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关键词： Polycystic ovary syndrome   IL2RG   Gasdermin E   Apoptosis   Granulosa cells  

摘要： Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder with significant impacts on women's reproductive health. Interleukin (IL)-2 receptor subunit gamma (IL2RG), a common receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been shown to interrupt estrous cycle, yet its role in PCOS remains unclear. Results The evaluated expression levels of IL2RG in human granulosa cells (GCs) and IL2RG-dependent cytokines (IL-2, IL-4, IL-15) in follicular fluid were demonstrated in 18 PCOS patients and 22 control subjects. The positive correlation between IL2RG and PCOS was analysed through GEO databases. In vivo, we found that in the PCOS model (6 mg/100 g body-weight of dehydroepiandrosterone subcutaneous injection for 21 days), the ovarian index, testosterone, glucose, and LH/FSH levels were elevated, and the estrous cycle was disrupted. Knocking down IL2RG (KO) restored the above levels. However, in the dehydroepiandrosterone-treated group, these levels did not recover even after IL2RG was knocked-down. The decreased expression of Gasdermin E (GSDME) but increased caspase-3 level in IL2RG KO rats compared with WT were found. In vitro, knockdown of IL2RG by siRNA inhibited caspase-3-mediated GSDME cleavage in testosterone-induced KGN cells. Furthermore, the caspase-3 inhibitor Z-DEVD-FMK and the caspase-1 inhibitor Belnacasan alleviated pyroptosis in testosterone-induced KGN cells by lactate dehydrogenase test, fluorescence assay, and flow cytometry. Conclusions IL2RG is expressed higher in PCOS patients, exerting an inhibitory effect on caspase-3-mediated GSDME cleavage upon knockdown. However, the knockout of IL2RG led to the conversion of GSDME-mediated pyroptosis into apoptosis. This study explores the function of IL2RG and provides insights for therapeutic targets in PCOS.

关键词： Osteoarthritis   Synovial microenvironment   Inflammation   Pain perception   Statistical modeling  

摘要： This study delineates distinct late-stage osteoarthritis (OA) profiles, characterized by NF-kappa B, TNF-alpha, and TGF-beta-mediated synovial inflammation and pain, in a cohort of 31 patients undergoing joint arthroplasty. Histopathological analysis demonstrated synoviocyte hyperplasia, increased stromal cellularity, inflammatory infiltrates, and enhanced vascularization, findings that correlated with higher synovitis scores and exacerbated movement-associated nociception. Increased expression of NF-kappa B and TNF-alpha in the synovial membrane confirmed their association with stronger inflammation and pain perception. Bayesian networks revealed relationships among NF-kappa B, TNF-alpha, and pain scores, suggesting that NF kappa B is a primary driver of pain in low-grade synovitis, while TNF-alpha becomes more influential in high-grade synovitis. Cluster analysis identified four distinct patient subgroups: (1) males with severe radiographic OA, elevated NF-kappa B in both the synovium and fluid, and the absence of synovitis;(2) predominantly females with metabolic comorbidities, a variable degree of synovitis, and elevated TNF-alpha in synovial fluid;(3) patients with low pain scores and no histopathologically confirmed synovial inflammation;and (4) patients with high-grade synovitis, pronounced tissue alterations, increased NF-kappa B, TNF-alpha, and TGF-beta expression in the synovial membrane, but without metabolic comorbidities. The findings clarify the influence of synovitis in late-stage OA and suggest that the identified profiles may assist in earlier disease stratification and the development of tailored treatments in the future.

关键词： cancer vaccine   humoral response   IL17A   pancreatic cancer   tumour immune microenvironment  

摘要： Background and Aims The pancreatic tumour microenvironment (TME) is a complex ecosystem where tumour cells, cancer-associated fibroblasts and immune cells interact, often in ways that contribute to tumour growth. The role of interleukin (IL17)A in pancreatic cancer progression is now more defined, and it is known to sustain a pro-tumoural microenvironment and inhibit the immune response. Here, we explore the effect of combining IL17A depletion with a cancer vaccine to enhance anti-tumour *** We used genetically engineered mice proficient or deficient in IL17A, and orthotopically injected mice with pancreatic tumour cells depleted or not in IL17A, to examine the vaccine effects on tumour growth and immune responses. Both humoral and cellular immune responses were analysed following vaccination in IL17A-deficient and control *** Mice lacking IL17A-either genetically or through pharmacological depletion-exhibited prolonged survival and smaller tumours, compared to vaccinated controls. Vaccination in IL17A-deficient mice significantly increased the influx of immune cells, including Natural Killer (NK) and effector/memory CD8 T cells, which displayed higher cytotoxic activity. CD8 T-cell depletion in these models notably reduced vaccine efficacy, underscoring the essential role of these cells. NK cell depletion in untreated models further demonstrated NK cells' critical function in controlling tumour growth when IL17A was absent. Overall, IL17A depletion enhanced both antigen-specific humoral and cellular immune responses, indicating a shift towards a more robust and responsive immune *** Our findings reveal that the absence of IL17A in the pancreatic TME reprograms it into a more immune-supportive environment, favouring the recruitment of effector/memory immune cells upon vaccination. This approach paves the way for novel therapeutic combinations in pancreatic cancer, where IL17A depletion may boost both immunotherapy efficacy a

关键词： 急性肝衰竭   解毒化瘀颗粒   白细胞介素6/Janus激酶2/信号传导和转录激活因子3   免疫炎症  

摘要： 目的 急性肝衰竭(Acute Liver Failure，ALF)是一种短期内死亡率很高的急危重症疾病。解毒化瘀颗粒(JDHY)已被临床证实是治疗ALF的有效方剂，用于治疗ALF已有20余年历史，但其疗效机制尚未被完全阐明。本文旨在探讨JDHY调控白细胞介素6（Interleukin-6，IL-6）/蛋白酪氨酸激酶（Janus Kinase 2，JAK2）/信号传导和转录激活因子3（Signal Transducer And Activator Of Transcription 3，STAT3）信号通路对D-氨基半乳糖( D-Galactosamine，D-GALN)和脂多糖( Lipopolysaccharides，LPS)诱导的ALF大鼠的作用机制及JDHY的干预效应。方法 用随机数字表法将雄性SD大鼠30只分为正常对照组（Control）、模型组（D-GALN/LPS）、D-GALN/LPS+JDHY组（JDHY），每组10只。D-GALN/LPS组和JDHY组按照D-GALN 600mg/kg 和LPS 20μg/kg腹腔注射构建ALF大鼠模型，JDHY组在造模前按0.22g/ml浓度中药液灌胃，每天1次，连续3天，Control组和D-GALN/LPS组则给予等量生理盐水灌胃，造模24小时后处死老鼠收集相关样本，观察肝脏大小、外观变化；检测血清谷丙转氨酶（Alanine aminotransferase，ALT）、谷草转氨酶（Aspartate aminotransferase，AST）、总胆红素（Total bilirubin，TBIL）、凝血酶原时间（Prothrombin time，PT）；HE染色观察肝组织病理学变化，酶联免疫吸附法（Enzyme-linked immunosorbent assay，ELISA）检测血清IL-6、白细胞介素-1β(Interleukin-1β，IL-1β)、核转录因子-κB（Nuclear factor kappa-B，NF-κB）、肿瘤坏死因子（Tumor necrosis factor-alpha，TNF-α）水平；蛋白质印迹（Western Blot，WB）检测肝组织JAk2、STAT3、P-JAk2、P-STAT3和该信号通路下游蛋白B细胞淋巴瘤-2(BCL-2)、BCL-2相关X蛋白(BAX)的表达；免疫组织化学法(Immunohistochemistry，IHC) 检测JAK2、STAT3、BCL-2、BAX蛋白表达；聚合酶链式反应（Quantitative real time polymerase chain reaction，q-PCR）检测JAK2、STAT3、BAX、BCL-2的mRNA表达。结果 经JDHY提前干预后，ALF大鼠的肝功能、凝血功能得到改善、肝组织炎症浸润范围缩小，死亡率降低，血清IL-6、IL-1β、NF-κB、TNF-α炎症细胞因子水平明显降低，肝组织JAK2、P-JAK2、STAT3、P-STAT3、BCL-2、BAX蛋白表达均下调，JAK2、P-JAK2、STAT3、P-STAT3 mRNA水平下降。结论 JDHY能有效改善ALF肝损伤，降低死亡率，其机制可能与下调IL-6/JAK2/STAT3信号通路表达有关。

关键词： Antigen   Cancer   Endocrinology   Immunology   Thyroid disease  

摘要： Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita-/- and H2-Ab1-/- ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.

关键词： Axial spondyloarthritis   HLA-B27   HLA-B alleles   diffuse idiopathic skeletal hyperostosis   palmoplantar pustulosis arthritis   osteitis condensans ilii  

摘要： Objective To assess whether extended HLA-B typing, together with simple clinical indices, distinguishes axial spondyloarthritis (axSpA) from radiographic mimics in Japanese *** We retrospectively reviewed 127 patients who underwent HLA-B typing at a single centre between 2008 and 2024. Ankylosing spondylitis met the 1987 modified New York criteria, and non-radiographic axSpA met the 2009 ASAS criteria. Diffuse idiopathic skeletal hyperostosis (DISH), palmoplantar pustulosis arthritis (PAO), and osteitis condensans ilii (OCI) were identified by characteristic imaging and clinical findings. Two rheumatologists reassigned final diagnoses. HLA-B phenotypes, age at onset, sex, and initial C-reactive protein (CRP) were compared across *** A total of 25 patients satisfied axSpA criteria;80% were HLA-B27-positive. DISH, PAO and OCI showed apparent enrichment of common Japanese alleles (B52, B61/B62, B39). DISH and PAO presented later than axSpA (54.0 y and 42.5 y versus 25.2 y) and DISH had lower CRP (0.31 versus 1.51 mg/dL, P = 0.003). OCI occurred exclusively in women and was *** In Japanese practice, no single non-B27 allele reliably separates axSpA from its mimics;instead, early age at onset, male sex, and raised CRP provide the most practical safeguards against diagnostic error and unnecessary therapy.

关键词： T cells   skin   epidermis   dermis   immune cells   adaptive immunity   HLA   proteomics  

摘要： T lymphocytes in human skin play essential roles in immune surveillance and tissue homeostasis, with distinct populations residing in the epidermal and dermal compartments. To characterize the molecular basis of their compartmentalized functional specialization, we performed proteomic analysis of total T cell populations isolated from healthy human skin, combining flow cytometry and liquid chromatography-tandem mass spectrometry. We quantified 5985 proteins across epidermal and dermal T cell populations, identifying 2177 significantly differentially expressed proteins (FDR < 0.05), including 1008 with >2-fold changes. Compared with dermal T cells, epidermal T cells showed elevated intensity of tissueresidency marker CD69, co-stimulatory protein CD27, complement components (C3, C4a, and Factors B and D), and proteins involved in oxidative phosphorylation and cholesterol metabolism. Epidermal T cells also exhibited higher levels of antimicrobial S100 proteins, chemokine receptor CCR6, IL-18, and MHC class I molecules, while, in contrast, dermal T cells showed increased expression of CXCR4, IL-16, and MHC class II-related proteins. While these distinct proteomic signatures suggest compartment-specific adaptations in metabolism, immune surveillance, and antigen presentation, the results should be interpreted as exploratory, given methodological limitations. Nonetheless, this study provides a valuable molecular resource for understanding the specialization of T cells within different skin layers and offers a basis for future investigations into skin immune biology and its potential implications in disease.

关键词： IL-6R   Inflammation   Inflammatory Bowel Disease   Intestinal epithelial cells   Tregs  

摘要： Mucosal homeostasis requires coordinated immune regulation and epithelial repair. Inflammatory bowel disease (IBD) arises from disrupted coordination between the immune system and intestinal epithelium, where resolution and repair must occur in parallel. Interleukin-6 (IL-6) plays a dual role: it promotes epithelial regeneration but destabilizes regulatory T cells (Tregs). We aimed to determine the contribution of Treg IL-6 receptor (IL-6R) signaling to intestinal inflammation and epithelial integrity. We developed a conditional knockout mouse model in which IL-6R was deleted from Tregs (Treg IL-6R knockout). These mice were subjected to dextran sodium sulfate (DSS)-induced colitis and a T cell transfer model of colitis. Soluble IL-6R production by Tregs was assessed in vitro, and transcriptional changes in epithelial cells were analyzed by RNA-seq. Human colonic organoids from IBD patients were treated with IL-6 or hyper-IL-6 (IL-6/sIL-6R fusion protein) to test downstream signaling effects. Tregs lacking IL-6R improved colitis to a similar extent as control Tregs in the adoptive transfer model, indicating intact suppressive function. However, Treg IL-6R knockout mice were more susceptible to DSS colitis than controls, suggesting a physiologic role for Treg IL-6R signaling in epithelial protection. In vitro, Tregs shed soluble IL-6R, enabling IL-6 trans-signaling to epithelial cells. Intestinal epithelial cells from Treg IL-6R knockout mice compared to WTcre controls revealed widespread transcriptional downregulation of genes related to survival and repair pathways at baseline, and impaired transcriptional responses following DSS treatment. In human organoids, IL-6 trans-signaling elicited stronger STAT3 activation than IL-6 alone. These findings reveal a previously unrecognized role for Treg-derived IL-6R in promoting epithelial resilience and maintaining mucosal homeostasis.

关键词： cannabinoid 2   inflammatory   microglia   morphine  

摘要： BACKGROUND:Pain has a seriously effect on patients' life quality. The use of morphine for pain is common, but tolerance limits its application in clinic. However, there is no exact mechanism for tolerance. In this study, we explored the effect of microglial polarization and the role of IL(interleukin)-4 in administrating microglial polarization in reducing morphine tolerance with CB2 receptor agonist. METHOD:The cells cultivated with morphine or combined CB2R agonist AM1241, CB2R antagonist AM630, CB1R antagonist AM281, and IL-4 inhibitor (IL-4I), and mice were injected with these drugs for 7 consecutive days, and hot plate behavioral tests were performed 30 minutes after administration respectively. Mice received a single morphine injection on day 8, and samples were taken after behavioral tests. The expression of iNOS, SOCS3, IL-4 and STAT6 mRNA were detected by qPCR; the expression of iNOS, SOCS3, p-STAT6 and STAT6 protein were detected by Western blot. Inflammatory cytokines were detected with Elisa kit. RESULTS:The M1 marker iNOS increased, the M2 marker SOCS3 decreased, p-STAT6 protein did not change, and the cytokines increased after morphine treatment. The PWL value, IL-4 mRNA and p-STAT6 protein increased after AM1241 treatment, iNOS decreased and SOCS3 increased after AM1241 treatment, AM1241 decreased the pro-inflammatory cytokines, increased IL-4, IL-10 secretion. AM630 and IL-4I reversed the effect of AM1241 on PWL, M1 M2 markers. CONCLUSION:The polarization of microglia in the direction of M1 caused morphine tolerance, AM1241 increased the IL-4 mRNA and induced the phosphorylation protein of STAT6 to reduce the tolerance, and AM1241 induced microglia to polarization in the direction of M2. AM1241 regulated microglia polarization through IL-4/STAT6 pathway, thereby reducing tolerance.

关键词： IL-22   rhIL-22BP-ABD   Renaturation of inclusion body   Psoriasis  

摘要： Psoriasis is a persistent immune-mediated inflammatory disorder that adversely affects the skin. Interleukin-22 (IL-22) is integral to the development and pathophysiology of psoriasis, and targeting IL-22 may serve as a promising therapeutic approach for treating the condition. IL-22 binding protein (IL-22BP) exhibits a binding affinity for IL-22 that far surpasses that of IL-22RA1 and functions as a natural antagonist of IL-22. Traditional IL-22BP production methods predominantly rely on eukaryotic animal cell expression systems, which generally require complex processes, resulting in low yield and high production costs. This study reports the expression of long-acting IL-22BP with a high yield and purity over 90% in Escherichia coli by fusion with the albumin-binding structural domain ABD. The biological functions of rhIL-22BP-ABD were assessed utilizing cell lines and a murine model. Our findings indicated that rhIL-22BP-ABD successfully suppressed IL-22-induced proliferation of HaCaT cells in vitro and alleviated imiquimod-induced psoriasis inflammation in mice. Furthermore, rhIL-22BP-ABD can effectively inhibit the signaling of its downstream signaling pathway STAT3 and the associated inflammatory factors by binding to IL-22, which is beneficial to the recovery of psoriasis. These findings provide a basis for forthcoming extensive studies on the rhIL-22BP-ABD protein for industrial manufacturing and pharmaceutical development.