Cytokine最新文献

{"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}

{"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":"2025-09-12","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":"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":"2025-09-03","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":"Genetic evidence for a causal relationship between oral bacterial taxa and asthma in east Asian population","authors":"Wenyan Wei ,&nbsp;Zejing Qiu ,&nbsp;Lu Xiao ,&nbsp;Yanlin Huang ,&nbsp;Min Chen","doi":"10.1016/j.cyto.2025.157021","DOIUrl":"10.1016/j.cyto.2025.157021","url":null,"abstract":"<div><h3>Background</h3><div>Emerging evidence highlights the significant role of microbiota (lung and gut) in the development of asthma. However, the potential effect between oral microbiota and asthma remains poorly understood.</div></div><div><h3>Methods</h3><div>This study performed a bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of oral microbiota, immune cell traits and asthma. Various MR analysis methods were employed, including inverse variance weighted (IVW), constrained maximum likelihood model averaging-based method (cML-MA-BIC), maximum likelihood (ML), weighted mode, weighted median, and MR-robust adjusted profile score (MR-RAPS). Additionally, mediation analyses were performed to identify the immune cell traits that mediate these effects.</div></div><div><h3>Results</h3><div>This study identified 12 oral bacterial taxa and 36 inflammatory cytokines associated with asthma. After identifying the oral microbiota and immune cell characteristics associated with asthma, we applied a mediation MR framework to investigate whether immune cell traits mediate the effect of microbiota on asthma. Finally, we identified eight immune cell traits that mediate asthma caused by bacteria.</div></div><div><h3>Conclusions</h3><div>Our results highlight the causal associations between oral bacterial taxa, immune cell traits, and asthma, providing evidence that various immune cell traits serve as critical mediators between the oral microbiota and asthma. The link between the oral microbiome and asthma has important implications for clinical practice.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157021"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922486","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":"2025-08-29","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":"2025-08-29","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":"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":"2025-08-28","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}