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.
Methods
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.
Results
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.
Conclusions
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.
{"title":"Clinical value of serum TNF-α and IL-2R as treatment predictive and prognostic biomarkers in metastatic colorectal cancer","authors":"Jinxiu Tian , Jinjia Chang , Zhujun Chen , 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":"2025-10-07","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}
The interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a crucial member of the interferon-stimulated gene (ISG) family, widely acknowledged for its antiviral activity. IFIT2 functions primarily through AU-rich RNA binding, aiding in viral suppression by inhibiting protein translation and promoting apoptosis via mitochondrial pathways. While traditionally known for its role in antiviral defence, emerging research highlights its broader significance in cancer, bacterial and fungal infections, autoimmune diseases, neurological disorders, and metabolic and cardiovascular conditions. Notably, IFIT2 is the only IFIT family member with established tumour suppressor properties, demonstrating anti-proliferative effects in multiple cancers, including lung, renal, colorectal, breast, and gallbladder cancers.
Beyond oncology, IFIT2 has been implicated in the host response to Mycobacterium tuberculosis, Plasmodium spp., Candida albicans, and Treponema pallidum, where it modulates immune responses and infection outcomes. It is upregulated in several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and multiple sclerosis, suggesting its potential as a diagnostic and therapeutic biomarker. Furthermore, transcriptomic analyses have linked IFIT2 to disease progression and treatment response in conditions like diabetic ulcers, gestational diabetes, ischaemic cardiomyopathy, schizophrenia, and Alzheimer's disease.
This review thoroughly examines the molecular structure, regulatory mechanisms, and diverse roles of IFIT2 in human diseases. It addresses its interaction with key immune pathways, its ability to modulate apoptosis and inflammation, and its potential as a prognostic marker and therapeutic target. Although its mechanistic functions in numerous diseases remain only partly understood, IFIT2 emerges as a versatile immune effector with considerable translational promise. Further investigation into its biological roles will be crucial for utilising its therapeutic potential across infectious, inflammatory, metabolic, and neoplastic diseases.
{"title":"Therapeutic potential of IFIT2 in human diseases","authors":"Ewura-Esi Manful , Francis Adu-Amankwaah , Abhilasha Madhvi , Kayla Bubb , Ray-Dean Pietersen , Bienyameen Baker","doi":"10.1016/j.cyto.2025.157049","DOIUrl":"10.1016/j.cyto.2025.157049","url":null,"abstract":"<div><div>The interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a crucial member of the interferon-stimulated gene (ISG) family, widely acknowledged for its antiviral activity. IFIT2 functions primarily through AU-rich RNA binding, aiding in viral suppression by inhibiting protein translation and promoting apoptosis via mitochondrial pathways. While traditionally known for its role in antiviral defence, emerging research highlights its broader significance in cancer, bacterial and fungal infections, autoimmune diseases, neurological disorders, and metabolic and cardiovascular conditions. Notably, IFIT2 is the only IFIT family member with established tumour suppressor properties, demonstrating anti-proliferative effects in multiple cancers, including lung, renal, colorectal, breast, and gallbladder cancers.</div><div>Beyond oncology, IFIT2 has been implicated in the host response to <em>Mycobacterium tuberculosis</em>, <em>Plasmodium</em> spp., <em>Candida albicans</em>, and <em>Treponema pallidum</em>, where it modulates immune responses and infection outcomes. It is upregulated in several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and multiple sclerosis, suggesting its potential as a diagnostic and therapeutic biomarker. Furthermore, transcriptomic analyses have linked IFIT2 to disease progression and treatment response in conditions like diabetic ulcers, gestational diabetes, ischaemic cardiomyopathy, schizophrenia, and Alzheimer's disease.</div><div>This review thoroughly examines the molecular structure, regulatory mechanisms, and diverse roles of IFIT2 in human diseases. It addresses its interaction with key immune pathways, its ability to modulate apoptosis and inflammation, and its potential as a prognostic marker and therapeutic target. Although its mechanistic functions in numerous diseases remain only partly understood, IFIT2 emerges as a versatile immune effector with considerable translational promise. Further investigation into its biological roles will be crucial for utilising its therapeutic potential across infectious, inflammatory, metabolic, and neoplastic diseases.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157049"},"PeriodicalIF":3.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218245","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}
Endometriosis is a chronic inflammatory condition often associated with infertility. The role of granzymes as cytotoxic proteases and immune regulators in endometriosis remains poorly understood. This study evaluated serum and peritoneal fluid levels of granzymes A, B, and K in women with endometriosis and their links to disease severity.
Methodology
An observational study of 87 infertile women undergoing diagnostic laparoscopy, including 44 with endometriosis and 43 benign gynecologic controls. Granzyme levels were measured using ELISA and correlated with clinical parameters.
Results
Serum GrB and GrK were significantly higher in women with endometriosis, particularly in advanced stages. Peritoneal fluid revealed reduced GrA and increased GrB in the endometriosis group. Serum GrB and GrK levels correlated positively with rASRM adhesion and endometriosis severity scores, while GrB levels correlated inversely with the Endometriosis Infertility Index (EFI) score, indicating their role in predicting infertility. Combining serum GrB and GrK effectively differentiated endometriosis from control, highlighting their diagnostic potential.
Conclusion
Elevated serum GrB and GrK levels suggest their involvement in endometriosis pathogenesis and infertility. These findings highlight granzymes as promising biomarkers for disease severity, diagnosis, and targeted therapy in endometriosis management.
{"title":"Extracellular granzyme B and K are associated with endometriosis severity in infertile women","authors":"Fadhil Ahsan , Budi Santoso , Nanda Yuli Rahmawati , Fidyah Nanda Alditia , Alfin Firasy Mufid , M.Y. Ardianta Widyanugraha , Ashon Sa'adi , Sri Ratna Dwiningsih , Arif Tunjungseto","doi":"10.1016/j.cyto.2025.157045","DOIUrl":"10.1016/j.cyto.2025.157045","url":null,"abstract":"<div><h3>Background</h3><div>Endometriosis is a chronic inflammatory condition often associated with infertility. The role of granzymes as cytotoxic proteases and immune regulators in endometriosis remains poorly understood. This study evaluated serum and peritoneal fluid levels of granzymes A, B, and K in women with endometriosis and their links to disease severity.</div></div><div><h3>Methodology</h3><div>An observational study of 87 infertile women undergoing diagnostic laparoscopy, including 44 with endometriosis and 43 benign gynecologic controls. Granzyme levels were measured using ELISA and correlated with clinical parameters.</div></div><div><h3>Results</h3><div>Serum GrB and GrK were significantly higher in women with endometriosis, particularly in advanced stages. Peritoneal fluid revealed reduced GrA and increased GrB in the endometriosis group. Serum GrB and GrK levels correlated positively with rASRM adhesion and endometriosis severity scores, while GrB levels correlated inversely with the Endometriosis Infertility Index (EFI) score, indicating their role in predicting infertility. Combining serum GrB and GrK effectively differentiated endometriosis from control, highlighting their diagnostic potential.</div></div><div><h3>Conclusion</h3><div>Elevated serum GrB and GrK levels suggest their involvement in endometriosis pathogenesis and infertility. These findings highlight granzymes as promising biomarkers for disease severity, diagnosis, and targeted therapy in endometriosis management.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157045"},"PeriodicalIF":3.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218247","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}
Pub Date : 2025-10-04DOI: 10.1016/j.cyto.2025.157048
XiaoYan Gao , XiuDan Li , CongYing Zhang , Jing Zhou , Kai Gu , XiaoQiang Liu , ChunYing Bai
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed in nearly all human tissues and cell types. The TGF-β signaling pathway is essential for embryonic development, cell and tissue differentiation, and tissue homeostasis in adults. Aberrant regulation of this pathway is closely associated with various diseases, indicating that the TGF-β signaling pathway represents a promising target for therapeutic intervention. Notably, diseases linked to the disruption of the TGF-β signaling pathway include cancer, vascular disorders, wound healing complications, tissue fibrosis, and autoimmune diseases. The development and optimization of selective inhibitors targeting TGF-β could provide viable therapeutic options for the clinical treatment of these conditions. Consequently, targeting the cytokine TGF-β and its signaling pathway may offer a novel and promising treatment strategy for related diseases. This review summarizes recent studies on the role of TGF-β in the pathogenesis and treatment of associated diseases.
{"title":"Inhibiting TGF-β signaling pathway for disease therapy: challenges and opportunities","authors":"XiaoYan Gao , XiuDan Li , CongYing Zhang , Jing Zhou , Kai Gu , XiaoQiang Liu , ChunYing Bai","doi":"10.1016/j.cyto.2025.157048","DOIUrl":"10.1016/j.cyto.2025.157048","url":null,"abstract":"<div><div>Transforming growth factor (TGF)-β is a multifunctional cytokine expressed in nearly all human tissues and cell types. The TGF-β signaling pathway is essential for embryonic development, cell and tissue differentiation, and tissue homeostasis in adults. Aberrant regulation of this pathway is closely associated with various diseases, indicating that the TGF-β signaling pathway represents a promising target for therapeutic intervention. Notably, diseases linked to the disruption of the TGF-β signaling pathway include cancer, vascular disorders, wound healing complications, tissue fibrosis, and autoimmune diseases. The development and optimization of selective inhibitors targeting TGF-β could provide viable therapeutic options for the clinical treatment of these conditions. Consequently, targeting the cytokine TGF-β and its signaling pathway may offer a novel and promising treatment strategy for related diseases. This review summarizes recent studies on the role of TGF-β in the pathogenesis and treatment of associated diseases.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157048"},"PeriodicalIF":3.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218246","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}
We studied the influence of the pregnancy hormone estriol (E3) and bacterial strains on the ability of NK cells to modulate levels of T regulatory (Treg) and IL-17-producing (Th17) lymphocytes from patients with multiple sclerosis (MS) and healthy donors. NK cell phenotype and cytokine production in co-cultures with CD4+ lymphocytes was also investigated after incubation with the hormone and bacterial cells. Treatment of NK cells with these factors stimulated Treg formation and inhibited Th17 development. Within 24 h, NK cell cytotoxicity and production of IL-2 and IFN-γ were inhibited, while IL-10 secretion increased. This was accompanied by a rise in IL-6 and TNF-α. After three days, NK cells showed increased IL-10 and decreased IL-17 expression. Notably, cells from MS patients were more sensitive to this regulatory influence than those from healthy donors.
{"title":"Regulation of TREG/TH17 balance by NK cells pretreated with ESTRIOL and bacterial cells in multiple sclerosis","authors":"Irina Nekrasova , Natalia Glebezdina , Irina Maslennikova , Irina Danchenko , Sergei Shirshev","doi":"10.1016/j.cyto.2025.157038","DOIUrl":"10.1016/j.cyto.2025.157038","url":null,"abstract":"<div><div>We studied the influence of the pregnancy hormone estriol (E<sub>3</sub>) and bacterial strains on the ability of NK cells to modulate levels of T regulatory (Treg) and IL-17-producing (Th17) lymphocytes from patients with multiple sclerosis (MS) and healthy donors. NK cell phenotype and cytokine production in co-cultures with CD4<sup>+</sup> lymphocytes was also investigated after incubation with the hormone and bacterial cells. Treatment of NK cells with these factors stimulated Treg formation and inhibited Th17 development. Within 24 h, NK cell cytotoxicity and production of IL-2 and IFN-γ were inhibited, while IL-10 secretion increased. This was accompanied by a rise in IL-6 and TNF-α. After three days, NK cells showed increased IL-10 and decreased IL-17 expression. Notably, cells from MS patients were more sensitive to this regulatory influence than those from healthy donors.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157038"},"PeriodicalIF":3.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218248","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}
Inflammation plays a crucial role in the pathogenesis of Hodgkin lymphoma. IL-18 is a proinflammatory cytokine. Therefore, we investigated the serum IL-18 levels and their prognostic significance in Hodgkin lymphoma patients.
Method
Serum IL-18 levels were compared between 30 newly diagnosed Hodgkin lymphoma patients and 30 healthy controls. The association between IL-18 levels, clinical findings, prognostic markers, and treatment response was also evaluated in Hodgkin lymphoma patients.
Results
The HL group's IL-18 level (29.28 ± 13.48 pg/mL) was significantly higher than that of the control group (16.69 ± 9.33 pg/mL) (p < 0.001). Significant associations were observed between IL-18 levels and extranodal involvement, B symptom presence, performance status, Ann-Arbor stage, bulky mass presence, bone marrow involvement, and treatment response in Hodgkin lymphoma patients (p = 0.013, p = 0.006, p = 0.009, p = 0.003, p = 0.001, p = 0.02, p = 0.03, respectively). IL-18 levels also positively correlated with LDH and beta-2 microglobulin levels (r = 0.37, p = 0.04, r = 0.5, p = 0.005, respectively).
Conclusion
Serum IL-18 levels are higher in Hodgkin lymphoma patients compared to healthy individuals. IL-18 levels may serve as a prognostic marker and a predictor of treatment response in Hodgkin lymphoma patients.
背景：炎症在霍奇金淋巴瘤的发病机制中起着至关重要的作用。IL-18是一种促炎细胞因子。因此，我们研究了霍奇金淋巴瘤患者血清IL-18水平及其预后意义。方法比较30例新诊断霍奇金淋巴瘤患者与30例健康对照者血清IL-18水平。在霍奇金淋巴瘤患者中，还评估了IL-18水平、临床表现、预后指标和治疗反应之间的关系。结果HL组IL-18水平（29.28±13.48 pg/mL）显著高于对照组（16.69±9.33 pg/mL） （p < 0.001）。在霍奇金淋巴瘤患者中，IL-18水平与结外受损伤、B症状存在、运动状态、an - arbor分期、大块肿块存在、骨髓受损伤和治疗反应之间存在显著相关性（p = 0.013, p = 0.006, p = 0.009, p = 0.003, p = 0.001, p = 0.02, p = 0.03）。IL-18水平与LDH和β -2微球蛋白水平呈正相关（r = 0.37, p = 0.04, r = 0.5, p = 0.005）。结论霍奇金淋巴瘤患者血清IL-18水平高于健康人群。IL-18水平可作为霍奇金淋巴瘤患者治疗反应的预后标志物和预测因子。
{"title":"The significance of serum IL-18 levels in Hodgkin lymphoma patients","authors":"Gülden Sincan , Suat Sincan , Çağrı Kızıltunç , Esra Eğilmez","doi":"10.1016/j.cyto.2025.157044","DOIUrl":"10.1016/j.cyto.2025.157044","url":null,"abstract":"<div><h3>Background</h3><div>Inflammation plays a crucial role in the pathogenesis of Hodgkin lymphoma. IL-18 is a proinflammatory cytokine. Therefore, we investigated the serum IL-18 levels and their prognostic significance in Hodgkin lymphoma patients.</div></div><div><h3>Method</h3><div>Serum IL-18 levels were compared between 30 newly diagnosed Hodgkin lymphoma patients and 30 healthy controls. The association between IL-18 levels, clinical findings, prognostic markers, and treatment response was also evaluated in Hodgkin lymphoma patients.</div></div><div><h3>Results</h3><div>The HL group's IL-18 level (29.28 ± 13.48 pg/mL) was significantly higher than that of the control group (16.69 ± 9.33 pg/mL) (<em>p</em> < 0.001). Significant associations were observed between IL-18 levels and extranodal involvement, B symptom presence, performance status, Ann-Arbor stage, bulky mass presence, bone marrow involvement, and treatment response in Hodgkin lymphoma patients (<em>p</em> = 0.013, <em>p</em> = 0.006, <em>p</em> = 0.009, <em>p</em> = 0.003, <em>p</em> = 0.001, <em>p</em> = 0.02, <em>p</em> = 0.03, respectively). IL-18 levels also positively correlated with LDH and beta-2 microglobulin levels (<em>r</em> = 0.37, <em>p</em> = 0.04, <em>r</em> = 0.5, <em>p</em> = 0.005, respectively).</div></div><div><h3>Conclusion</h3><div>Serum IL-18 levels are higher in Hodgkin lymphoma patients compared to healthy individuals. IL-18 levels may serve as a prognostic marker and a predictor of treatment response in Hodgkin lymphoma patients.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157044"},"PeriodicalIF":3.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218249","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}
N6-methyladenosine (m6A) is the most prevalent internal modification found in eukaryotic mRNAs and plays a critical role in shaping immune response. It acts as a dynamic regulatory step modulating the splicing, stability, degradation and translation of target mRNAs involved in regulating immune outcome. These effects are mediated by the dynamic interplay of m6A methyltransferases ("writers"), demethylases ("erasers"), and binding proteins ("readers") which work in concert to fine-tune immune activation and suppression. m6A modifications modulate both innate and adaptive immune responses by regulating chemokine signaling, inflammation, and guiding the lineage commitment and function of various cells involved in immune regulation. For example, m6A-modified mRNAs encoding interferons and pro-inflammatory cytokines are translated more efficiently, facilitating a swift response to infection, while m6A-mediated degradation of pro-inflammatory transcripts offers a counterbalance, allowing immune cells to fine-tune responses and limit overactivation. In T cells, m6A readers influence antigen responsiveness and immune tolerance, while in regulatory T cells, m6A plays a key role in maintaining immune equilibrium. In this review, we present an in-depth overview of how m6A methylation shapes immune function and outline its potential as a therapeutic target. A detailed understanding of the interplay between m6A and immune regulation may provide valuable insights for developing novel therapies for immune-related diseases.
{"title":"Epitranscriptomic regulation of immunity: The role of m6A in shaping immune response dynamics.","authors":"Devesh Srivastava, Vinayak Nayak, Srijoni Pahari, Gopu Sandeep, Ashish Misra","doi":"10.1016/j.cyto.2025.157011","DOIUrl":"10.1016/j.cyto.2025.157011","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) is the most prevalent internal modification found in eukaryotic mRNAs and plays a critical role in shaping immune response. It acts as a dynamic regulatory step modulating the splicing, stability, degradation and translation of target mRNAs involved in regulating immune outcome. These effects are mediated by the dynamic interplay of m6A methyltransferases (\"writers\"), demethylases (\"erasers\"), and binding proteins (\"readers\") which work in concert to fine-tune immune activation and suppression. m6A modifications modulate both innate and adaptive immune responses by regulating chemokine signaling, inflammation, and guiding the lineage commitment and function of various cells involved in immune regulation. For example, m6A-modified mRNAs encoding interferons and pro-inflammatory cytokines are translated more efficiently, facilitating a swift response to infection, while m6A-mediated degradation of pro-inflammatory transcripts offers a counterbalance, allowing immune cells to fine-tune responses and limit overactivation. In T cells, m6A readers influence antigen responsiveness and immune tolerance, while in regulatory T cells, m6A plays a key role in maintaining immune equilibrium. In this review, we present an in-depth overview of how m6A methylation shapes immune function and outline its potential as a therapeutic target. A detailed understanding of the interplay between m6A and immune regulation may provide valuable insights for developing novel therapies for immune-related diseases.</p>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"194 ","pages":"157011"},"PeriodicalIF":3.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811490","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}
Pub Date : 2025-10-01Epub Date: 2025-08-07DOI: 10.1016/j.cyto.2025.157007
Changyang Liu, Miao Zhao, Xi Wang, Shuai Wang, Xiaochen Wang
<p><strong>Background: </strong>Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach.</p><p><strong>Methods: </strong>A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders.</p><p><strong>Results: </strong>In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95 % CI: 1.04-1.21, P = 0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95 % CI: 1.06-1.36, P = 0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95 % CI: 1.02-1.16, P = 0.013), and stem cell factor (SCF) (OR: 1.09, 95 % CI: 1.03-1.15, P = 0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95 % CI: 0.82-0.95, P = 0.002), interleukin-18 (IL-18) (OR: 0.92, 95 % CI: 0.86-0.99, P = 0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95 % CI: 0.92-1.00, P = 0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95 % CI: 0.86-0.97, P = 0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95 % CI: 0.88-1.00, P = 0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95 % CI: 0.84-0.95, P = 4.63 × 10<sup>-4</sup>), IL-18 (OR: 0.93, 95 % CI: 0.89-0.97, P = 0.002), IL-18R1 (OR: 0.96, 95 % CI: 0.93-0.99, P = 0.023), and LIF (OR: 1.18, 95 % CI: 1.04-1.34, P = 0.013). Sensitivity analyses further supported the robustness of these findings.</p><p><strong>Conclusion: </strong>This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the
背景：青光眼，尤其是原发性开角型青光眼（POAG）是导致不可逆视力丧失的主要原因。虽然眼压升高是主要的危险因素，但POAG的发病机制还涉及遗传、氧化应激、异常血流动力学和炎症因素。全身性炎症在POAG中的作用仍然是一个有争议的话题。本研究旨在利用双向孟德尔随机化（MR）方法研究循环炎症蛋白与POAG之间的因果关系。方法：采用全基因组关联研究汇总统计进行双向双样本MR分析。初级阶段涉及91种循环炎症蛋白和POAG，随后是使用独立数据和荟萃分析验证重要发现的复制阶段。采用随机效应反方差加权模型作为主要方法，辅以多重敏感性分析以确保稳健性，包括多变量MR来调整潜在的混杂因素。结果：在初级阶段，发现9种循环炎症蛋白与POAG有显著的因果关系。具体来说，Delta和notch样表皮生长因子相关受体（DNER） （OR: 1.12, 95% CI: 1.04-1.21, P = 0.004）、白血病抑制因子（LIF） （OR: 1.20, 95% CI: 1.06-1.36, P = 0.003）、基质金属蛋白酶-10 (MMP-10) （OR: 1.08, 95% CI: 1.02-1.16, P = 0.013）和干细胞因子（SCF） （OR: 1.09, 95% CI: 1.03-1.15, P = 0.005）的较高水平与POAG的风险呈正相关。相反，成纤维细胞生长因子19 (FGF-19) （OR: 0.88, 95% CI: 0.82-0.95, P = 0.002）、白细胞介素18 (IL-18) （OR: 0.92, 95% CI: 0.86-0.99, P = 0.019）、IL-18受体1 (IL-18R1) （OR: 0.96, 95% CI: 0.92-1.00, P = 0.037）、肿瘤坏死因子配体超家族成员14 (TNFSF14) （OR: 0.91, 95% CI: 0.86-0.97, P = 0.004）和肿瘤坏死因子相关激活诱导的细胞因子（TRANCE） （OR: 0.94, 95% CI: P = 0.004）的水平：0.88-1.00, P = 0.041)与POAG风险呈负相关。校正混杂因素的多变量MR分析支持DNER、FGF-19、IL-18、IL18R1、LIF和SCF的作用。复制阶段证实了FGF-19 （OR: 0.89, 95% CI: 0.84-0.95, P = 4.63 × 10-4）、IL-18 （OR: 0.93, 95% CI: 0.89-0.97, P = 0.002）、IL-18R1 （OR: 0.96, 95% CI: 0.93-0.99, P = 0.023）和LIF （OR: 1.18, 95% CI: 1.04-1.34, P = 0.013）的显著相关性。敏感性分析进一步支持了这些发现的稳健性。结论：本研究阐明了循环炎症蛋白与POAG之间的因果关系，强调了FGF-19、IL-18、IL-18R1和LIF是潜在的治疗靶点。这些发现为POAG的预防和管理提供了新的见解，尽管需要进一步的研究来了解确切的生物学机制。
{"title":"Causal association between 91 circulating inflammatory proteins and primary open-angle glaucoma: a bidirectional Mendelian randomization study.","authors":"Changyang Liu, Miao Zhao, Xi Wang, Shuai Wang, Xiaochen Wang","doi":"10.1016/j.cyto.2025.157007","DOIUrl":"10.1016/j.cyto.2025.157007","url":null,"abstract":"<p><strong>Background: </strong>Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach.</p><p><strong>Methods: </strong>A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders.</p><p><strong>Results: </strong>In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95 % CI: 1.04-1.21, P = 0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95 % CI: 1.06-1.36, P = 0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95 % CI: 1.02-1.16, P = 0.013), and stem cell factor (SCF) (OR: 1.09, 95 % CI: 1.03-1.15, P = 0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95 % CI: 0.82-0.95, P = 0.002), interleukin-18 (IL-18) (OR: 0.92, 95 % CI: 0.86-0.99, P = 0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95 % CI: 0.92-1.00, P = 0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95 % CI: 0.86-0.97, P = 0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95 % CI: 0.88-1.00, P = 0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95 % CI: 0.84-0.95, P = 4.63 × 10<sup>-4</sup>), IL-18 (OR: 0.93, 95 % CI: 0.89-0.97, P = 0.002), IL-18R1 (OR: 0.96, 95 % CI: 0.93-0.99, P = 0.023), and LIF (OR: 1.18, 95 % CI: 1.04-1.34, P = 0.013). Sensitivity analyses further supported the robustness of these findings.</p><p><strong>Conclusion: </strong>This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"194 ","pages":"157007"},"PeriodicalIF":3.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803080","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}
Pub Date : 2025-10-01DOI: 10.1016/j.cyto.2025.157042
Antonio Piralla , Sabrina Gioria , Giuditta Guerrini , Greta Petazzoni , Guglielmo Ferrari , Alessandro Ferrari , Federica Giardina , Federica Bergami , Anita Orlando , Silvia Mongodi , Federico Capra Marzani , Mara De Amici , Giorgia Testa , Luigi Calzolai , Fausto Baldanti
This study explores the immune response dynamics in critically ill SARS-CoV-2 patients compared to non-SARS-CoV-2 controls both hospitalized in intensive care unit (ICU), focusing on localized and systemic inflammatory profiles to identify patterns linked to clinical outcomes. A cohort of ICU patients (37 SARS-CoV-2 positive, 17 controls) underwent bronchoalveolar lavage (BAL) and plasma analysis to assess inflammatory markers using a multiplex assay. SARS-CoV-2 patients showed distinct clinical and immunological features, including prolonged ICU stays and elevated markers of systemic inflammation. Cluster analysis revealed subgroup-specific immune signatures, with COVID-19 survivors demonstrating coordinated cytokine/chemokine interactions suggestive of adaptive immune regulation, while non-survivors exhibited dysregulated profiles indicative of maladaptive inflammation. The study underscores the spatial segregation of immune responses, with lung-specific inflammation in BAL contrasting with systemic profiles, highlighting the importance of tissue-targeted monitoring. These findings suggest that immune profiling could inform stratification for tailored immunomodulatory therapies, advancing precision approaches in critical care for severe SARS-CoV-2 infections.
{"title":"Differential cytokine and chemokine signatures in bronchoalveolar lavage and plasma predict clinical outcomes of COVID-19 patients hospitalized in intensive care unit","authors":"Antonio Piralla , Sabrina Gioria , Giuditta Guerrini , Greta Petazzoni , Guglielmo Ferrari , Alessandro Ferrari , Federica Giardina , Federica Bergami , Anita Orlando , Silvia Mongodi , Federico Capra Marzani , Mara De Amici , Giorgia Testa , Luigi Calzolai , Fausto Baldanti","doi":"10.1016/j.cyto.2025.157042","DOIUrl":"10.1016/j.cyto.2025.157042","url":null,"abstract":"<div><div>This study explores the immune response dynamics in critically ill SARS-CoV-2 patients compared to non-SARS-CoV-2 controls both hospitalized in intensive care unit (ICU), focusing on localized and systemic inflammatory profiles to identify patterns linked to clinical outcomes. A cohort of ICU patients (37 SARS-CoV-2 positive, 17 controls) underwent bronchoalveolar lavage (BAL) and plasma analysis to assess inflammatory markers using a multiplex assay. SARS-CoV-2 patients showed distinct clinical and immunological features, including prolonged ICU stays and elevated markers of systemic inflammation. Cluster analysis revealed subgroup-specific immune signatures, with COVID-19 survivors demonstrating coordinated cytokine/chemokine interactions suggestive of adaptive immune regulation, while non-survivors exhibited dysregulated profiles indicative of maladaptive inflammation. The study underscores the spatial segregation of immune responses, with lung-specific inflammation in BAL contrasting with systemic profiles, highlighting the importance of tissue-targeted monitoring. These findings suggest that immune profiling could inform stratification for tailored immunomodulatory therapies, advancing precision approaches in critical care for severe SARS-CoV-2 infections.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157042"},"PeriodicalIF":3.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211095","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}
Pub Date : 2025-09-30DOI: 10.1016/j.cyto.2025.157041
K.L. Milan, R. Adhi Shree, N. Nandana, R. Leela, K.M. Ramkumar
Gestational diabetes mellitus (GDM) is a pregnancy-associated condition resulting from glucose intolerance affecting approximately 14 % of pregnant women worldwide and contributing to both maternal and neonatal complications. Macrophages, essential components of the innate immune system, exist in three main polarization states: M0 (resting), M1 (pro-inflammatory), and M2 (anti-inflammatory). In normal pregnancy, a proper balance between M1 and M2 phenotypes is critical for successful placentation and fetal development. Although this classification provides a useful framework, emerging evidence indicates that macrophages exist along a dynamic continuum of activation states with overlapping functional characteristics rather than discrete polarization categories. Recent studies further reveal that macrophage behavior in pregnancy involves context-dependent and plastic responses that cannot be fully captured by the M1/M2 paradigm alone. However, in GDM, hyperglycaemia significantly influences macrophage reprogramming toward a pro-inflammatory phenotype. The manuscript examines how dysregulated macrophage polarization contributes to insulin resistance, placental dysfunction, and adverse pregnancy outcomes. Emerging evidence suggests that hyperglycaemia induces trained immunity in macrophages, characterized by persistent expression of pro-inflammatory genes. In the GDM placenta, research indicates an altered M1/M2 ratio, though findings vary regarding specific polarization patterns. This review highlights promising therapeutic strategies targeting macrophage repolarization from M1 toward M2 phenotypes, including pharmacological approaches, RNA-based therapies, and ex vivo macrophage manipulation. Understanding macrophage reprogramming in GDM presents novel opportunities for interventions that may improve maternal-fetal outcomes and long-term metabolic health.
{"title":"Role of macrophages reprogramming in pathogenesis of gestational diabetes mellitus","authors":"K.L. Milan, R. Adhi Shree, N. Nandana, R. Leela, K.M. Ramkumar","doi":"10.1016/j.cyto.2025.157041","DOIUrl":"10.1016/j.cyto.2025.157041","url":null,"abstract":"<div><div>Gestational diabetes mellitus (GDM) is a pregnancy-associated condition resulting from glucose intolerance affecting approximately 14 % of pregnant women worldwide and contributing to both maternal and neonatal complications. Macrophages, essential components of the innate immune system, exist in three main polarization states: M0 (resting), M1 (pro-inflammatory), and M2 (anti-inflammatory). In normal pregnancy, a proper balance between M1 and M2 phenotypes is critical for successful placentation and fetal development. Although this classification provides a useful framework, emerging evidence indicates that macrophages exist along a dynamic continuum of activation states with overlapping functional characteristics rather than discrete polarization categories. Recent studies further reveal that macrophage behavior in pregnancy involves context-dependent and plastic responses that cannot be fully captured by the M1/M2 paradigm alone. However, in GDM, hyperglycaemia significantly influences macrophage reprogramming toward a pro-inflammatory phenotype. The manuscript examines how dysregulated macrophage polarization contributes to insulin resistance, placental dysfunction, and adverse pregnancy outcomes. Emerging evidence suggests that hyperglycaemia induces trained immunity in macrophages, characterized by persistent expression of pro-inflammatory genes. In the GDM placenta, research indicates an altered M1/M2 ratio, though findings vary regarding specific polarization patterns. This review highlights promising therapeutic strategies targeting macrophage repolarization from M1 toward M2 phenotypes, including pharmacological approaches, RNA-based therapies, and <em>ex vivo</em> macrophage manipulation. Understanding macrophage reprogramming in GDM presents novel opportunities for interventions that may improve maternal-fetal outcomes and long-term metabolic health.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"196 ","pages":"Article 157041"},"PeriodicalIF":3.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205069","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}
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