Cytokine最新文献

{"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":"2025-12-01","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":"Clinical value of serum TNF-α and IL-2R as treatment predictive and prognostic biomarkers in metastatic colorectal cancer","authors":"Jinxiu Tian ,&nbsp;Jinjia Chang ,&nbsp;Zhujun Chen ,&nbsp;Wenhua Li","doi":"10.1016/j.cyto.2025.157046","DOIUrl":"10.1016/j.cyto.2025.157046","url":null,"abstract":"<div><h3>Background</h3><div>Metastatic colorectal cancer remains a major global health concern, with advanced-stage disease posing significant challenges in terms of treatment and prognosis. Cytokines, key mediators of immune regulation and inflammation, have emerged as potential prognostic biomarkers in CRC. However, their prognostic value in the context of first-line standard therapy remains unclear.</div></div><div><h3>Methods</h3><div>This retrospective observational study included 95 patients with metastatic colorectal cancer who underwent first-line therapy at Fudan University Shanghai Cancer Center between 2020 and 2021. Baseline levels of TNF-α, IL-1β, IL-2R, IL-6, IL-8, and IL-10 before treatment were assessed, and patients were categorized into high and low cytokine expression groups. Survival outcomes were analyzed based on baseline cytokine levels and dynamic changes before and after treatment.</div></div><div><h3>Results</h3><div>Higher baseline levels of TNF-α and IL-2R were associated with poorer progression-free survival outcomes. Dynamic changes of TNF-α and IL-2R before and after treatment were also predictive of survival, with persistently elevated levels associated with worse outcomes. Additionally, clinical characteristics such as liver metastasis and surgical intervention were correlated with cytokine expression levels and survival outcomes.</div></div><div><h3>Conclusions</h3><div>Baseline cytokine levels of TNF-α and IL-2R and their dynamic changes before and after treatment are potential prognostic indicators in patients with metastatic colorectal cancer undergoing first-line standard therapy. Monitoring cytokine profiles may aid in risk stratification and treatment decision-making, ultimately improving patient outcomes.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157046"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249125","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":"Unveiling the role of trace elements in modulating inflammatory and oxidative pathways in CAG repeat–driven spinocerebellar ataxia","authors":"Surbhi Singh ,&nbsp;Deepika Joshi ,&nbsp;Abhay Kumar Yadav ,&nbsp;Shani Vishwakarma ,&nbsp;Janki Makani ,&nbsp;Janhavi Yadav ,&nbsp;Anil Kumar Maurya ,&nbsp;Gulabi Yadav ,&nbsp;Chandmayee Mohanty ,&nbsp;Anand Kumar ,&nbsp;Royana Singh","doi":"10.1016/j.cyto.2025.157050","DOIUrl":"10.1016/j.cyto.2025.157050","url":null,"abstract":"<div><div>Spinocerebellar ataxias are genetically inherited neurodegenerative disorders, primarily caused by CAG trinucleotide repeat expansions in genes. While these genetic mutations initiate disease onset, increasing evidence suggests that systemic factors, particularly trace element imbalance, oxidative stress, and immune dysregulation, play critical roles in disease progression. In this study, peripheral blood samples from genetically confirmed SCA patients (<em>n</em> = 15) and age- and sex-matched healthy controls (<em>n</em> = 18) were analyzed. Atomic Absorption Spectroscopy revealed significant alterations in plasma concentrations of both essential and toxic trace elements, suggesting their involvement in neurotoxicity, redox imbalance, and inflammation. To explore these links, oxidative stress markers, including malondialdehyde, superoxide dismutase, and glutathione peroxidase, as well as cytokines such as interleukin-6, interleukin-4, and interleukin-10, were quantified using ELISA. Receiver operating characteristic analysis demonstrated high diagnostic accuracy of these markers, particularly GPx and IL-10. A strong interconnection was observed among trace element dysregulation, oxidative stress, and inflammatory responses, indicating a synergistic role in exacerbating neurodegeneration. Molecular docking revealed that abnormal trace element levels may impair antioxidant enzyme function by disrupting metal-binding interactions, offering mechanistic insight into enzymatic dysfunction. Bioinformatics analyses, including functional enrichment and protein–protein interaction mapping, identified significant associations with mitochondrial dysfunction, reactive oxygen species metabolism, and cytokine signaling pathways. These findings suggest that SCA pathogenesis is not driven by genetic mutation alone. The combined effects of trace element imbalance, oxidative stress, and inflammation contribute to a complex pathogenic network, reinforcing the importance of targeting both genetic and systemic factors in therapeutic strategies.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157050"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278592","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":"Long non-coding RNA MEG3 rs7158663 polymorphism confers susceptibility to the development of sepsis and is associated with sepsis-induced inflammatory responses","authors":"Xiemuziya Maimaitirexiati ,&nbsp;Minxin Wang ,&nbsp;Huijing Zhao","doi":"10.1016/j.cyto.2025.157019","DOIUrl":"10.1016/j.cyto.2025.157019","url":null,"abstract":"<div><h3>Background</h3><div>The polymorphism of long non-coding RNA (lncRNA) can influence the susceptibility of patients to certain diseases.</div></div><div><h3>Objectives</h3><div>This study compared the genotype distribution of lncRNA MEG3 rs7158663 polymorphism in sepsis patients and controls. Furthermore, it elaborated on the relationship between rs7158663 and prognosis as well as the inflammatory response of the patients.</div></div><div><h3>Materials and methods</h3><div>350 sepsis patients and 320 controls were incorporated to conduct genotyping of the rs7158663 locus and to measure the serum MEG3 levels. The connection between genotypes and prognosis was appraised via the construction of K-M curves. The levels of serum inflammatory factors were measured with ELISA.</div></div><div><h3>Results</h3><div>Rs7158663 GG genotype occurred more frequently in sepsis patients than the control group, whereas the frequencies of the GA and AA genotypes were lower in the former. MEG3 rs7158663 GA and AA genotypes were non-susceptible genotypes for sepsis, and a similar genetic association was observed in the dominant model. Stratified analysis indicated that the genetic association between rs7158663 and sepsis was more significant in cases with non-smoking, non-drinking, older age, and low BMI. MEG3 rs7158663 GG genotype carriers had increased MEG3, excessive release of inflammatory factors, and poor prognosis in patients with sepsis.</div></div><div><h3>Conclusion</h3><div>MEG3 rs7158663 GG genotype may be a susceptibility genotype for sepsis and is associated with patients' poor prognosis. It might be related to rs7158663-mediated increase of MEG3 expression and excessive release of inflammatory cytokines.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157019"},"PeriodicalIF":3.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912522","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":"Differential chemokine profiles between lacrimal and salivary glands in a murine model of primary Sjögren disease","authors":"Ruka Nagao ,&nbsp;Kunihiro Otsuka ,&nbsp;Shigefumi Matsuzawa ,&nbsp;Aya Ushio ,&nbsp;Takaaki Tsunematsu ,&nbsp;Naozumi Ishimaru","doi":"10.1016/j.cyto.2025.157023","DOIUrl":"10.1016/j.cyto.2025.157023","url":null,"abstract":"<div><h3>Background</h3><div>Primary Sjögren disease (pSjD) is an autoimmune disorder that primarily targets the lacrimal glands (LGs) and salivary glands (SGs). However, the differences in immune pathogenesis between LGs and SGs remain poorly understood. In this study, we investigated LG-specific immune responses in comparison to SGs using a murine model of pSjD. Histopathological analyses of LGs and SGs were conducted in control and pSjD model mice.</div></div><div><h3>Methods</h3><div>The mRNA expression levels of 18 chemokines associated with T-cell migration were evaluated by quantitative PCR. Gene expression of selected chemokines was further examined in LG tissues by <em>in situ</em> hybridization. The phenotype and function of T-cells were assessed using flow cytometry and <em>in vitro</em> migration assays.</div></div><div><h3>Results</h3><div>Lymphocytic infiltration was observed earlier in LGs than in SGs in pSjD model mice. Among the chemokines analyzed, C-X-C motif chemokine ligand 4 (CXCL4) was specifically upregulated in LGs. <em>Cxcl4</em> expression was localized to macrophages within LG tissues. Moreover, CXCR3 expression on CD4⁺ T-cells in lymphoid tissues was significantly higher in pSjD model mice compared to controls. T-bet was more highly expressed in CXCR3⁺CD4⁺ T cells than in CXCR3⁻CD4⁺ T cells in pSjD model mice. Finally, CXCL4 enhanced the migration of CD4⁺ T cells derived from pSjD model mice more effectively than those from control mice.</div></div><div><h3>Conclusions</h3><div>These findings suggest that CXCL4-producing macrophages may promote the recruitment of CXCR3⁺ Th1 cells into the LGs in pSjD, thereby contributing to LG-specific autoimmune inflammation. This mechanism may represent a potential therapeutic target for managing dry eye in pSjD.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157023"},"PeriodicalIF":3.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912757","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":"Delving deeper in the eye of the hurricane: Immunopathogenesis & molecular characterization of cytokine storm in COVID-19, association with disease severity & the therapeutic regimens","authors":"Umaiya Muzaffar ,&nbsp;Kamal Shaik Fakiruddin ,&nbsp;Yasaman Talebiashtiany ,&nbsp;Syahril Abdullah","doi":"10.1016/j.cyto.2025.157025","DOIUrl":"10.1016/j.cyto.2025.157025","url":null,"abstract":"<div><div>The COVID-19 pandemic elicited by SARS-CoV-2 has led to a world-wide crisis, affecting a substantial percentage of the entire global population, and has engendered profound morbidity and fatalities. SARS-CoV-2 mediates its entry into human respiratory epithelial cells via interaction between viral Spike protein (S) and ACE2 receptor and enacts the host cell tropism by numerous molecular factors and inflammatory signaling pathways. The complex molecular immunopathogenesis involves loss of regulatory control of the generation &amp; release of proinflammatory cytokines at both local as well as systemic levels. Excessive secretion of pro-inflammatory cytokines and chemokines leads to the dysregulation of the innate immune system leading to the cytokine storm. Owing to the enormous release of inflammatory factors and active mediators, cytokine storm induces severe damage to secondary tissues, leading to Acute Respiratory Distress Syndrome (ARDS) or multiple-organ failure, which evokes aggravation of the disease and eventually death. Comparisons amid COVID-19 cytokine storm and several other types of cytokine storm associated diseases, gives proper insights about the etiology of cytokine storm in COVID-19. Various genetic and physiological factors contribute to severe disease progression and aggravation of the disease. In that view, several immunoregulatory therapies have been tailored to curb the cytokine storm, which might be crucial in improving the success rates of various treatment strategies as well as in lowering the mortality rate in COVID-19 patients. This review elucidates the hallmarks of COVID-19 cytokine storm, immunopathogenesis, disease progression, biomarkers, and therapeutic interventions.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157025"},"PeriodicalIF":3.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045070","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":"2025-11-01","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}

{"title":"Inactivation of LHAVglut2 neurons relieves stress-induced intestine inflammation by sympathetic nerve- intestinal epithelial cell Cxcl1 communication","authors":"Keyi Liu ,&nbsp;Xinyan Tan ,&nbsp;Lianguo Fu ,&nbsp;Fengfeng Mo","doi":"10.1016/j.cyto.2025.157024","DOIUrl":"10.1016/j.cyto.2025.157024","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to elucidate the role of lateral hypothalamic area (LHA) Vglut2 neurons in stress-induced intestinal inflammation and to investigate the underlying mechanisms involving neuro-immune interactions. Specifically, we hypothesized that LHA Vglut2 neuron activation exacerbates intestinal inflammation via sympathetic-driven IL-1β and Cxcl1 signaling.</div></div><div><h3>Methods</h3><div>Transgenic mice (Vglut2-cre) and wild-type controls were subjected to chronic restraint stress (CRS). Chemogenetic silencing of LHA Vglut2 neurons was achieved using hM4Di DREADD receptors. Techniques included qPCR, RNA sequencing, pseudorabies virus (PRV) retrograde tracing, immunofluorescence, and histopathology. Sympathetic ablation (6-OHDA) and vagotomy were performed to dissect neural pathways.</div></div><div><h3>Results</h3><div>CRS upregulated IL-1β and Cxcl1 in the gut, increased c-Fos expression in LHA neurons, and impaired intestinal barrier integrity (reduced ZO-1/Occludin, elevated MUC2). Silencing LHA Vglut2 neurons reversed these effects, reducing inflammation and restoring barrier proteins. RNA sequencing revealed IL-1β-Cxcl1 as a key pathway. Sympathetic ablation mirrored these improvements, while vagotomy showed no effect, indicating a predominant sympathetic-mediated mechanism.</div></div><div><h3>Conclusion</h3><div>LHA Vglut2 neurons drive stress-induced intestinal inflammation via sympathetic activation of the IL-1β-Cxcl1 axis. Targeting this hypothalamic-sympathetic circuit may offer therapeutic potential for stress-related gastrointestinal disorders.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157024"},"PeriodicalIF":3.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932740","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":"Aspergillus fumigatus and Mycobacterium tuberculosis synergistically induce TNF and IL-1β via different pathways in human peripheral blood mononuclear cells","authors":"Intan M.W. Dewi ,&nbsp;Mariolina Bruno ,&nbsp;Nico A.F. Janssen ,&nbsp;Mark S. Gresnigt ,&nbsp;Arjan van Laarhoven ,&nbsp;Reinout van Crevel ,&nbsp;Frank L. van de Veerdonk","doi":"10.1016/j.cyto.2025.157018","DOIUrl":"10.1016/j.cyto.2025.157018","url":null,"abstract":"<div><div><em>Aspergillus fumigatus</em> may cause infections in individuals with underlying lung damage, such as those with pulmonary tuberculosis (TB). Simultaneous exposure to <em>A. fumigatus</em> and <em>Mycobacterium tuberculosis</em> may worsen lung tissue damage, but the combined immune response to these pathogens has not yet been fully characterized.</div><div>Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with <em>A. fumigatus</em> conidia, <em>M. tuberculosis</em> H37Rv lysate, or both combined. TNF and IL-1β were measured from culture supernatants. The role of different pattern recognition receptors (PRRs) important for the recognition of both pathogens were explored by using PRR inhibitors and PBMCs from donors deficient in certain pathways.</div><div><em>A. fumigatus</em> and <em>M. tuberculosis</em> synergistically induced TNF and IL-1β release by PBMCs, and this response was independent of TLR2 and dectin-1. We found that the synergy is regulated through distinct intracellular pathways. The activation of the intracellular receptor NOD2 by <em>M. tuberculosis</em> and NADPH oxidase complex-dependent ROS production triggered by <em>A. fumigatus</em> mediate TNF but not IL-1β synergy.</div><div>Together, these findings indicate that <em>A. fumigatus</em> and <em>M. tuberculosis</em> jointly exacerbate proinflammatory responses. This may help to explain the persistent inflammation and immunopathology observed in patients with concurrent TB and aspergillosis.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157018"},"PeriodicalIF":3.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890853","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":"Global transcriptomic profiling reveals nicotinamide metabolism as a key regulator of nitric oxide-modulated interferon-γ responses in macrophages","authors":"Avik Chattopadhyay ,&nbsp;Sai Shyam ,&nbsp;Shreyasee Das ,&nbsp;Dipankar Nandi","doi":"10.1016/j.cyto.2025.157015","DOIUrl":"10.1016/j.cyto.2025.157015","url":null,"abstract":"<div><div>Interferon-gamma (IFN-γ) is a key regulator of immune responses. A hallmark of IFN-γ responses is inducible nitric oxide (NO), driven primarily by nitric oxide synthase (NOS)2. In this study, we investigated the influence of NO on the IFN-γ-induced transcriptomic and metabolic changes in the RAW 264.7 macrophage cell line. IFN-γ activation led to NO-dependent lactate production and lower cell survival. Bulk RNA sequencing analysis identified genes differentially expressed early by IFN-γ that were either NO-independent or NO-dependent. Inhibition of NO modulated a minor subset of the transcriptome, notably affecting <em>Klf6</em> (a tumor suppressor) and <em>Zfp36</em> (a regulator of pro-inflammatory cytokines). Interestingly, both <em>Klf6</em> and <em>Zfp36</em> correlatively showed high expression in most cancers. The protein-protein interaction (PPI) network exhibited dense clustering with scale-free and small-world properties, identifying <em>Stat1</em>, <em>Irf7</em>, <em>Irf1</em>, <em>Cxcl10</em>, and <em>Isg15</em> as top five hubs. Interestingly, the RNA seq analysis identified IFN-γ upregulated genes, <em>Nampt, Pnp</em> and <em>Pnp2</em>, to be involved in nicotinamide metabolism. This novel aspect was experimentally tested to show that IFN-γ induced NAD⁺ amounts in a NO-dependent manner. Importantly, the inhibition of purine nucleoside phosphorylase (PNP) which is involved in the endogenous pathway for NAD⁺ generation, lowered IFN-γ-induced nitrite and increased cell survival, demonstrating biological relevance of this study. Interestingly, <em>NAMPT</em> and <em>PNP</em> are expressed in multiple organs in humans and Epstein Barr Virus (EBV)-transformed lymphocytes. In addition, polymorphisms in <em>NAMPT</em> and <em>PNP</em> are associated with several diseases. Functionally, enriched nicotinamide metabolism by IFN-γ may regulate inflammatory responses and the implications of our findings are discussed.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157015"},"PeriodicalIF":3.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912430","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}