Cytokine最新文献

{"title":"Cardiotrophin-1 as a predictor of critical COVID-19, mortality, and persistence of pulmonary fibrosis after the acute phase of infection","authors":"María Íñiguez ,&nbsp;Patricia Pérez-Matute ,&nbsp;Pablo Villoslada-Blanco ,&nbsp;Emma Recio-Fernandez ,&nbsp;Diana Ezquerro-Pérez ,&nbsp;Jorge Alba ,&nbsp;Concepción García-García ,&nbsp;Galadriel Pellejero ,&nbsp;M. Lourdes Ferreira-Laso ,&nbsp;Dolores del Puerto García ,&nbsp;Carlos Ruiz-Martínez ,&nbsp;José A. Oteo","doi":"10.1016/j.cyto.2025.157037","DOIUrl":"10.1016/j.cyto.2025.157037","url":null,"abstract":"<div><div>Pulmonary fibrosis remains a long-term complication in some COVID-19 recovered patients, particularly in those who suffered from severe disease. Cardiotrophin-1 (CT-1) is an antiapoptotic cytokine related with the progression of fibrotic disease in heart and kidney. This study examines the association between CT-1 plasma levels, COVID-19 severity, and post-COVID pulmonary fibrosis. CT-1 levels were analyzed in patients with asymptomatic/mild (<em>n</em> = 33), severe (<em>n</em> = 39), and critical (<em>n</em> = 57) COVID-19, as well as in those with post-COVID pulmonary fibrosis. Elevated CT-1 levels were associated with a higher risk of severe disease, mortality, and persistent pulmonary fibrosis even a year after discharge. Furthermore, CT-1 was associated with non-COVID-19-related pulmonary fibrosis, suggesting a broader role of this cytokine in chronic lung diseases. These findings propose CT-1 as a potential biomarker and therapeutic target for pulmonary fibrosis and provide new insights for its role in chronic respiratory conditions, such as idiopathic pulmonary fibrosis (IPF), post-COVID interstitial lung disease or chronic hypersensitivity pneumonitis.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157037"},"PeriodicalIF":3.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T1-mapping quantitative assessment of renal function and changes in serum cytokine levels after renal transplantation in children","authors":"XueyingWang ,&nbsp;Jun Hu","doi":"10.1016/j.cyto.2025.157027","DOIUrl":"10.1016/j.cyto.2025.157027","url":null,"abstract":"<div><div>Background: Postoperative renal function assessment in pediatric kidney transplant recipients faces the challenge of insufficient sensitivity of traditional indicators. T1-mapping, a non-invasive imaging technique, can quantify changes in the microscopic structure of renal tissue. However, its application in the pediatric population and its relationship with serum cytokines remain unclear. This study hypothesized that T1-mapping can quantitatively assess early renal microstructural damage in pediatric kidney transplant recipients and that T1 values correlate with the activation of immune-inflammatory responses (reflected by serum cytokine levels). It aimed to explore the value of T1-mapping in evaluating renal function and its mechanistic association with inflammatory responses.</div><div>Materials and Methods: A total of 31 pediatric kidney transplant recipients (observation group, Obs group) and 31 healthy children (control group, Ctrl group) were enrolled. In the Obs group, T1-mapping was performed at 1, 3, and 6 months post-transplantation to measure T1 values in the renal cortex, medulla, and whole kidney. Serum creatinine (SCr), glomerular filtration rate (GFR), and other renal function indicators were assessed, along with CD4+, CD8+ lymphocyte counts, and levels of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Based on the 6-month postoperative prognosis, participants were divided into the good prognosis group (GPG, <em>n</em> = 20) and poor prognosis group (PPG, <em>n</em> = 11).</div><div>Results: The T1 values of the renal cortex, medulla, and whole kidney in the Obs group were significantly higher than those in the Ctrl group (<em>P</em> &lt; 0.05). Specifically, the cortical T1 value in the PPG was (1820 ± 110) ms, significantly higher than that in the GPG (1650 ± 80) ms (<em>P</em> &lt; 0.05). The SCr in the PPG was (220 ± 35) μmol/L, and the GFR was (22 ± 5) mL/min/1.73m², both significantly worse than the GPG (85 ± 12 μmol/L, 78 ± 10 mL/min/1.73m², <em>P</em> &lt; 0.05). The CD4+/CD8+ ratio in the GPG (1.49 ± 0.21) was higher than that in the PPG (0.87 ± 0.15), while the CD8+ cell count (550 ± 60 × 10⁶/L) in the GPG was lower than that in the PPG (780 ± 75 × 10⁶/L, <em>P</em> &lt; 0.05). Levels of IL-6 (28.8 ± 6.5 pg/mL) and TNF-α (45.5 ± 8.3 pg/mL) in the PPG were significantly higher than those in the GPG (12.5 ± 3.0 pg/mL, 18.2 ± 4.1 pg/mL, <em>P</em> &lt; 0.05).</div><div>Conclusion: T1-mapping technology can quantitatively assess changes in renal function following pediatric kidney transplantation, with increased T1 values closely associated with immune-inflammatory activation and renal function damage. Serum cytokine levels reflect the intensity of the inflammatory response, providing new evidence for postoperative monitoring and intervention.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157027"},"PeriodicalIF":3.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145107834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon tau in ruminant reproduction: Mechanisms of maternal recognition of pregnancy and implications for fertility enhancement","authors":"Iqra Batool ,&nbsp;Rehana Kausar ,&nbsp;Muhammad Shahbaz Qamar","doi":"10.1016/j.cyto.2025.157035","DOIUrl":"10.1016/j.cyto.2025.157035","url":null,"abstract":"<div><div>Low conception rates and early embryonic loss remain major constraints to reproductive efficiency in ruminants, particularly during the peri-implantation period. Maternal recognition of pregnancy (MRP) is largely mediated by interferon tau (IFNT), a ruminant-specific type I interferon secreted by the elongating conceptus. Initially recognized for its anti-luteolytic action through suppression of endometrial prostaglandin F2α, (PGF2α). IFNT is now known to exert systemic effects beyond the uterus. It induces interferon-stimulated genes in endometrial and peripheral immune cells, shaping an immune environment conducive to embryo tolerance. By modulating nuclear factor kappa B, signal transducer and activator of transcription 1, and interferon regulatory factors, IFNT downregulates pro-inflammatory cytokines such as tumor necrosis factor alpha and interferon gamma, while enhancing anti-inflammatory mediators including interleukin-10 and interleukin-4. This shift promotes a T-helper 2-dominant immune profile favorable for maternal–fetal tolerance. In addition, IFNT safeguards corpus luteum function by mitigating PGF2α-induced luteolysis and preserving vascular integrity. This occurs through downregulation of pro-regression genes such as transforming growth factor beta 1, endothelin 1, thrombospondin 1/2, and serpin family E member 1, alongside upregulation of angiogenic mediators such as platelet-derived growth factor subunit B. These actions stabilize the luteal microenvironment and ensure sustained progesterone secretion. This review highlights IFNT's pivotal role in MRP, emphasizing its endocrine and paracrine actions on luteal maintenance, ISG induction, and immune modulation. It also explores IFNT's potential as a biomarker for early pregnancy detection and its applications in reproductive biotechnology, with bovine data supported by ovine, murine, and human models for translational insights.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157035"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuregulin 4 attenuates osteoarthritis by decreasing macrophage M1 polarization through PI3K/AKT signaling","authors":"Chao Wang ,&nbsp;Jinjian Zheng ,&nbsp;Chengxin Li ,&nbsp;Puyi Sheng ,&nbsp;Linli Zheng","doi":"10.1016/j.cyto.2025.157036","DOIUrl":"10.1016/j.cyto.2025.157036","url":null,"abstract":"<div><div>Altered polarization of synovial macrophages has been identified as a key pathogenic factor in sustaining synovial inflammation and driving osteoarthritis(OA) progression.Neuregulin 4 (Nrg4) is widely involved in inflammatory diseases, such as hepatic inflammation, Crohn's disease, and atherosclerosis.In this study, we aimed to investigate the effects of Nrg4 on macrophages and synovitis and to elucidate the underlying mechanisms in the development of OA.We first evaluated the expression of Nrg4 and ErbB4 in OA patients and mouse model. The adeno-associated virus 5 vector carrying the Nrg4 gene (AAV5-Nrg4) was injected into the knee joints to overexpress Nrg4 in two OA models.In vitro, RAW264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs) were cultured, induced to M1 macrophages, and then treated with Nrg4. RNA interference (RNAi) technique was used to inhibit the expression of the Nrg4 receptor ErbB4.The results demonstrated that Nrg4-ErbB4 signaling was decreased during OA. In vitro experiments showed that Nrg4 treatment significantly inhibited the M1 polarization of RAW264.7 cells and BMDMs and down-regulated the expression of pro-inflammatory genes.RNA sequencing (RNA-seq) analysis and related experiments revealed that Nrg4 regulated macrophage polarization mainly by inhibiting the PI3K/AKT signaling pathway.Intra-articular injection of AAV5-Nrg4 effectively alleviated joint damage and synovitis in collagenase-induced OA (CIOA) and destabilization of the medial meniscus(DMM)-induced OA models.</div><div>Nrg4-mediated suppression of M1 macrophage polarization in vivo was evidenced by attenuated iNOS concomitant with upregulated CD206 expression.In conclusion, our findings demonstrated that targeting Nrg4-ErbB4 axis may be a promising way to treat OA by reducing M1 macrophage polarization in synovial tissues.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157036"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual role of IL-2 in systemic lupus erythematosus: balancing pro-inflammatory and anti-inflammatory effects","authors":"Hao Li ,&nbsp;Xiang Lin ,&nbsp;Jing He","doi":"10.1016/j.cyto.2025.157032","DOIUrl":"10.1016/j.cyto.2025.157032","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by chronic inflammation and immune dysregulation. Interleukin-2 (IL-2), a central cytokine in T-cell biology, plays a paradoxical role in SLE pathogenesis. On one hand, it promotes effector T cell and natural killer (NK) cell activity, thereby amplifying inflammation; on the other, it supports the expansion and function of regulatory T cells (Tregs), which are essential for maintaining immune tolerance. This dual functionality makes IL-2 a driver of autoimmunity and a potential immunotherapeutic target. This review outlines the molecular mechanisms underlying IL-2's pro- and anti-inflammatory roles in SLE, highlights the regulatory factors that shape its functional balance, such as receptor affinity, dosing, exposure duration, and the immune microenvironment, and discusses recent progress in low-dose IL-2therapy and engineered IL-2 variants. A comprehensive understanding of IL-2 signaling dynamics is essential for the designing development of precision therapies designed to restore immune homeostasis in SLE.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157032"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the mechanisms underpinning interleukin-15Rα-mediated protection against sepsis and candidiasis","authors":"Jin Yang ,&nbsp;Banglao Xu ,&nbsp;Ju Cao ,&nbsp;Yuhan Liu ,&nbsp;Ling Tang ,&nbsp;Ping Zhao ,&nbsp;Sen Li ,&nbsp;Xin Li ,&nbsp;Jiayu Liu ,&nbsp;Renlin Yu ,&nbsp;Yin Tang ,&nbsp;Wang Tan ,&nbsp;Hao Ding ,&nbsp;Jin Li ,&nbsp;Yao Liu","doi":"10.1016/j.cyto.2025.157026","DOIUrl":"10.1016/j.cyto.2025.157026","url":null,"abstract":"<div><div>The interleukin (IL)-15Rα receptor has crucial, protective roles in sepsis and candidiasis via binding to its ligand, IL-15. However, the underlying mechanisms remain largely unexplored. In our study, we first confirmed the protective effects of IL-15 using clinical samples from patients with sepsis and candidiasis, and also in animal models with those conditions. We therapeutically administered IL-15 to IL-15Rα-deficient mice to elucidate the roles of IL-15Rα in sepsis and candidiasis treatment. Bacterial and fungal infections expedite mortality, caused organ damage, elevated the microbial burden in organs, and impaired macrophage recruitment, and subsequent microbial killing capacity. Notably, these adverse effects were alleviated via recombinant IL-15 supplementation, but this did not improve compromised conditions in IL-15Rα-deficient mice with sepsis. We show that IL-15Rα is required for protection against both bacterial and fungal sepsis, suggesting that this receptor could become a potential target for treating clinical sepsis and may hold significant clinical therapeutic value.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157026"},"PeriodicalIF":3.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationalized combinatorial targeting of immune co-receptors leads to tumor regression","authors":"Saleha Nisar ,&nbsp;Prashant Chauhan ,&nbsp;Ashok Patidar ,&nbsp;Neelam Bodhale ,&nbsp;Uddipan Sarma ,&nbsp;Kalpana Pai ,&nbsp;Bhaskar Saha","doi":"10.1016/j.cyto.2025.157030","DOIUrl":"10.1016/j.cyto.2025.157030","url":null,"abstract":"<div><div>Different co-stimulatory and co-inhibitory molecules influence the dynamicity of an immune response. As their expression levels may collectively decide the amplitude and quality of an anti-tumor immune response, we proposed that the expression of these molecules would be dynamically modulated during a progressive tumor growth and that the study of their expression levels would guide fixing a combinatorial target for anti-tumor immunotherapy. Based on the kinetics of expression of 33 immune molecules within the tumor and draining lymph nodes during RM-1-induced progressive prostate tumor model in C57BL/6 mice, a three-phase combinatorial anti-tumor immunotherapy was designed. Phase- specific treatments with combinations of blocking antibodies against co-inhibitory receptors and agonistic antibodies against stimulatory receptors resulted in significant tumor regression and cytokines' expression, suggesting a strategic personalized anti-tumor immunotherapy with enhanced therapeutic efficacy, reduced toxicity and the risk of treatment failures.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157030"},"PeriodicalIF":3.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-33 links inflammation and bone remodeling in experimental spondyloarthritis and human joint biopsies","authors":"Susana Aideé González-Chávez ,&nbsp;Mario Loya-Rivera ,&nbsp;Soumya Nair ,&nbsp;Rodrigo Prieto-Carrasco ,&nbsp;Eduardo Chaparro-Barrera ,&nbsp;Daniel Alberto Ruizesparza-Hinojos ,&nbsp;Sourav Roy ,&nbsp;César Pacheco-Tena","doi":"10.1016/j.cyto.2025.157031","DOIUrl":"10.1016/j.cyto.2025.157031","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the pathogenic role of IL-33 in spondyloarthritis (SpA) by analyzing its expression in both murine and human joint tissues and functionally assessing its impact on fibroblasts. The study evaluated synovial and entheseal biopsies from patients with SpA to explore the potential contribution of IL-33 to joint inflammation and tissue remodeling.</div></div><div><h3>Methods</h3><div>A spontaneous arthritis model (SpAD) in DBA/1 mice was used to assess IL-33 expression via histology, immunohistochemistry, transcriptomics, RT-qPCR, and western blot. Sacroiliac and tarsal biopsies from patients with SpA were also analyzed. Differential gene expression was checked, and pathway enrichment was performed using Ingenuity Pathway Analysis. Primary fibroblasts were isolated from the joints of the mice's front and rear limbs, transfected with siRNA targeting <em>Il33</em>, and evaluated by RT-qPCR and western blot for inflammatory (<em>Tnf</em>, <em>Nfkb</em>) and osteogenic (<em>Wnt2</em>, <em>Bmp2</em>) markers. Cell viability was assessed via MTT assay.</div></div><div><h3>Results</h3><div>IL-33 expression was elevated in murine and human SpA joints, with strong cartilage and subchondral bone localization. Transcriptomic data indicated upregulation of IL-33 signaling and enrichment of proinflammatory and fibrotic pathways. Silencing of <em>Il33</em> in fibroblasts significantly reduced IL-33 protein levels and decreased <em>Tnf</em> and <em>Wnt2</em> expression at both mRNA and protein levels, while <em>Bmp2</em> reduction was observed only at the transcript level.</div></div><div><h3>Conclusion</h3><div>IL-33 contributes to joint inflammation and may regulate osteogenic pathways implicated in pathological bone formation. These findings support IL-33 as a potential dual-action therapeutic target in SpA.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157031"},"PeriodicalIF":3.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically predicted plasma metabolites mediate the causal role of immune cells in atrial fibrillation","authors":"Yichao Yu ,&nbsp;Korff Krause ,&nbsp;Stefan Zarsteck ,&nbsp;Kejiang Cao ,&nbsp;Shan Lu ,&nbsp;Yun Liu ,&nbsp;Jian Zhang","doi":"10.1016/j.cyto.2025.157028","DOIUrl":"10.1016/j.cyto.2025.157028","url":null,"abstract":"<div><h3>Objective</h3><div>Determining and measuring the possible mediating function of plasma metabolites in the causative link between immunophenotype and atrial fibrillation (AF).</div></div><div><h3>Methods</h3><div>A bi-directional two-sample Mendelian randomization (MR) analysis of 731 immune cell phenotypes and atrial fibrillation was conducted using summary-level data from a genome-wide association study (GWAS). Subsequent investigations centered on examining 1400 plasma metabolites for potential mediating roles in immune cell-induced atrial fibrillation using two-step MR.</div></div><div><h3>Results</h3><div>After screening 29 immune cells linked to AF risk, this study found that 15 of them were linked to an increased risk of AF and 14 to a lower risk. Furthermore, a possible causal link between 22 plasma metabolites and atrial fibrillation was found. Five immune cell-metabolite matches were ultimately shown to have mediating functions in the pathology of atrial fibrillation. Of the five final sets of data, one group showed a partial mediation effect, two metabolites and one metabolite ratio showed suppression effects of moderating the process of immune cell-caused atrial fibrillation.</div></div><div><h3>Conclusion</h3><div>The results point to a potential major role for immune cells and plasma metabolites in the initiation and progression of AF. For the purpose of preventing and treating AF, these findings could offer novel biomarkers or therapeutic targets in the unclarified pathogenesis of atrial fibrillation, particularly for immune-related pathways.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157028"},"PeriodicalIF":3.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental and computational studies of IL-6 signaling in endothelial cells under hypoxia serum starvation conditions","authors":"Min Song ,&nbsp;Youli Wang ,&nbsp;Brian H. Annex ,&nbsp;Aleksander S. Popel","doi":"10.1016/j.cyto.2025.157029","DOIUrl":"10.1016/j.cyto.2025.157029","url":null,"abstract":"<div><div>Many diseases associated with angiogenesis involve inflammatory cytokine mediated responses. Targeting angiogenesis as a predominant strategy has shown limited effects in many contexts including peripheral arterial disease (PAD). One potential reason for the unsuccessful outcome is the interdependence between inflammation and angiogenesis. Inflammation-based therapies primarily target inflammatory cytokines such as interleukin-6 (IL-6) in T cells, macrophages, cancer cells, muscle cells. However, the mechanism of how these cytokines act on endothelial cells under PAD-specific hypoxia serum starvation (HSS) conditions are not well understood. Thus, we focus on one of the major inflammatory cytokines, IL-6, mediated intracellular signaling in endothelial cells under HSS conditions by conducting relevant in vitro experiments on human umbilical vein endothelial cells (HUVECs) and developing an experimentally validated computational model. Our model quantitatively characterized the effects of IL-6 classic and trans-signaling in activating the signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling to phosphorylate STAT3, extracellular regulated kinase (ERK) and Akt, respectively in endothelial cells under HSS condition. The trained and validated experiment-based computational model was used to characterize the dynamics of phosphorylated STAT3 (pSTAT3), Akt (pAkt), and ERK (pERK) in response to IL-6 classic and/or trans-signaling under HSS conditions. The model predicts that IL-6 classic and trans-signaling induced responses are dose dependent. In addition, IL-6 trans-signaling induces greater downstream signaling responses compared to classic signaling and plays a dominant role in the overall effects due to a tighter binding of the ligand and receptors and an abundant supply of soluble receptor sIL-6R because of the experimental setting. Moreover, our model identifies the species and kinetic parameters that specifically have a significant impact on the phosphorylation of STAT3, Akt, and ERK, which represent potential targets for the inflammatory cytokine mediated signaling and angiogenesis-based therapies under HSS conditions. Overall, the model predicts the effects of IL-6 classic and/or trans-signaling stimulation under HSS condition quantitatively and provides a framework for analyzing and integrating experimental data. More broadly, this model can be applied to identify potential targets that influence inflammatory cytokine mediated signaling in endothelial cells under HSS conditions and to investigate the effects of angiogenesis- and inflammation-based therapies specific to PAD.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157029"},"PeriodicalIF":3.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}