineages, IRF4 is one of the key transcription factors regulating M2-like macrophage polarization and differentiation of both monocyte-derived DC and conventional DC 2 (cDC2). On the other hand, on the differentiation and fate determination of adaptive immune cell subgroups, IRF4 plays a broad role and controls all levels of differentiation of these immune cell subgroups in that IRF4 regulates the differentiation of the naive CD4⁺ T cells into various subsets (Th1, Th2, Th9, Th17, Treg, and follicular helper T cell ［Tfh］). In addition, it also dictates the differentiation of naive CD8⁺ T cells into effector cells. At the same time, IRF4 also regulates B cell differentiation cycle and plasma cell function, thereby affecting humoral immunity. The recent progress in the study of IRF4's involvement in the regulation of immune cell lineage differentiation and fate determination is summarized in this review.
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  Inflammatory pain-related miR-34a mediates mitochondrial homeostasis via XIST  and attenuates cell apoptosis

  FANG Jing, GONG Cheng, XIANG Ling-yun, SUN Wen, LIU Zhong-yuan, FEN Jue-ping

  Current Immunology. 2024, 44(2): 96-103.

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  The goal of this study is to elucidate the mechanism by which inflammatory pain regulated mitochondrial function and apoptosis of macrophages via down-regulation of miR-34a and up-regulation of X-inactive specific transcript (XIST). For this purpose, the expressions of XIST were measured in miR-34a over-expressed or LPS-treated J774A.1 (female mouse cell line) and the SH-SY5Y (female human cell line) cells; And the in vivo correlation between the expressions of miR-34a and XIST  was also analyzed. MitoTracker and TMRE (tetramethylrhodamine ethyl ester) staining were used to analyze the mitochondrial volume and membrane potential in J774A.1 cell line. The mitochondrial stress assay (Seahorse) was conducted to test the mitochondrial function in J774A.1 cells after over-expressing miR-34a and/or stimulated with LPS. TUNEL assay was used to assess cell line apoptosis. CFA (complete Freund's adjuvant)-induced acute inflammatory pain model was established to detect the pain reaction threshold and the expression of XIST and miR-34a in acute and chronic phases and healthy controls, respectively. Real-time PCR was used to detect the expression of XIST in the blood of complex regional pain syndrome (CRPS) patients and healthy controls. The results showed that there was no significant difference in XIST expression between the control group and the CRPS group in total human samples (t=1.528, P=0.131). And there was no statistical difference between the two groups (t=0.945, P=0.353) when only male patients were analyzed. However, in female patients, the XIST expression of the CRPS group was significantly higher than that of the control group (t=2.764, P=0.008). Over-expression of miR-34a reduced XIST expression in J774A.1 and SH-SY5Y cells. The datum from patients showed that the expression of miR-34a and XIST exhibited a negative correlation (r2=0.681, P＜0.001). LPS treatment inhibited the expression of miR-34a and up-regulated XIST expression in J774A.1 cell line. In mouse pain model, XIST expression was up-regulated (t=1.810, P＜0.001) and miR-34a expression was down-regulated (t=2.220, P＜0.001) at 4 h time point, and the difference disappeared at D14. LPS up-regulated mitochondrial volume and membrane potential, while over-expression of miR-34a led to down-regulation of both. And the effects of the two treatments compensated for each other. LPS stimulation significantly decreased cellular oxygen consumption (t=4.323, P=0.014), ATP production (t=4.323, P=0.014) and the maximum oxygen consumption (t=1.885, P=0.008), while miR-34a over-expression had the opposite effect （t=4.245, P=0.004）. LPS reduced cell apoptosis whereas miR-34a over-expression promoted it. XIST over-expression can reverse the cell apoptosis mediated by miR-34. In conclusion, inflammation may promote the expression of XIST by down-regulating miR-34a and the former suppresses cell apoptosis by promoting the maintenance of mitochondrial function.
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  Therapeutic effect of dehydropachymic acid on rats with eczema and its effect on immune response

  HE Hong-mei, CHENG Yan, MA Ru-long, ZHANG Yong

  Current Immunology. 2024, 44(2): 104-111.

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  In order to evaluate the therapeutic effect of dehydropachymic acid (DPA) on eczema rats and its effect on immune response, a rat model of eczema induced by dinitrochlorobenzene (DNCB) was established. Different concentrations of DPA (10, 40, and 80 mg/kg) were used to treat eczema rats for fourteen days, and compound glycyrrhizin (CG) (15 mg/kg) was used as the positive treatment control. H-E staining was used to observe the histopathological morphology of rat skin tissues. ELISA was used to detect the levels of serum IL-4 and IFN-γ as well as IgA, IgM and IgG. Concanavalin A (ConA)-activated lymphocytes were co-cultured with human keratinocyte HaCaT, followed by treatment of 40 μg/mL DPA. The proliferation of HaCaT cells was detected by MTT method, and the apoptosis of HaCaT cells was detected by TUNEL method. H-E staining outcomes showed that DPA relieved the skin lesions of eczema rats in a dose-dependent manner. DPA decreased the levels of serum IL-4, IgA, IgM and IgG in rats with eczema, and increased the level of IFN-γ (all with P＜0.05). The reliefs of eczema in middle-dose (40 mg/kg) and high-dose (80 mg/kg) DPA-treated rats were equivalent to that of 15 mg/kg CG-treated positive control rats. DPA did not affect the proliferation of HaCaT cells (P＞0.05). However, DPA inhibited the apoptosis of HaCaT cells co-cultured with lymphocytes (P＜0.05). Therefore, DPA regulates the immune function of the eczema rats by improving the Th1/Th2 balance, thereby alleviating eczema-related lesions.
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  miR-153-3p regulates malignant biological behaviors of esophageal cancer cells by targeting ACTN4

  YANG Nan, XU Bao-hua, YUAN Zhi-li

  Current Immunology. 2024, 44(2): 112-120.

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  The study aims to explore the effects of miR-153-3p on the proliferation, migration and invasion of esophageal cancer (ESCA) cells by targeting and regulating α-actinin 4 (ACTN4). The expression of miR-153-3p and ACTN4 mRNA in different cell lines was detected by qRT-PCR. The targeting relationship between miR-153-3p and ACTN4 was verified by double luciferase assay. ECA109 cells were cultured in vitro and divided into six groups: blank group, mimic control (miR-NC) group, mimic (miR-153-3p) group, empty vector group, ACTN4 overexpression (ACTN4) group, the mimic and ACTN4 overexpression (miR-153-3p+ACTN4) group. qRT-PCR and Western blotting were performed to measure the expression of miR-153-3p and ACTN4; CCK-8 and colony formation experiment was performed to measure the proliferation of cells; Transwell was performed to measure the migration and invasion of cells. Western blotting was used to detect the protein levels of Ki67, E-cadherin, and N-cadherin. A nude mouse model of subcutaneous xenograft tumors was constructed in vivo and the effect of up-regulation of miR-153-3p on tumor growth was detected. Immunohistochemistry was performed to measure the expression levels of ACTN4, Ki67, E-cadherin and N-cadherin in tumor tissues. The results showed that, the expression of miR-153-3p in the ESCA cell line was low (P<0.05), and ACTN4 mRNA was highly expressed (P<0.05). miR-153-3p was able to negatively regulate ACTN4 expression (P<0.05). Overexpression of miR-153-3p can reduce cell viability, colony formation, migration and invasion, inhibit Ki67 and N-cadherin expression, and up regulate E-cadherin expression (P<0.05). ACTN4 overexpression showed the opposite effects (P<0.05); overexpression of ACTN4 can reverse the effects of miR-153-3p overexpression on ESCA cell behavior (P<0.05). In vivo studies have shown that overexpression of miR-153-3p can inhibit the expression of ACTN4, Ki67, N-cadherin, increase the expression of E-cadherin, and slow down tumor growth. This study suggests that overexpression of miR-153-3p may inhibit the proliferation, invasion and migration of ESCA cells by targeting ACTN4 negatively.
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  Regulation of lymphocyte function by IL-17A preconditioned adipose-derived mesenchymal stem cells

  LONG Yi-yin, LI Chang-lin, DU Peng, CHEN Xiao-bo, WANG Yu-liang

  Current Immunology. 2024, 44(2): 121-125.

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  The aim of this study is to investigate the immuno-modulatory effect of IL-17A preconditioned (ameliorated) adipose-derived mesenchymal stem cells (ADSCs）on peripheral blood lymphocytes and to explore the underlying mechanism.  Subcutaneous adipose tissue was collected from four abdominal surgery patients consulting Tianjin People's Hospital, along with the peripheral blood. ADSCs  were isolated, cultured and identified. Next, ADSCs were divided into two groups preconditioned with or without IL-17A (named ADSC-17 group and ADSC group, respectively), which were co-cultured with phytohemagglutinin (PHA)+IL-2-stimulated lymphocytes. The proliferation inhibitory rate of activated lymphocytes was analyzed by MTT assay. The percentage of CD4⁺CD25⁺ T lymphocytes was detected by FACS. ELISA was performed to detect the TGF-β1 level in culture supernatants. The results revealed that after in vitro culturing, both ADSC and ADSC-17 groups strongly expressed cluster of differentiation (CD)90, CD105, and CD73 as well as displayed osteogenic and adipogenic potentials. The ADSC-17 group showed significantly enhanced proliferation inhibitory rate of activated lymphocytes in a dose-dependent manner compared to that of the ADSC group (all with P＜0.01). The percentage of CD4⁺CD25⁺ T lymphocytes and the secretion of TGF-β1 in ADSC-17 group were significantly increased (both P＜0.05) compared to those of the ADSC group. Altogether, the preconditioning of ADSCs by IL-17A can augment the capacity of ADSC to inhibit lymphocyte proliferation and to induce CD4⁺CD25⁺ T lymphocyte  differentiation so as to become an effective strategy for inducing lymphocytes hypo-responsiveness.
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  Regulatory effects and mechanisms of miR-409-3p on myocardial injury in young rats with Kawasaki disease

  TONG Li-ga, ZHANG Qing-shan, WU Chun-xia

  Current Immunology. 2024, 44(2): 126-133.

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  To study the influence of miR-409-3p on myocardial injury in young mice with Kawasaki disease (KD) through silent information regulator 1 (SIRT1)/forkhead transcription factor O1 (FOXO1) signaling pathway, SD juvenile male rats were randomly divided into control group, model group, miR-409-3p antagomir group, miR-409-3p antagomir negative control group, EX527 (SIRT1 inhibitor,  1 μg/kg) group, and miR-409-3p antagomir+EX527 (1 μg/kg) group, 12 per group. The expression of miR-409-3p in rat myocardium was detected by qRT-PCR; ELISA was performed to detect levels of creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), cardiac troponin T (cTnT), TNF-α, IL-17, IL-18 in serum. The result showed that compared with the model group and the miR-409-3p antagomir+EX527 group, the pathological injuries in myocardial tissue of the miR-409-3p antagomir group were alleviated, the serum CK-MB, cTnI, cTnT, TNF-α, IL-17, and IL-18 levels, myocardial acely-FOXO1/FOXO1 were decreased (P<0.05), the cardiac function indexes the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS), and the expression of SIRT1 in myocardial tissue were increased (P<0.05); the pathological injuries in myocardial tissue of   the EX527 group were aggravated, the serum CK-MB, cTnI, cTnT, TNF-α, IL-17, and IL-18 levels, myocardial acely-FOXO1/FOXO1 were increased (P<0.05), the cardiac function indexes LVEF and LVFS, and the expression of SIRT1 in myocardial tissue were decreased (P<0.05). miR-409-3p was able to target down-regulation of SIRT1 expression in rat cardiomyocytes. The study suggests that miR-409-3p can target down-regulate SIRT1 expression to participate in the process of myocardial injury in KD young rats. Down-regulation of miR-409-3p expression can play an anti-inflammatory effect by activating SIRT1/FOXO1 signal, thereby reducing myocardial injury in KD young rats.
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  Therapeutic effect and mechanism of shikonin on myocardial injury in spontaneous hypertension rats

  WANG Jia-lu, GUO Liang, JIN An-lin

  Current Immunology. 2024, 44(2): 134-140.

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  To understand the therapeutic effect and mechanism of shikonin (Shi) on myocardial injury in spontaneous hypertension rat (SHR), rats were divided into Wistar-Kyoto (WKY) group, SHR model group, SHR+Shi treatment group (Shi 50 mg/［kg·d］), and SHR+losartan(Los) treatment group (Los 10 mg/ ［kg·d］). The rats were treated for 4 consecutive weeks. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) were analyzed by echocardiography. H-E staining kit, Sirius scarlet staining kit, and Masson tricolor staining kit were used for histopathological examinations. The myocardial injury (atrial natriuretic peptide ［ANP］ and lactate dehydrogenase ［LDH］), inflammation (IL-17 and TGF-β), and oxidative stress (superoxide dismutase ［SOD］, catalase ［CAT］ and malondialdehyde ［MDA］ ) parameters of rats in each group were measured. The expressions of Notch2 and Hes1 in myocardial tissue were detected by RT-PCR and Western blotting. The results showed that compared to those of the SHR group, the LVEF and LVFS of the SHR+Shi group and SHR+Los group were significantly increased（P<0.05）, while the LVEDD and LVESD were significantly decreased (P<0.05). The area of myocardial fibrosis in the SHR group was increased, while the areas of myocardial fibrosis in the SHR+Shi group and the SHR+Los group were significantly reduced. Compared to those of the SHR group, the plasma ANP and LDH levels of the SHR+Shi group and the SHR+Los group were significantly reduced (P<0.05), and the thickness of the thoracic aorta media was significantly reduced (P<0.05). In addition, the serum SOD and CAT levels were significantly increased（P<0.05）, while the MDA level was significantly decreased (P<0.05) in the SHR+Shi group and the SHR+Los group. Compared to those of the SHR group, the serum IL-17 levels of the SHR+Shi group and the SHR+Los group were significantly reduced（P<0.05）, while the TGF-β levels were significantly increased (P<0.05). The mRNA and protein expressions of Notch2 and Hes1 in the myocardium of the SHR+Shi group and the SHR+Los group were significantly reduced (P<0.05) compared to those of the SHR group. This study shows that Shi can alleviate myocardial injury in SHR  by inhibiting inflammation and oxidative stress via down-regulation of the Notch2 pathway.
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  Effects of LncRNA NEAT1 on proliferation, apoptosis, and PD-1/PD-L1 expression in non-small cell lung cancer cells through miR-128-3p/HNRNPL axis

  ZHAO Hai-long, LI Bin, ZHENG Feng-chang, ZHU Xiao-kang, BAI Yue

  Current Immunology. 2024, 44(2): 141-151.

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  To investigate the role and mechanism of long non-coding RNA (LncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in immune escape of non-small cell lung cancer (NSCLC), the tumor tissues and adjacent normal tissues of 96 NSCLC patients were collected in this study.  qRT-PCR was used to detect the expression of NEAT1 in NSCLC tumors and normal tissues, and its correlation with the clinicopathologic feature of NSCLC patients was analyzed.  In addition, qRT-PCR was used to detect the expression of NEAT1, miR-128-3p, heterogeneous nuclear ribonucleoprotein L (HNRNPL), and PD-L1 mRNAs in bronchial epithelial cells 16HBE and NSCLC cell lines. NEAT1 interference plasmid (si-NEAT1), miR-128-3p inhibitor, and controls (si-NC and inhibitor-NC) were transfected into A549 cells and divided into control group, si-NC group, si-NEAT1 group, si-NEAT1+anti-NC group, and si-NEAT1+anti-miR-128-3p group. The mRNA and protein expressions of HNRNPL and PD-L1 were measured and the regulatory mechanisms of NEAT1, miR-128-3p, and HNRNPL were verified by RNA pull-down experiment. A549 cells were co-cultured with CD8⁺ T cells to verify the role of NEAT1 knockdown in NSCLC immune escape. The levels of PD-L1 and IFN-γ were detected by ELISA. The results showed that NEAT1 was highly expressed in NSCLC tumor tissues, and it significantly correlated with NSCLC tumor size, TNM stage, and lymph node metastasis (P<0.05). In NSCLC tumor cells, NEAT1, HNRNPL, and PD-L1 were significantly overexpressed, while miR-128-3p was significantly underexpressed (all P<0.05). Knockdown of NEAT1 up-regulated miR-128-3p while inhibiting HNRNPL and PD-L1 expressions, which in turn significantly reduced NSCLC cell viability and induced NSCLC cell apoptosis (all P<0.05). NEAT1 targeted and bound miR-128-3p in NSCLC cells. In the co-culture system, knocking down NEAT1 in A549 cells could activate CD8⁺ T cells, inhibit their apoptosis and reduce the levels of PD-L1 and IFN-γ (all P<0.05). Down-regulation of miR-128-3p increased the expressions of HNRNPL and PD-L1, and attenuated the impact of NEAT1 knockdown on NSCLC cell proliferation, apoptosis, and CD8⁺ T cell activation (all P<0.05). Therefore, NEAT1 may promote PD-L1 expression through the miR-128-3p/HNRNPL axis, thereby leading to immune escape in NSCLC.
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  Research progress and overview on the relationships between TCR CDR3 repertoire characteristics and the composition of HLA alleles with COVID-19

  ZHOU De-wei, LI Jun, LI Yang-yang, YAO Xin-sheng

  Current Immunology. 2024, 44(2): 152-157.

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  Corona virus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health emergency. Adaptive immune response plays a critical role in clearing virus-infected host cells, mainly relying on T cells. The structure of the T cell receptor (TCR) determines the specificity of viral antigen cluster recognition, and the characteristics of the TCR complementarity determining region 3 (CDR3) repertoire of infected individuals have indications  for the occurrence and development of COVID-19 disease. Additionally, human leukocyte antigen (HLA) gene is the main factor responsible for individual varieties in immune responses to antigens and plays an important role in human immune responses. This review focuses on the research progress and overview of the relationships of TCR CDR3 repertoire characteristics and of the composition of host HLA alleles with COVID-19.
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  Research progress on the effect of NLRP3 inflammasome in periodontal-related cells on periodontitis and related targeting therapy

  CHEN Bai-xi, CHEN Guang-jie

  Current Immunology. 2024, 44(2): 158-164.

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  NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is a protein complex that stimulates the activation of caspase and the maturation of IL-1β, and promotes the pathogenesis and development of various inflammations. The occurrence of periodontitis (PD) is related to the dysbacteriosis of periodontal tissue. NLRP3 inflammasomes are involved in the activation of neutrophil, macrophage, osteoclast (OC), and human periodontal ligament fibroblast (HPLF). This review summarizes the effects of NLRP3 inflammasome in the related immune and stromal cells on PD, and outlines new ideas for PD treatment targeting NLRP3 inflammasome.
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  Effects of NOX2 in adaptive immune response and its correlation with autoimmune diseases associated with chronic granulomatous disease

  SU Xiao-ya, HONG Li, CHEN Tong-xin

  Current Immunology. 2024, 44(2): 165-169.

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  Phagocyte nicotinamide adenine dinucleotide phosphate oxidase (NOX2), is a multicomponent enzyme complex that plays an important role in host immune defense and immune regulation. Functional defect of NOX2 correlates with the occurrence of chronic granulomatous disease (CGD). NOX2 deficiency may alter innate immune response which is the main cause of CGD infectious diseases. Further study on the pathogenesis of CGD finds that NOX2 deficiency may regulate T and B cell-mediated immune responses, thus affecting the occurrence and development of autoimmune diseases in CGD patients. This review discusses the changes in adaptive immunity caused by NOX2 deficiency and its relationship with concomitant autoimmune diseases in CGD patients.
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  Immunological mechanisms of the regulatory effects of gut microbiota on the pathogenesis and progression of parenteral tumors

  DING Gui-qing, CHENG Xiao-dong

  Current Immunology. 2024, 44(2): 170-173.

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  Gut microbiota dysbiosis exists in patients with different types of cancer, including melanoma, breast cancer, brain glioma, and other parenteral solid tumors. Dysregulated gut microbiota induces the formation of immunosuppressive tumor microenvironment through a variety of mechanisms, causes the occurrence of tumor immune escape, and affects the host's responses to immune checkpoint inhibitors (ICI). The regulatory effects of gut microbiota can enhance the function of immune killer cells and inhibit tumor progression. This review summarizes the regulatory effect of gut microbiota on the progression of parenteral solid tumors and the underlying immunological mechanisms, so as to provide insights for further basic research and clinical application. 
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  Research progress on the correlation of RAGE and pulmonary diseases and intervention by traditional Chinese medicine

  WANG Shu-min, LI Xue-jun, JIANG Zhi-yan, XIAO Zhen

  Current Immunology. 2024, 44(2): 174-179.

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  Receptor for advanced glycation end products (RAGE), a type of membrane protein, is a member of the immunoglobulin superfamily. Over the past ten years, hundreds of papers have described the correlation between RAGE and the pathophysiological status and prognosis of lung diseases including severe pneumonia, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung carcinoma. However, many findings were inconsistent. This review summarizes the origin and biological function of RAGE. It also discusses the acting mechanism of RAGE in lung diseases and the therapeutic effect of traditional Chinese medicine via RAGE regulation, aiming to provide new ideas and strategies for improving related lung diseases.
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  The clinical value of TNF-α and its antagonists in reproductive immune diseases

  WANG Juan, WANG Chen, HUANG Jin-ge, MOU Fang-xiang, WANG Fang

  Current Immunology. 2024, 44(2): 180-184.

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  TNF-α is a pro-inflammatory Th1-type cytokine secreted by immune and placental cells, which plays important roles in regulating the inflammatory and immune mechanisms of embryo implantation, placentation，and final pregnancy outcome. Moderate increase of TNF-α in early pregnancy may be beneficial to embryo implantation. However, over-expression of TNF-α can lead to the occurrence of reproductive immune diseases through different pathways, and cause unexpected pregnancy and birth outcomes. In recent years, the clinical application of TNF-α in reproductive immune diseases has become a hotspot in reproductive medicine. Nonetheless, questions on whether TNF-α can be used as a routine screening target for reproductive immune diseases, whether TNF-α antagonists can improve pregnancy outcomes, or whether short-term/long-term use of TNF-α is safe for mother and fetus are required to be carefully considered. Based on above questions, this review discusses the value of TNF-α and its antagonists on the diagnosis and treatment of reproductive immune diseases, for providing new ideas to develop clinical diagnosis and treatment strategies.