Cytokine最新文献_第4页

Characterising interleukin-27 (IL-27) responses in human blood derived macrophage cells 人血源性巨噬细胞中白细胞介素-27 （IL-27）反应的表征

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-22 DOI: 10.1016/j.cyto.2025.157097

Thomas Helps , Christa Baker , Heather M. Wilson , Simon Arthur , Graeme I Murray , Mairi H. McLean

Macrophages are key cells in the pathogenesis of chronic inflammatory diseases. Interleukin (IL)-27 is a pleiotropic cytokine with mostly immunoregulatory functions and associated with a wide array of diseases. There is little knowledge on the effects of IL-27 on human macrophages. Here, we characterise the effect of IL-27 on human blood derived CD14+ monocyte derived macrophages (MDMs), in resting state and under inflammatory stimulation (+LPS/PepG), through targeted transcriptomic expression profile, phagocytosis of E. coli bioparticles and expression of intracellular and secreted proteins by DIA mass spectrometry and multiplex ELISA, respectively. There was no change in pro-inflammatory cytokine gene expression with IL-27. IL-27 led to changes in the chemokine secretome, inducing a significant upregulation of the chemokines CXCL9 and CXCL10 and reduced expression of CCL2, CCL7, CCL13, CCL18, CCL24, CXCL13, IL-10 and Midkine. Macrophage phagocytosis was not affected by IL-27. IL-27 effects on intracellular proteome were subtle overall. Using unadjusted p values, changes were most pronounced in the resting state, with a significant (p < 0.05) increase in 106 and decrease in 11 proteins. Enrichment analysis suggested regulation of several biological processes by IL-27, including cellular response to type II interferon. Overall, we demonstrate novel biology of IL-27 mediated effects in human macrophages.

巨噬细胞是慢性炎性疾病发病的关键细胞。白细胞介素(IL)-27是一种多效性细胞因子，主要具有免疫调节功能，与多种疾病有关。目前对IL-27对人巨噬细胞的作用知之甚少。在这里，我们通过靶向转录组表达谱、大肠杆菌生物颗粒的吞噬以及细胞内和分泌蛋白的表达，分别通过DIA质谱和多重ELISA分析了IL-27对静息状态和炎症刺激（+LPS/PepG）下的人血源性CD14+单核细胞源性巨噬细胞（MDMs）的影响。IL-27对促炎细胞因子基因表达无明显影响。IL-27导致趋化因子分泌组的改变，诱导趋化因子CXCL9和CXCL10的显著上调，CCL2、CCL7、CCL13、CCL18、CCL24、CXCL13、IL-10和Midkine的表达降低。巨噬细胞吞噬不受IL-27的影响。IL-27对细胞内蛋白质组的影响总体上是微弱的。使用未调整的p值，变化在静息状态下最为明显，显著(p

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引用次数: 0

Association between pan-immune inflammatory values and chronic kidney disease: An insight originating from the NHANES database 泛免疫炎症值与慢性肾脏疾病之间的关联：来自NHANES数据库的见解。

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-22 DOI: 10.1016/j.cyto.2025.157095

Zihan Liu , Haiyang Wang , Zihao Zhang , Wenyan Wang , Chen Wang , Xingfu Lu , Zhepeng Liu , Tao Shen

Background

Pan-immune-inflammatory value (PIV) is a novel inflammatory biomarker that integrates four immune cell types to generate a holistic inflammatory profile. Its comprehensive nature has positioned PIV as a clinically relevant predictor. Chronic kidney disease (CKD), characterized by irreversible kidney damage, is increasingly recognized as an inflammatory disorder, yet the clinical utility of PIV in CKD remains underexplored.

Methods

This cross-sectional study analyzed data from 39,156 participants in the 2011–2018 National Health and Nutrition Examination Survey (NHANES) cycles. Weighted multivariate logistic regression models were employed to evaluate the association between PIV levels and CKD prevalence. Non-linear relationships were assessed using restricted cubic spline (RCS) analyzes with smoothed curve fitting. Subgroup analyses and interaction tests were conducted to examine potential effect modification by demographic and clinical confounders.

Results

Multivariate logistic regression revealed a significant positive association between elevated PIV and CKD prevalence. RCS analyzes demonstrated a J-shaped relationship, suggesting that the risk of developing chronic kidney disease increases when PIV is elevated. Subgroup interactions were non-significant, suggesting consistent associations across strata of gender, educational attainment, comorbidity status, or lifestyle factors.

Conclusion

This study identifies a non-linear positive association between PIV and incident CKD that is independent of traditional confounders. RCS analyzes demonstrated a J-shaped relationship, suggesting that when PIV is elevated, there is also an increased risk of developing chronic kidney disease. These findings support PIV as a complementary biomarker for CKD risk stratification and warrant mechanistic studies investigating its role in renal inflammation pathways, alongside prospective validation in cross-sectional study.

背景：泛免疫炎症值（Pan-immune-inflammatory value， PIV）是一种新的炎症生物标志物，它整合了四种免疫细胞类型来产生一个整体的炎症谱。其综合性使PIV成为临床相关的预测指标。慢性肾脏疾病（CKD）以不可逆的肾脏损害为特征，越来越被认为是一种炎症性疾病，但PIV在CKD中的临床应用仍未得到充分探索。方法：本横断面研究分析了2011-2018年国家健康与营养检查调查（NHANES）周期中39,156名参与者的数据。采用加权多变量logistic回归模型评估PIV水平与CKD患病率之间的关系。非线性关系评估使用限制三次样条（RCS）分析与平滑曲线拟合。进行亚组分析和相互作用试验，以检查人口统计学和临床混杂因素对潜在效果的影响。结果：多因素logistic回归显示PIV升高与CKD患病率呈正相关。RCS分析显示出j型关系，表明PIV升高时发生慢性肾脏疾病的风险增加。亚组相互作用不显著，表明性别、受教育程度、合并症状况或生活方式因素之间存在一致的关联。结论：本研究确定了PIV与CKD事件之间的非线性正相关，独立于传统混杂因素。RCS分析显示出j型关系，表明当PIV升高时，患慢性肾脏疾病的风险也会增加。这些发现支持PIV作为CKD风险分层的补充生物标志物，并支持对其在肾脏炎症途径中的作用进行机制研究，同时在横断面研究中进行前瞻性验证。

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引用次数: 0

Unlocking potentials of a prenylated flavonoid: Xanthohumol's role in combating inflammatory conditions and Rhematic diseases 解锁烯酰化类黄酮的潜力：黄腐酚在对抗炎症条件和血液疾病中的作用。

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-21 DOI: 10.1016/j.cyto.2025.157092

Farag M.A. Altalbawy , Ahmed Hussein Zwamel , Ashok Kumar Bishoyi , Suhas Ballal , Rishiv Kalia , Kamal Kant Joshi , Subhashree Ray , Atreyi Pramanik , Jasur Rizaev , Khursheed Muzammil

Xanthohumol, a prenylated flavonoid derived from hops (Humulus lupulus), has garnered significant attention for its multifaceted therapeutic potential. This review highlights xanthohumol's ability to modulate key signaling pathways, including NF-κB, STAT3, and Nrf2, which are central to inflammation, oxidative stress, and cancer progression. As a flavonoid, xanthohumol exhibits potent antioxidant and anti-inflammatory properties, making it effective in alleviating inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and inflammatory bowel disease. In cancer, xanthohumol demonstrates remarkable efficacy by inhibiting tumor growth, angiogenesis, and metastasis through the suppression of critical pathways like CXCR4 and STAT3. Preclinical studies have shown that xanthohumol selectively targets cancer cells while sparing normal cells, underscoring its potential as a safe and effective anticancer agent. Beyond its anti-inflammatory and anticancer effects, xanthohumol also plays a significant role in metabolic regulation. It improves glucose homeostasis, lipid metabolism, and gut microbiota composition, offering therapeutic benefits for metabolic syndrome and diabetes. Clinical trials and preclinical research further validate xanthohumol's safety and efficacy, with emerging evidence supporting its use in managing chronic diseases. This review provides a comprehensive overview of xanthohumol's mechanisms of action, therapeutic applications, and future directions in clinical research, positioning it as a promising natural compound for the prevention and treatment of a wide range of diseases.

黄腐酚（Xanthohumol）是一种从啤酒花（Humulus lupulus）中提取的烯酰化类黄酮，因其多方面的治疗潜力而受到广泛关注。这篇综述强调了黄腐酚调节关键信号通路的能力，包括NF-κB、STAT3和Nrf2，它们是炎症、氧化应激和癌症进展的核心。作为一种黄酮类化合物，黄腐酚显示出有效的抗氧化和抗炎特性，使其有效缓解炎症，如骨关节炎、类风湿关节炎和炎症性肠病。在癌症中，黄腐酚通过抑制CXCR4和STAT3等关键通路抑制肿瘤生长、血管生成和转移，显示出显著的疗效。临床前研究表明，黄腐酚选择性靶向癌细胞而不影响正常细胞，强调其作为一种安全有效的抗癌药物的潜力。除了抗炎和抗癌作用，黄腐酚还在代谢调节中起着重要作用。它可以改善葡萄糖稳态，脂质代谢和肠道微生物群组成，为代谢综合征和糖尿病提供治疗益处。临床试验和临床前研究进一步验证了黄腐酚的安全性和有效性，越来越多的证据支持其用于治疗慢性疾病。本文综述了黄腐酚的作用机制、治疗应用和临床研究方向，并将其定位为一种有前景的天然化合物，用于预防和治疗多种疾病。

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引用次数: 0

Associations between plasma ANGPTL4 levels and the risk of 24 cancers: a prospective cohort study 血浆ANGPTL4水平与24种癌症风险之间的关系：一项前瞻性队列研究

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-20 DOI: 10.1016/j.cyto.2025.157089

Xi Cheng , Shuzhen Zhao , Mingyi Du , Chengnan Guo , Xingdong Chen , Tiejun Zhang , Zhenqiu Liu

Background

Angiopoietin-like 4 (ANGPTL4) is a hepatokine involved in metabolism and inflammation and has been implicated in oncogenesis, yet its relationship with cancer risk in humans remains unclear.

Methods

We analyzed 35,716 cancer-free UK Biobank participants with baseline plasma ANGPTL4. Multivariable Cox models and restricted cubic splines assessed associations with 24 site-specific incident cancers; bidirectional two-sample Mendelian randomization (MR) evaluated causality.

Results

During a median follow-up of 12.5 years, 9304 incident cancer cases occurred. Compared with the lowest quartile (Q1), the higher quartiles (Q2, Q3, and Q4) of ANGPTL4 levels were significantly associated with the risks of ten cancers, including cancers of the bladder, breast, cervix uteri, colorectum/anus, esophagus, kidney, liver, mesothelial/soft tissues, multiple myeloma, and ovary (hazard ratios ranging from 1.02 to 3.98). Risks generally increased across ANGPTL4 quartiles, and spline analyses supported approximately linear dose–response patterns. Adding ANGPTL4 to an age–sex model improved discrimination across several sites (ΔC-index 0–0.071), with statistical significance observed only for breast cancer. Associations were directionally consistent but heterogeneous by age, sex, and BMI. Forward MR provided no evidence that genetically proxied ANGPTL4 causally increases cancer risk. In reverse MR, genetic liability to liver cancer showed a nominal positive association with circulating ANGPTL4, suggesting ANGPTL4 may be elevated as part of tumor-related biology.

Conclusions

Higher circulating ANGPTL4 is associated with increased risk of multiple cancers, with sex-and tissue-specific heterogeneity. Although MR does not support a universal causal role, ANGPTL4 remains a promising pan-cancer biomarker for risk stratification and early prevention.

生成素样4 （ANGPTL4）是一种参与代谢和炎症的肝因子，并与肿瘤发生有关，但其与人类癌症风险的关系尚不清楚。方法我们分析了35,716名无癌症的英国生物银行参与者，他们的基线血浆ANGPTL4。多变量Cox模型和受限三次样条评估了与24种位点特异性癌症的关联；双向双样本孟德尔随机化（MR）评估因果关系。结果在12.5年的中位随访期间，共发生9304例癌症。与最低四分位数（Q1）相比，ANGPTL4水平较高的四分位数（Q2、Q3和Q4）与10种癌症的风险显著相关，包括膀胱癌、乳腺癌、子宫颈癌、结直肠/肛门癌、食道癌、肾癌、肝癌、间皮/软组织癌、多发性骨髓瘤和卵巢癌（风险比从1.02到3.98）。在ANGPTL4四分位数中，风险普遍增加，样条分析支持近似线性的剂量-反应模式。将ANGPTL4添加到年龄-性别模型中可以改善多个位点的歧视（ΔC-index 0-0.071），仅在乳腺癌中观察到统计学意义。相关性在方向上是一致的，但在年龄、性别和BMI方面存在异质性。正向磁共振没有证据表明基因介导的ANGPTL4会增加癌症风险。在反向MR中，肝癌的遗传易感性与循环ANGPTL4呈名义正相关，表明ANGPTL4可能作为肿瘤相关生物学的一部分而升高。结论较高的循环ANGPTL4与多种癌症风险增加相关，且存在性别和组织特异性异质性。尽管MR不支持普遍的因果作用，ANGPTL4仍然是一个有希望的泛癌症生物标志物，用于风险分层和早期预防。

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引用次数: 0

IL-36γ signalling promotes a proinflammatory macrophage state that is associated with reduced lipid uptake IL-36γ信号传导促进与脂质摄取减少相关的促炎巨噬细胞状态。

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-15 DOI: 10.1016/j.cyto.2025.157091

Jillian Yong Xin Sieh , Gabriel Osborn , Sophia N. Karagiannis , Francesca Capon

Macrophages exhibit remarkable functional plasticity, adopting immune activating or immune suppressive states in response to environmental cues. While these phenotypic shifts are essential to immune homeostasis, the mechanisms whereby they are regulated in humans are poorly understood. Here, we investigated the role of interleukin (IL)-36γ, a barrier cytokine that is strongly induced in response to infection. We show that IL-36γ signalling modifies the anti-inflammatory phenotype of human alternatively activated (M2a) macrophages, by decreasing the expression the CD163 M2 marker. This change was accompanied by the upregulation of M1 surface markers (CD40, CD80) and M1 cytokines (e.g. TNFα, CXCL8). IL-36γ treatment of M2a macrophages also reduced the expression of TREM2 and CD36, two lipid-binding receptors that sustain the energy requirements of the M2 state. Accordingly, we also observed a decrease in the uptake of CD36 and TREM2 ligands (oxidized low-density lipoproteins). These findings indicate that IL-36γ shifts the immune and metabolic profile of M2a macrophages towards an M1-like state.

巨噬细胞表现出显著的功能可塑性，可根据环境信号采取免疫激活或免疫抑制状态。虽然这些表型变化对免疫稳态至关重要，但它们在人类中受到调节的机制尚不清楚。在这里，我们研究了白细胞介素(IL)-36γ的作用，IL -36γ是一种屏障细胞因子，在感染反应中被强烈诱导。我们发现IL-36γ信号通过降低CD163 M2标记物的表达来改变人M2a巨噬细胞的抗炎表型。这种变化伴随着M1表面标记物（CD40、CD80）和M1细胞因子（如TNFα、CXCL8）的上调。IL-36γ处理M2a巨噬细胞也降低了TREM2和CD36的表达，这两种脂质结合受体维持M2状态的能量需求。因此，我们还观察到CD36和TREM2配体（氧化低密度脂蛋白）的摄取减少。这些发现表明，IL-36γ将M2a巨噬细胞的免疫和代谢谱转变为m1样状态。

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引用次数: 0

Dynamic changes in the frequency of classical CD14HighCD16- and inflammatory CD14++CD16+ monocyte subsets in patients with advanced liver fibrosis 晚期肝纤维化患者经典CD14HighCD16-和炎性CD14++CD16+单核细胞亚群频率的动态变化

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-13 DOI: 10.1016/j.cyto.2025.157088

Pedro V. da Silva-Neto , Grenda L. Pereira , Priscila S. Souza , Diana M. Toro , Wivian da C.C. Silva , Geyse A.S. Soares , Walter L. Lima-Neves , Juliana S. Affonso , Keyla S. Sousa , Jéssica A. Silva , Allyson G. Costa , Flamir S. Victoria , Marilu Barbieri-Victoria , Andréa M. Tarragô , Adriana Malheiro

Hepatitis C is a global health problem, with approximately 71 million individuals chronically infected worldwide. During chronic inflammatory processes, the elevated expression of inflammatory mediators appears to influence the phenotype of circulating monocytes. Our objective was to investigate changes in the phenotypes of peripheral monocyte subsets and the profile of circulating mediators in patients from the Brazilian Amazon during chronic hepatitis C and associated with different degrees of liver fibrosis.

Material and methods

This is an observational study involving 30 individuals treated with DAAs and 15 healthy controls, tested for liver function, fibrosis scores (AST/platelet ratio index, FIB-4), percentage of peripheral blood monocyte subsets assessed with based on CD14/CD16 expression. The analysis of soluble immunological biomarkers was performed using the flow cytometry methodology.

Results

Chronic HCV patients showed decreased platelet counts and increased viral load, ALT, AST, alkaline phosphatase in individuals with high fibrosis scores (FIB-4 ≥ F2). Data analysis demonstrated a lower frequency of CD14^HighCD16⁻HLA-DR⁺ cells, while inflammatory CD14⁺⁺CD16⁺HLA-DR⁺ monocytes increased the expression of CD11a and CD11b integrins, CD49d activation markers, and the inflammatory receptor P2X7. Serum cytokine expression showed that liver fibrosis is associated with higher serum levels of IL-6, CXCL8, and CXCL9 compared to mild liver disease.

Conclusions

In conclusion, our findings demonstrated that Chronic HCV infection alters the frequency of peripheral inflammatory monocyte subsets, impacting cellular markers and activation in severe liver impairment (FIB-4 ≥ F2). Soluble biomarkers modulate pro-inflammatory monocyte phenotypes, linked to inflammation and fibrosis.

丙型肝炎是一个全球性的健康问题，全世界约有7100万人慢性感染。在慢性炎症过程中，炎症介质的表达升高似乎影响循环单核细胞的表型。我们的目的是研究巴西亚马逊地区慢性丙型肝炎患者外周血单核细胞亚群表型的变化以及与不同程度肝纤维化相关的循环介质的特征。材料和方法这是一项观察性研究，涉及30名接受DAAs治疗的个体和15名健康对照者，检测肝功能，纤维化评分（AST/血小板比率指数，FIB-4），基于CD14/CD16表达评估外周血单核细胞亚群百分比。可溶性免疫生物标志物分析采用流式细胞术方法。结果慢性HCV患者在纤维化评分高（FIB-4≥F2）的人群中血小板计数下降，病毒载量、ALT、AST、碱性磷酸酶升高。数据分析表明，CD14HighCD16−HLA-DR+细胞的频率较低，而炎症性CD14++CD16+HLA-DR+单核细胞增加了CD11a和CD11b整合素、CD49d激活标记物和炎症受体P2X7的表达。血清细胞因子表达显示，与轻度肝病相比，肝纤维化与较高的血清IL-6、CXCL8和CXCL9水平相关。结论：我们的研究结果表明，慢性HCV感染改变了外周炎症单核细胞亚群的频率，影响了严重肝损害患者的细胞标记物和激活（FIB-4≥F2）。可溶性生物标志物调节促炎单核细胞表型，与炎症和纤维化有关。

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引用次数: 0

SMAD signaling in cancer: integrative roles in tumor progression, immune evasion, and therapeutic resistance 肿瘤中的SMAD信号：肿瘤进展、免疫逃避和治疗抵抗的综合作用

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-12 DOI: 10.1016/j.cyto.2025.157090

Hai Zhao , Fan Yang , Jiaxin Yang , Sheng Yang

Transforming growth factor-beta (TGF-β)/SMAD signaling exerts pleiotropic effects in cancer, orchestrating epithelial–mesenchymal transition (EMT), immune evasion, stemness, and therapeutic resistance. While canonically regarded as tumor-suppressive, emerging data reposition SMAD proteins, particularly SMAD2, SMAD3, and SMAD4, as central effectors of pro-tumorigenic reprogramming in advanced malignancies. Here, we delineate the multifaceted contributions of SMAD signaling across tumor-intrinsic and microenvironmental contexts, highlighting post-translational regulation, immune remodeling, and crosstalk with non-coding RNAs. We show how SMADs mediate dynamic EMT programs, modulate innate and adaptive immune landscapes, and drive chemoresistance through transcriptional and metabolic rewiring. In the tumor microenvironment (TME), SMAD-driven axes involving macrophages, neutrophils, and CAFs reinforce immune suppression and metastasis. Moreover, engineering SMAD pathways in CAR-T and NK cells enhances immunotherapeutic efficacy. We also identify SMAD-based transcriptional and epigenetic signatures with prognostic and predictive utility across multiple tumor types. This integrative review provides a unified framework for understanding the SMAD signaling network as both a mechanistic driver and therapeutic vulnerability in cancer.

转化生长因子-β (TGF-β)/SMAD信号在癌症中发挥多效作用，协调上皮-间质转化（EMT）、免疫逃避、干性和治疗抗性。虽然通常被认为是肿瘤抑制，但新出现的数据重新定位SMAD蛋白，特别是SMAD2， SMAD3和SMAD4，作为晚期恶性肿瘤中致瘤性重编程的中心效应物。在这里，我们描述了SMAD信号在肿瘤内在和微环境背景下的多方面贡献，强调了翻译后调控、免疫重塑和与非编码rna的串扰。我们展示了smad如何介导动态EMT程序，调节先天和适应性免疫景观，并通过转录和代谢重新布线驱动化学耐药。在肿瘤微环境（TME）中，涉及巨噬细胞、中性粒细胞和CAFs的smad驱动轴加强了免疫抑制和转移。此外，在CAR-T和NK细胞中设计SMAD通路可以提高免疫治疗效果。我们还发现基于smad的转录和表观遗传特征在多种肿瘤类型中具有预后和预测效用。这一综合综述为理解SMAD信号网络作为癌症的机制驱动和治疗易感性提供了一个统一的框架。

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引用次数: 0

IL-35 alleviates ferroptosis in macrophage by activating the NRF2/GPX4 pathway to improve sepsis-induced ARDS IL-35通过激活NRF2/GPX4通路减轻巨噬细胞铁凋亡，改善败血症诱导的ARDS。

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-09 DOI: 10.1016/j.cyto.2025.157086

Panting Liu , Chen Zhang , Minkang Guo , Shanmu Ai , Yisi Zhao , Renjie Luo , Fang Xu , Zhengtao Zhang

Objective

Macrophage M1/M2 polarization is essential to mitigate acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Ferroptosis is pivotal in sepsis-induced ALI and interleukin (IL)-35 has been reported to exert anti-inflammatory effects. Therefore, we aimed to investigate the effect of IL-35 on ferroptosis and macrophage polarization in ARDS.

Methods

We constructed an in vitro inflammation model using lipopolysaccharide (LPS) to assess the macrophage polarization, ferroptosis, phagocytosis, and killing effects after IL-35 treatment. A cecal ligation and puncture model was established, and lung injury, ferroptosis, and macrophage polarization were detected following rIL-35 treatment. The indexes showed changes after the use of an NRF2 inhibitor. Additionally, we quantified the injury and apoptosis of MLE-12 cells after co-culture with RAW264.7 cells and detected IL-10 expression.

Results

IL-35 blocked LPS-induced polarization of RAW264.7 and bone marrow-derived macrophages to M1 and promoted M2 generation. It up-regulated the NRF2/GPX4 pathway and attenuated ferroptosis in macrophages. When NRF2 was inhibited, the regulatory effects of IL-35 on the macrophage phenotype and ferroptosis were reversed. After co-culture with IL-35-treated RAW264.7, the apoptosis of MLE-12 cells was reduced and IL-10 expression was increased.

Conclusion

IL-35 alleviates ALI by reducing macrophage ferroptosis and attenuating the activation of proinflammatory macrophages via the NRF2/GPX4 pathway. IL-35-induced macrophages phenotypic remodeling reduce the apoptosis of lung epithelial cells by secreting IL-10.

目的：巨噬细胞M1/M2极化对减轻急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）至关重要。铁下沉是脓毒症诱导的ALI的关键，白细胞介素(IL)-35已被报道具有抗炎作用。因此，我们旨在探讨IL-35在ARDS中对铁上吊和巨噬细胞极化的影响。方法：采用脂多糖（LPS）构建体外炎症模型，观察IL-35对巨噬细胞极化、铁凋亡、吞噬和杀伤作用的影响。建立盲肠结扎穿刺模型，观察il -35对大鼠肺损伤、铁下垂、巨噬细胞极化的影响。使用NRF2抑制剂后，各项指标均有变化。此外，我们量化MLE-12细胞与RAW264.7细胞共培养后的损伤和凋亡情况，并检测IL-10的表达。结果：IL-35阻断lps诱导的RAW264.7和骨髓源性巨噬细胞向M1极化，促进M2生成。上调NRF2/GPX4通路，减轻巨噬细胞铁下垂。当NRF2被抑制时，IL-35对巨噬细胞表型和铁下垂的调节作用被逆转。与il -35处理的RAW264.7共培养后，MLE-12细胞凋亡减少，IL-10表达增加。结论：IL-35可通过NRF2/GPX4通路减少巨噬细胞铁沉，减弱促炎巨噬细胞活化，从而减轻ALI。il -35诱导的巨噬细胞表型重塑通过分泌IL-10减少肺上皮细胞的凋亡。

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引用次数: 0

Macrophage USP14 suppresses Wnt/β-catenin signaling via NLK deubiquitination to enhance immune response 巨噬细胞USP14通过NLK去泛素化抑制Wnt/β-catenin信号，增强免疫应答

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-06 DOI: 10.1016/j.cyto.2025.157079

Mingming Zhao , Junjie Shi , Xinqi Wei , Wenze Tian , Yuee Chen

Macrophages are key immune cells that regulate the body's immune response by promoting the release of inflammatory cytokines upon recognition of both endogenous and exogenous pathogens. USP14, a critical deubiquitinase, plays a vital role in various cellular processes, especially in modulating immune responses. This study aims to investigate the role of USP14 in regulating macrophage immune responses. USP14 overexpression and knockdown were performed in RAW264.7 cells and mouse bone marrow macrophages via plasmid transfection and lentiviral infection, respectively. Our research demonstrates that USP14 overexpression amplified the LPS-induced inflammatory response and promoted macrophage migration, whereas USP14 knockdown produced the opposite effects. USP14 interacts with NLK, thereby attenuating Wnt/β-catenin signaling and concurrently activating the NF-κB pathway in macrophages. USP14 facilitates the deubiquitination of NLK, thereby stabilizing its activity. Moreover, the USP14 inhibitor IU1 reduces the LPS-induced inflammatory response in macrophages. Mechanistically, macrophage USP14 facilitates the deubiquitination of NLK, thereby maintaining its activity, inhibiting the Wnt/β-catenin pathway, activating the NF-κB pathway, and enhancing the cellular immune response.

巨噬细胞是调节机体免疫反应的关键免疫细胞，在识别内源性和外源性病原体时，通过促进炎症因子的释放来调节机体的免疫反应。USP14是一种关键的去泛素酶，在各种细胞过程中起着至关重要的作用，特别是在调节免疫反应中。本研究旨在探讨USP14在调节巨噬细胞免疫应答中的作用。通过质粒转染和慢病毒感染分别在RAW264.7细胞和小鼠骨髓巨噬细胞中过表达和敲低USP14。我们的研究表明，USP14过表达放大了lps诱导的炎症反应，促进了巨噬细胞的迁移，而USP14敲低则产生相反的效果。USP14与NLK相互作用，从而减弱巨噬细胞中Wnt/β-catenin信号通路，同时激活NF-κB通路。USP14促进NLK的去泛素化，从而稳定其活性。此外，USP14抑制剂IU1可降低lps诱导的巨噬细胞炎症反应。机制上，巨噬细胞USP14促进NLK去泛素化，从而维持其活性，抑制Wnt/β-catenin通路，激活NF-κB通路，增强细胞免疫应答。

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Systemic immune inflammation index, systemic inflammatory response index and pan-immune inflammation value in the prediction of idiopathic late-onset fetal growth restriction 全身性免疫炎症指数、全身性炎症反应指数和泛免疫炎症在预测特发性迟发性胎儿生长受限中的价值

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-12-05 DOI: 10.1016/j.cyto.2025.157081

Murat Levent Dereli , Sadun Sucu , Dilara Sarıkaya Kurt , Ahmet Kurt , Fahri Burçin Fıratlıgil , Tuğba Ağbal , Ali Turhan Çağlar

Background

Fetal growth restriction (FGR) is a major pregnancy complication associated with stillbirth, perinatal morbidity, mortality and long-term consequences for the offspring. Therefore, its prediction, early detection and appropriate follow-up are essential components of prenatal care. In most cases, also referred to as late-onset idiopathic FGR (IL-FGR), symptoms appear after 34 weeks and the underlying pathology is unclear. Our aim was to investigate the relationship between altered inflammation and pathogenesis using inflammatory indices calculated from the complete blood count.

Methods

We conducted a retrospective case-control study in a large tertiary hospital between 2022 and 2023. Data from all participants at the time of screening for fetal aneuploidy and structural anomalies at 11–14 weeks were retrospectively reviewed and compared.

Results

A total of 106 eligible participants with IL-FGR and 106 women who experienced a healthy prenatal and perinatal period were included. Neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), pan-immune inflammation value (PIV) and SIRI/body-mass index (BMI) were significantly higher in the IL-FGR group (p < 0.001 for all). SIRI/BMI with a cut-off value of >76.3 × 10³ × kg/μL × m² (64 % sensitivity, 80 % specificity) showed the best discriminatory performance for IL-FGR prediction. Correlation analysis of gestational age-adjusted parameters with these indices showed a negative correlation with birthweight, suggesting that higher values of the inflammatory indices at the 11–14-week aneuploidy screening are associated with a greater likelihood of severe IL-FGR.

Conclusions

Our results suggest an association between high SII, SIRI, PIV and SIRI/BMI and an increased risk of future IL-FGR. SIRI/BMI may be an important component of regression models that could be used in the future as a screening tool for predicting FGR. However, our results require further validation by future studies to confirm the specific clinical implications of these indices.

胎儿生长受限（FGR）是一种主要的妊娠并发症，与死产、围产期发病率、死亡率和后代的长期后果有关。因此，其预测，早期发现和适当的随访是产前护理的重要组成部分。在大多数病例中，也被称为迟发性特发性FGR (IL-FGR)，症状在34周后出现，潜在病理尚不清楚。我们的目的是通过全血细胞计数计算炎症指数来研究炎症改变与发病机制之间的关系。方法于2022 - 2023年在某大型三级医院进行回顾性病例对照研究。所有参与者在11-14周进行胎儿非整倍体和结构异常筛查时的数据进行回顾性回顾和比较。结果共纳入106名IL-FGR患者和106名产前和围产期健康的妇女。中性粒细胞与淋巴细胞比率（NLR）、全身免疫炎症指数（SII）、全身炎症反应指数（SIRI）、泛免疫炎症值（PIV）和SIRI/体重指数（BMI）在IL-FGR组均显著升高（p < 0.001）。SIRI/BMI的临界值为76.3 × 103 × kg/μL × m2（敏感性64%，特异性80%），对IL-FGR的预测具有最佳的鉴别效果。孕龄调整参数与这些指标的相关性分析显示，这些指标与出生体重呈负相关，表明在11 - 14周非整倍体筛查时，炎症指标越高，发生严重IL-FGR的可能性越大。结论高SII、SIRI、PIV和SIRI/BMI与未来IL-FGR风险增加有关。SIRI/BMI可能是回归模型的一个重要组成部分，可以作为未来预测FGR的筛选工具。然而，我们的结果需要通过未来的研究进一步验证，以确认这些指标的具体临床意义。

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