The purpose of this systematic review and meta-analysis was to summarize the existing evidence of the IL1RN variable number (usually two to six) of tandem repeat (VNTR) polymorphism in modulating the susceptibility to immune thrombocytopenia purpura (ITP), with the aim of clarifying its potential as a genetic marker for disease risk stratification. An extensive literature review was performed utilizing the Cochrane Library, NCBI PubMed, and Clarivate Web of Science databases, covering publications up to October 11, 2025. R language was employed to perform pooled estimation and present the results. The odds ratios and corresponding 95% confidence intervals were estimated to assess the strength of the effect. A total of 12 case-control studies comprising 770 ITP cases and 1424 controls were integrated for further synthetic analyses. Summary estimates in all genetic models suggested that the individuals carrying the variant with two repeats are more susceptible to this hematologic disorder. When stratified by geographic region, only the pooled estimates for Latin American and North African countries were statistically significant. No significant publication bias was evident. In conclusion, this meta-analysis indicated that the IL1RN VNTR polymorphism was significantly associated with ITP susceptibility, particularly in Latin American and North African populations.
本系统综述和荟萃分析的目的是总结现有的IL1RN串联重复序列（VNTR）可变数目（通常为2至6个）多态性在调节免疫性血小板减少性紫癜（ITP）易感性中的证据，目的是阐明其作为疾病风险分层遗传标记的潜力。我们利用Cochrane图书馆、NCBI PubMed和Clarivate Web of Science数据库进行了广泛的文献综述，涵盖了截至2025年10月11日的出版物。采用R语言进行池估计并给出结果。估计比值比和相应的95%置信区间来评估效果的强度。共纳入了12项病例对照研究，包括770例ITP病例和1424例对照，用于进一步的综合分析。所有遗传模型的总结估计表明，携带两个重复变体的个体更容易患这种血液病。当按地理区域分层时，只有拉丁美洲和北非国家的汇总估计值具有统计学意义。没有明显的发表偏倚。总之，这项荟萃分析表明，IL1RN VNTR多态性与ITP易感性显著相关，特别是在拉丁美洲和北非人群中。
{"title":"The interleukin-1 receptor antagonist gene VNTR polymorphism confers a genetic contribution to the risk of immune thrombocytopenia purpura: A systematic review and meta-analysis","authors":"Huifang Wei , Yuyang Xie , Qingyang Huai , Zixiao Hua , Xinyu Yang , Lingxi Chen , Youyi Kong , Wen Xue , Caiming Zhao , Shangshang Gao , Xiaoqin Yang","doi":"10.1016/j.cyto.2026.157112","DOIUrl":"10.1016/j.cyto.2026.157112","url":null,"abstract":"<div><div>The purpose of this systematic review and meta-analysis was to summarize the existing evidence of the <em>IL1RN</em> variable number (usually two to six) of tandem repeat (VNTR) polymorphism in modulating the susceptibility to immune thrombocytopenia purpura (ITP), with the aim of clarifying its potential as a genetic marker for disease risk stratification. An extensive literature review was performed utilizing the Cochrane Library, NCBI PubMed, and Clarivate Web of Science databases, covering publications up to October 11, 2025. R language was employed to perform pooled estimation and present the results. The odds ratios and corresponding 95% confidence intervals were estimated to assess the strength of the effect. A total of 12 case-control studies comprising 770 ITP cases and 1424 controls were integrated for further synthetic analyses. Summary estimates in all genetic models suggested that the individuals carrying the variant with two repeats are more susceptible to this hematologic disorder. When stratified by geographic region, only the pooled estimates for Latin American and North African countries were statistically significant. No significant publication bias was evident. In conclusion, this meta-analysis indicated that the <em>IL1RN</em> VNTR polymorphism was significantly associated with ITP susceptibility, particularly in Latin American and North African populations.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157112"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964552","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 : 2026-01-12DOI: 10.1016/j.cyto.2026.157110
Guangjian Wang , Hui Lian , Hongmin Zhang , Xiaoting Wang , Shuyang Zhang , Xuefeng Ni
Background
Abnormal inflammatory responses and viral infections play a critical role in the pathogenesis of critical illnesses. Critically ill patients frequently develop multiple organ dysfunction syndrome (MODS), a key determinant of clinical outcomes and a marker of poor prognosis. Interferon-γ (IFNγ), an important inflammatory regulatory cytokine, may serve as a more accurate indicator of viral infection severity and holds potential as a predictor of MODS and prognosis in critically ill patients.
Purpose
To evaluate the association between IFNγ levels and clinical outcomes in critically ill patients.
Methods
This prospective study, conducted from January 1 to May 31, 2023, at Peking Union Medical College Hospital, used data from electronic medical records to collect baseline characteristics, ICU parameters, laboratory tests, and clinical outcomes. MODS was diagnosed on the basis of Sequential Organ Failure Assessment (SOFA) scores. Generalized Additive Models were employed to explore linear and nonlinear associations, while survival analyses were performed using the Kaplan–Meier method.
Results
A total of 208 patients were analyzed. IFNγ levels demonstrated a significant positive linear correlation with MODS in both sepsis (odds ratio [OR] 1.041, 95% confidence interval [CI]: 0.962–1.126) and non-sepsis (OR 1.025, 95% CI: 0.907–1.157) subgroups (intergroup P < 0.001). The relationship between IFNγ levels and 28-day mortality followed a U-shaped curve, with a threshold of 5.3 ng/mL. In the sepsis subgroup, patients with low IFNγ levels exhibited poorer prognoses compared with those with high IFNγ levels (P = 0.021). No significant difference in prognosis was observed between procalcitonin (PCT) subgroups (P = 0.087). Among patients with elevated IFNγ levels, a positive correlation between PCT and 28-day mortality was identified (OR 1.098, 95% CI: 0.815–1.481).
Conclusion
IFNγ is strongly associated with MODS and prognosis in critically ill patients, highlighting its potential as a biomarker for predicting MODS occurrence and patient outcomes. These findings underscore the clinical value of IFNγ in critical care, providing a foundation for further research in this area.
{"title":"Interferon-γ (IFNγ), a double-edge sword that affects prognoses in critically ill patients: A prospective study","authors":"Guangjian Wang , Hui Lian , Hongmin Zhang , Xiaoting Wang , Shuyang Zhang , Xuefeng Ni","doi":"10.1016/j.cyto.2026.157110","DOIUrl":"10.1016/j.cyto.2026.157110","url":null,"abstract":"<div><h3>Background</h3><div>Abnormal inflammatory responses and viral infections play a critical role in the pathogenesis of critical illnesses. Critically ill patients frequently develop multiple organ dysfunction syndrome (MODS), a key determinant of clinical outcomes and a marker of poor prognosis. Interferon-γ (IFNγ), an important inflammatory regulatory cytokine, may serve as a more accurate indicator of viral infection severity and holds potential as a predictor of MODS and prognosis in critically ill patients.</div></div><div><h3>Purpose</h3><div>To evaluate the association between IFNγ levels and clinical outcomes in critically ill patients.</div></div><div><h3>Methods</h3><div>This prospective study, conducted from January 1 to May 31, 2023, at Peking Union Medical College Hospital, used data from electronic medical records to collect baseline characteristics, ICU parameters, laboratory tests, and clinical outcomes. MODS was diagnosed on the basis of Sequential Organ Failure Assessment (SOFA) scores. Generalized Additive Models were employed to explore linear and nonlinear associations, while survival analyses were performed using the Kaplan–Meier method.</div></div><div><h3>Results</h3><div>A total of 208 patients were analyzed. IFNγ levels demonstrated a significant positive linear correlation with MODS in both sepsis (odds ratio [OR] 1.041, 95% confidence interval [CI]: 0.962–1.126) and non-sepsis (OR 1.025, 95% CI: 0.907–1.157) subgroups (intergroup <em>P</em> < 0.001). The relationship between IFNγ levels and 28-day mortality followed a U-shaped curve, with a threshold of 5.3 ng/mL. In the sepsis subgroup, patients with low IFNγ levels exhibited poorer prognoses compared with those with high IFNγ levels (<em>P</em> = 0.021). No significant difference in prognosis was observed between procalcitonin (PCT) subgroups (<em>P</em> = 0.087). Among patients with elevated IFNγ levels, a positive correlation between PCT and 28-day mortality was identified (OR 1.098, 95% CI: 0.815–1.481).</div></div><div><h3>Conclusion</h3><div>IFNγ is strongly associated with MODS and prognosis in critically ill patients, highlighting its potential as a biomarker for predicting MODS occurrence and patient outcomes. These findings underscore the clinical value of IFNγ in critical care, providing a foundation for further research in this area.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157110"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964525","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 : 2026-01-10DOI: 10.1016/j.cyto.2026.157107
Kedeye Tuerxun , Lisa Kurland , Eva Särndahl , Ulrika Wallgren , Daniel Eklund , Robert Kruse , X-HiDE Consortium
The host immune response in sepsis involves both pro- and anti-inflammatory mechanisms, with monocytes playing a central role in the process. We have previously identified an in vitro response profile of endotoxin (LPS) tolerant primary human monocytes, consisting of eight cytokines/chemokines as well as a set of five transcription factors. In the current study, we evaluated differences in expression levels of these investigated molecular markers across different patient groups (patients with or without infection, and with or without sepsis), and their association with clinical outcomes (septic shock and in-hospital mortality), among 809 ambulance patients. The results showed that patients with sepsis displayed the lowest HLA-DRA expression levels together with the lowest TNF/IL-10 ratio, while most other cytokine/chemokines and gene expressions were elevated. Higher levels of HGF, CCL8, CCL2, TNF and IL-10, as well as upregulation of HIF1A and NFKBIA were seen in septic patients with septic shock. The data suggests that the investigated immunological markers linked to immunosuppressed monocyte responses are associated with patients with sepsis and septic shock.
{"title":"Inflammatory imbalance in ambulance patients is associated with sepsis and septic shock","authors":"Kedeye Tuerxun , Lisa Kurland , Eva Särndahl , Ulrika Wallgren , Daniel Eklund , Robert Kruse , X-HiDE Consortium","doi":"10.1016/j.cyto.2026.157107","DOIUrl":"10.1016/j.cyto.2026.157107","url":null,"abstract":"<div><div>The host immune response in sepsis involves both pro- and anti-inflammatory mechanisms, with monocytes playing a central role in the process. We have previously identified an in vitro response profile of endotoxin (LPS) tolerant primary human monocytes, consisting of eight cytokines/chemokines as well as a set of five transcription factors. In the current study, we evaluated differences in expression levels of these investigated molecular markers across different patient groups (patients with or without infection, and with or without sepsis), and their association with clinical outcomes (septic shock and in-hospital mortality), among 809 ambulance patients. The results showed that patients with sepsis displayed the lowest <em>HLA-DRA</em> expression levels together with the lowest TNF/IL-10 ratio, while most other cytokine/chemokines and gene expressions were elevated. Higher levels of HGF, CCL8, CCL2, TNF and IL-10, as well as upregulation of <em>HIF1A</em> and <em>NFKBIA</em> were seen in septic patients with septic shock. The data suggests that the investigated immunological markers linked to immunosuppressed monocyte responses are associated with patients with sepsis and septic shock.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157107"},"PeriodicalIF":3.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951106","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 : 2026-01-10DOI: 10.1016/j.cyto.2026.157113
Yang Bei-bei , Liu Ji-zan , Rui Hong-bing , Xue Juan , Xiao Hua
Objective
To explore the impact of joint fluid (JF) from difficult-to-treat (D2T)rheumatoid arthritis (RA) patients on joint inflammation.
Methods
We compared the clinical characteristics of D2T RA and non-D2T RA patients. Joint fluid samples from patients with various forms of chronic arthritis were analyzed. The activation of IL-6/STAT3 and TGF-β/SMAD3 pathways in normal Fibroblast-like synoviocytes (FLS) after exposure to D2T RA joint fluid was also evaluated, along with the effects of pathway inhibitors on cell proliferation, apoptosis, invasion, and migration.
Results
D2T RA joint fluid showed elevated levels of IL-6 and TGF-β1 compared to non-D2T RA, osteoarthritis, and ankylosing spondylitis samples. The IL-6/STAT3 pathway was directly activated in normal FLS upon exposure to D2T RA joint fluid, while the TGF-β/SMAD3 pathway was indirectly activated through IL-6 trans-signaling, resulting in increased proliferation, migration, invasion, and anti-apoptotic properties of FLS. The use of SMAD3 Inhibitory Selective 3 (SIS3) to block the TGF-β/SMAD3 pathway partially mitigated the effects of D2T RA joint fluid. Tocilizumab and the soluble glycoprotein 130 Fc fusion protein (sgp130Fc) successfully inhibited IL-6–associated pSMAD3 activation, highlighting a mediating role of IL-6.
Conclusion
The joint fluid milieu may contribute to persistent synovial activation in D2T RA, and highlights IL-6 trans-signaling as a potential therapeutic target in this context. In addition, timely aspiration of joint fluid from patients with D2T RA may help modulate the local inflammatory microenvironment and could represent a supportive strategy in disease management.
{"title":"IL-6 trans-signaling activates the TGF-β pathway via soluble factors in difficult-to-treat rheumatoid arthritis joint fluid","authors":"Yang Bei-bei , Liu Ji-zan , Rui Hong-bing , Xue Juan , Xiao Hua","doi":"10.1016/j.cyto.2026.157113","DOIUrl":"10.1016/j.cyto.2026.157113","url":null,"abstract":"<div><h3>Objective</h3><div>To explore the impact of joint fluid (JF) from difficult-to-treat (D2T)rheumatoid arthritis (RA) patients on joint inflammation.</div></div><div><h3>Methods</h3><div>We compared the clinical characteristics of D2T RA and non-D2T RA patients. Joint fluid samples from patients with various forms of chronic arthritis were analyzed. The activation of IL-6/STAT3 and TGF-β/SMAD3 pathways in normal Fibroblast-like synoviocytes (FLS) after exposure to D2T RA joint fluid was also evaluated, along with the effects of pathway inhibitors on cell proliferation, apoptosis, invasion, and migration.</div></div><div><h3>Results</h3><div>D2T RA joint fluid showed elevated levels of IL-6 and TGF-β1 compared to non-D2T RA, osteoarthritis, and ankylosing spondylitis samples. The IL-6/STAT3 pathway was directly activated in normal FLS upon exposure to D2T RA joint fluid, while the TGF-β/SMAD3 pathway was indirectly activated through IL-6 trans-signaling, resulting in increased proliferation, migration, invasion, and anti-apoptotic properties of FLS. The use of SMAD3 Inhibitory Selective 3 (SIS3) to block the TGF-β/SMAD3 pathway partially mitigated the effects of D2T RA joint fluid. Tocilizumab and the soluble glycoprotein 130 Fc fusion protein (sgp130Fc) successfully inhibited IL-6–associated pSMAD3 activation, highlighting a mediating role of IL-6.</div></div><div><h3>Conclusion</h3><div>The joint fluid milieu may contribute to persistent synovial activation in D2T RA, and highlights IL-6 trans-signaling as a potential therapeutic target in this context. In addition, timely aspiration of joint fluid from patients with D2T RA may help modulate the local inflammatory microenvironment and could represent a supportive strategy in disease management.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157113"},"PeriodicalIF":3.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923710","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 : 2026-01-10DOI: 10.1016/j.cyto.2026.157109
Jing Zhang , Dandan Liu , Chuanyu Jia , Shuyang Wang , Yuhui Li
Background
Danshensu Sodium (DSS-S), the sodium salt of a principal water-soluble active compound from Salvia miltiorrhiza, was investigated for its effects on cerebral ischemic-reperfusion (I/R) injury and the underlying molecular mechanisms.
Methods
Neuroprotection by DSS-S was evaluated in vivo using a transient middle cerebral artery occlusion (tMCAO) model in male C57BL/6J mice and in vitro using an oxygen-glucose deprivation/reperfusion (OGD/R) model in Neuro-2a mouse neuroblastoma cells.
Results
High-mobility group box 1 (HMGB1) was identified as a key target of DSS-S. Following I/R or OGD/R, levels of IL-1β, IL-6, TNF-α, IL-18, and HMGB1 were significantly elevated in both mouse serum and cell culture supernatant, and these increases were substantially attenuated by DSS-S treatment. DSS-S reduced cytoplasmic HMGB1 accumulation, promoted its nuclear retention, down-regulated the receptor for advanced glycation end-products (RAGE), and weakened the HMGB1-RAGE interaction. Pyroptosis was activated in both tMCAO and OGD/R models, and DSS-S intervention effectively inhibited pyroptosis by suppressing the HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation.
Conclusion
DSS-S exerts neuroprotective effects against cerebral I/R injury in vivo and reduces OGD/R-induced injury in vitro. The protection is mediated through inhibition of pyroptosis, achieved by targeting the HMGB1/RAGE axis and suppressing NLRP3 inflammasome activation.
{"title":"Danshensu sodium attenuates pyroptosis in ischemic stroke by targeting the HMGB1/RAGE axis and downstream NLRP3/GSDMD/ASC/Caspase-1 pathway","authors":"Jing Zhang , Dandan Liu , Chuanyu Jia , Shuyang Wang , Yuhui Li","doi":"10.1016/j.cyto.2026.157109","DOIUrl":"10.1016/j.cyto.2026.157109","url":null,"abstract":"<div><h3>Background</h3><div>Danshensu Sodium (DSS-S), the sodium salt of a principal water-soluble active compound from <em>Salvia miltiorrhiza</em>, was investigated for its effects on cerebral ischemic-reperfusion (I/R) injury and the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>Neuroprotection by DSS-S was evaluated <em>in vivo</em> using a transient middle cerebral artery occlusion (tMCAO) model in male C57BL/6J mice and <em>in vitro</em> using an oxygen-glucose deprivation/reperfusion (OGD/R) model in Neuro-2a mouse neuroblastoma cells.</div></div><div><h3>Results</h3><div>High-mobility group box 1 (HMGB1) was identified as a key target of DSS-S. Following I/R or OGD/R, levels of IL-1β, IL-6, TNF-α, IL-18, and HMGB1 were significantly elevated in both mouse serum and cell culture supernatant, and these increases were substantially attenuated by DSS-S treatment. DSS-S reduced cytoplasmic HMGB1 accumulation, promoted its nuclear retention, down-regulated the receptor for advanced glycation end-products (RAGE), and weakened the HMGB1-RAGE interaction. Pyroptosis was activated in both tMCAO and OGD/R models, and DSS-S intervention effectively inhibited pyroptosis by suppressing the HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation.</div></div><div><h3>Conclusion</h3><div>DSS-S exerts neuroprotective effects against cerebral I/R injury <em>in vivo</em> and reduces OGD/R-induced injury <em>in vitro</em>. The protection is mediated through inhibition of pyroptosis, achieved by targeting the HMGB1/RAGE axis and suppressing NLRP3 inflammasome activation.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157109"},"PeriodicalIF":3.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923709","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 : 2026-01-10DOI: 10.1016/j.cyto.2026.157115
Jun Huang, Chao Wu, Yulan Zhang, Yifan Wu, Feiran Wang, Yi Zhou, Lu Shi
Background
Thyroid eye disease (TED), the most prevalent extrathyroidal manifestation of Graves' disease, involves insulin-like growth factor-1 (IGF-1) as a central pathogenic factor. Interleukin-36α (IL-36α), a key member of the IL-1 superfamily, has emerged as a critical regulator in autoimmune diseases.
Objective
To investigate the role of IL-36α in TED pathogenesis and elucidate the molecular mechanisms by which IGF-1 regulates IL-36α expression.
Methods
Specimens including serum and orbital connective tissues were obtained from TED subjects and controls. Orbital fibroblasts (OFs) were isolated from patients with TED. Enzyme-linked immunosorbent assay, immunohistochemistry, quantitative real-time PCR and Western blot analysis were performed.
Results
We demonstrated that IL-36α levels increased in the circulation and orbital connective tissues of patients with TED compared with controls, and levels were positively correlated with the clinical activity score. In vitro, IGF-1 induced IL-36α expression in OFs through NF-κB and p38 MAPK pathway activation. Furthermore, we revealed that IL-36α stimulation promoted robust pro-inflammatory cytokine production, which was effectively blocked by Interleukin-36 receptor antagonist (IL-36Ra) treatment.
Conclusions
IGF-1 upregulates IL-36α expression via NF-κB and p38 MAPK pathways to promote inflammation in TED, with IL-36α levels significantly correlating with disease activity. These findings identify IL-36α as a promising biomarker and therapeutic target for TED management.
{"title":"IGF-1 upregulates IL-36α expression via NF-κB and p38 MAPK pathways to promote inflammation in thyroid eye disease","authors":"Jun Huang, Chao Wu, Yulan Zhang, Yifan Wu, Feiran Wang, Yi Zhou, Lu Shi","doi":"10.1016/j.cyto.2026.157115","DOIUrl":"10.1016/j.cyto.2026.157115","url":null,"abstract":"<div><h3>Background</h3><div>Thyroid eye disease (TED), the most prevalent extrathyroidal manifestation of Graves' disease, involves insulin-like growth factor-1 (IGF-1) as a central pathogenic factor. Interleukin-36α (IL-36α), a key member of the IL-1 superfamily, has emerged as a critical regulator in autoimmune diseases.</div></div><div><h3>Objective</h3><div>To investigate the role of IL-36α in TED pathogenesis and elucidate the molecular mechanisms by which IGF-1 regulates IL-36α expression.</div></div><div><h3>Methods</h3><div>Specimens including serum and orbital connective tissues were obtained from TED subjects and controls. Orbital fibroblasts (OFs) were isolated from patients with TED. Enzyme-linked immunosorbent assay, immunohistochemistry, quantitative real-time PCR and Western blot analysis were performed.</div></div><div><h3>Results</h3><div>We demonstrated that IL-36α levels increased in the circulation and orbital connective tissues of patients with TED compared with controls, and levels were positively correlated with the clinical activity score. In vitro, IGF-1 induced IL-36α expression in OFs through NF-κB and p38 MAPK pathway activation. Furthermore, we revealed that IL-36α stimulation promoted robust pro-inflammatory cytokine production, which was effectively blocked by Interleukin-36 receptor antagonist (IL-36Ra) treatment.</div></div><div><h3>Conclusions</h3><div>IGF-1 upregulates IL-36α expression via NF-κB and p38 MAPK pathways to promote inflammation in TED, with IL-36α levels significantly correlating with disease activity. These findings identify IL-36α as a promising biomarker and therapeutic target for TED management.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157115"},"PeriodicalIF":3.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923711","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 : 2026-01-08DOI: 10.1016/j.cyto.2026.157108
Zheng Gu , Zong-tong Lin , Zhong-jie Yang , Qi-Yuan Zou , En-Mei Liu , Wei Kou , Ping Wei
Background
Adenoid hypertrophy (AH) is a common condition in children that can lead to various complications and significantly affect their growth and development. However, the underlying pathogenesis is not fully understood. This study aims to investigate Th2-M2 polarization in the pathogenesis of AH, focusing on a predominant type 2 inflammatory pattern.
Methods
We recruited control participants without AH and patients with AH combined with allergic rhinitis (AR), and investigated the predominant inflammatory type in AH with concomitant AR by measuring the Th cell sub-populations and the expression of their key transcription factors, and the levels of type 2 inflammatory factors IL-4 and IL-13 in the adenoid tissue. Additionally, the distribution and quantity of M2 macrophages (M2) in the adenoid tissue were detected to determine their involvement in the pathogenesis of type 2 inflammation-predominant AH. Finally, differentially expressed genes were identified through transcriptome RNA sequencing, followed by their functional validation. A co-culture system of CD68+ macrophages and CD4+ T cells was established, with IL-4 and dermatophagoides farinae intervention used to explore the role of Th2-M2 polarization in the pathogenesis of type 2 inflammatory predominant AH.
Results
We found that the predominant inflammatory subtypes in AH with concomitant AR were type 2 inflammation and Th17-type inflammation. Further investigation revealed that M2 is involved in the pathogenesis of type 2 inflammation- predominant AH. Transcriptome RNA sequencing identified differentially expressed genes CHI3L2, SOCS1, and STAT6. Functional validation revealed that the Th2-M2 polarization crosstalk promote M2 polarization and may participate in the pathogenesis of AH through the STAT6/SOCS1 pathway. Furthermore, CHI3L2 was found to be highly expressed in the adenoid tissue with a predominant type 2 inflammatory profile. The co-culture of CD68+ macrophages and CD4+ T cells along with IL-4 and dermatophagoides farina intervention further validated the sequencing results.
Conclusion
The Th2-M2 polarization may be involved in the pathogenesis of type 2 inflammatory predominant AH, possibly through the STAT6/SOCS1 pathway, which promotes the polarization of M2 macrophages, increases cellular proliferation in the adenoid tissue, and drives the disease process. CHI3L2 was highly expressed in type 2 inflammation–predominant AH and may serve as a promising biomarker candidate for this inflammatory subtype. Further studies are required to determine whether CHI3L2 functionally contributes to adenoid hypertrophy or immune-cell proliferation, which could serve as a therapeutic target.
{"title":"Th2-M2 polarization in the pathogenesis of adenoid hypertrophy is predominantly characterized by type 2 inflammation","authors":"Zheng Gu , Zong-tong Lin , Zhong-jie Yang , Qi-Yuan Zou , En-Mei Liu , Wei Kou , Ping Wei","doi":"10.1016/j.cyto.2026.157108","DOIUrl":"10.1016/j.cyto.2026.157108","url":null,"abstract":"<div><h3>Background</h3><div>Adenoid hypertrophy (AH) is a common condition in children that can lead to various complications and significantly affect their growth and development. However, the underlying pathogenesis is not fully understood. This study aims to investigate Th2-M2 polarization in the pathogenesis of AH, focusing on a predominant type 2 inflammatory pattern.</div></div><div><h3>Methods</h3><div>We recruited control participants without AH and patients with AH combined with allergic rhinitis (AR), and investigated the predominant inflammatory type in AH with concomitant AR by measuring the Th cell sub-populations and the expression of their key transcription factors, and the levels of type 2 inflammatory factors IL-4 and IL-13 in the adenoid tissue. Additionally, the distribution and quantity of M2 macrophages (M2) in the adenoid tissue were detected to determine their involvement in the pathogenesis of type 2 inflammation-predominant AH. Finally, differentially expressed genes were identified through transcriptome RNA sequencing, followed by their functional validation. A co-culture system of CD68<sup>+</sup> macrophages and CD4<sup>+</sup> T cells was established, with IL-4 and dermatophagoides farinae intervention used to explore the role of Th2-M2 polarization in the pathogenesis of type 2 inflammatory predominant AH.</div></div><div><h3>Results</h3><div>We found that the predominant inflammatory subtypes in AH with concomitant AR were type 2 inflammation and Th17-type inflammation. Further investigation revealed that M2 is involved in the pathogenesis of type 2 inflammation- predominant AH. Transcriptome RNA sequencing identified differentially expressed genes CHI3L2, SOCS1, and STAT6. Functional validation revealed that the Th2-M2 polarization crosstalk promote M2 polarization and may participate in the pathogenesis of AH through the STAT6/SOCS1 pathway. Furthermore, CHI3L2 was found to be highly expressed in the adenoid tissue with a predominant type 2 inflammatory profile. The co-culture of CD68+ macrophages and CD4<sup>+</sup> T cells along with IL-4 and dermatophagoides farina intervention further validated the sequencing results.</div></div><div><h3>Conclusion</h3><div>The Th2-M2 polarization may be involved in the pathogenesis of type 2 inflammatory predominant AH, possibly through the STAT6/SOCS1 pathway, which promotes the polarization of M2 macrophages, increases cellular proliferation in the adenoid tissue, and drives the disease process. CHI3L2 was highly expressed in type 2 inflammation–predominant AH and may serve as a promising biomarker candidate for this inflammatory subtype. Further studies are required to determine whether CHI3L2 functionally contributes to adenoid hypertrophy or immune-cell proliferation, which could serve as a therapeutic target.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"199 ","pages":"Article 157108"},"PeriodicalIF":3.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908816","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 : 2026-01-06DOI: 10.1016/j.cyto.2026.157106
Halah Amer Abduljabbar , Methaq J. Al-Jboori , Manal Taha Al-Obeidi , Majid Mohammed Mahmood
Polycystic ovary syndrome (PCOS) affects 4–21 % of reproductive-aged women, with elevated prevalence in Iraq. It involves chronic inflammation and dysregulated pro-inflammatory cytokines. This study investigates serum IL-17 A levels and its rs2275913 polymorphism, alongside the novel relevance of IL-36γ and its rs28947206/rs28947207 variants in PCOS pathogenesis. A total of 178 women underwent clinical, hormonal, and cytokine profiling. Genetic analysis was performed on a subset (n = 63) using PCR-Sanger sequencing. PCOS patients showed significantly elevated IL-17 A (48.7 ± 12.3 vs 32.1 ± 8.9 pg/ml) and IL-36γ (142.6 ± 28.4 vs 58.9 ± 14.7 pg/ml) levels (p < 0.001), with IL-36γ demonstrating superior diagnostic accuracy (AUC = 0.970 vs 0.851). Hormonal dysregulation included reduced FSH and elevated testosterone, AMH, LH, LH/FSH ratio, prolactin, and BMI (P < 0.05). Clinical features such as hirsutism, acne, alopecia, menstrual irregularities, and poor pregnancy outcomes were more prevalent (P < 0.05). IL-36γ rs28947206/rs28947207 variants were monomorphic in all subjects, marking the first report of these SNPs in PCOS. IL-17 A rs2275913 was significantly associated with PCOS, with the A allele (OR = 4.71) and AA genotype (OR = 10.71) linked to altered AMH, prolactin, and LH/FSH levels. IL-36γ is a promising diagnostic biomarker, while IL-17 A rs2275913 represents a genetic risk factor for PCOS in the Iraqi population.
多囊卵巢综合征（PCOS）影响4- 21%的育龄妇女，在伊拉克患病率升高。它涉及慢性炎症和促炎细胞因子失调。本研究探讨了血清il - 17a水平及其rs2275913多态性，以及IL-36γ及其rs28947206/rs28947207变异与PCOS发病机制的新相关性。共有178名妇女接受了临床、激素和细胞因子分析。使用PCR-Sanger测序对一个子集（n = 63）进行遗传分析。PCOS患者IL-17 A（48.7±12.3 vs 32.1±8.9 pg/ml）和IL-36γ（142.6±28.4 vs 58.9±14.7 pg/ml）水平显著升高（p . 2）
{"title":"Functional impact of IL-36γ rs28947206/rs28947207 and IL-17 a rs2275913 polymorphisms in polycystic ovary syndrome: Novel insights from the Iraqi population","authors":"Halah Amer Abduljabbar , Methaq J. Al-Jboori , Manal Taha Al-Obeidi , Majid Mohammed Mahmood","doi":"10.1016/j.cyto.2026.157106","DOIUrl":"10.1016/j.cyto.2026.157106","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) affects 4–21 % of reproductive-aged women, with elevated prevalence in Iraq. It involves chronic inflammation and dysregulated pro-inflammatory cytokines. This study investigates serum IL-17 A levels and its rs2275913 polymorphism, alongside the novel relevance of IL-36γ and its rs28947206/rs28947207 variants in PCOS pathogenesis. A total of 178 women underwent clinical, hormonal, and cytokine profiling. Genetic analysis was performed on a subset (<em>n</em> = 63) using PCR-Sanger sequencing. PCOS patients showed significantly elevated IL-17 A (48.7 ± 12.3 vs 32.1 ± 8.9 pg/ml) and IL-36γ (142.6 ± 28.4 vs 58.9 ± 14.7 pg/ml) levels (<em>p</em> < 0.001), with IL-36γ demonstrating superior diagnostic accuracy (AUC = 0.970 vs 0.851). Hormonal dysregulation included reduced FSH and elevated testosterone, AMH, LH, LH/FSH ratio, prolactin, and BMI (<em>P</em> < 0.05). Clinical features such as hirsutism, acne, alopecia, menstrual irregularities, and poor pregnancy outcomes were more prevalent (P < 0.05). IL-36γ rs28947206/rs28947207 variants were monomorphic in all subjects, marking the first report of these SNPs in PCOS. <em>IL-17 A</em> rs2275913 was significantly associated with PCOS, with the A allele (OR = 4.71) and AA genotype (OR = 10.71) linked to altered AMH, prolactin, and LH/FSH levels. IL-36γ is a promising diagnostic biomarker, while IL-17 A rs2275913 represents a genetic risk factor for PCOS in the Iraqi population.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"198 ","pages":"Article 157106"},"PeriodicalIF":3.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916389","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 TNF superfamily, composed of cytokines and their receptors, plays a central role in regulating immune responses, apoptosis, inflammation, and tissue regeneration. TNF itself is a key orchestrator of the cytokine cascade in many diseases and is often described as a “master regulator.” It engages in complex ligand-receptor interactions, making the study of these dynamics essential for the development of new therapeutic strategies.
This review summarizes the current experimental and computational tools used to study ligand–receptor interactions within the TNF superfamily, highlighting both their strengths and limitations. Particular attention is given to methods for analyzing protein–protein interactions, which are fundamental to deciphering the regulatory functions of this family. While traditional in vitro, in vivo, and in situ approaches have confirmed numerous authentic ligand–receptor pairs, in silico analyses reveal a much broader landscape of predicted interactions. These computational predictions do not represent experimentally validated binding events; rather, they indicate possible ligand–receptor compatibilities based on structural homology, interface similarity, and docking-derived binding energies. Such predictions suggest that the TNF interaction network may be more extensive than previously recognized, underscoring the need for systematic experimental validation to uncover additional biologically relevant interactions.
{"title":"Integrated experimental and computational approaches to analyze TNF superfamily ligand–receptor interactions","authors":"Anne-Laure Favier , Cyril Salama , Chloé Cervera , Diane Riccobono , Krisztina Nikovics","doi":"10.1016/j.cyto.2025.157100","DOIUrl":"10.1016/j.cyto.2025.157100","url":null,"abstract":"<div><div>The TNF superfamily, composed of cytokines and their receptors, plays a central role in regulating immune responses, apoptosis, inflammation, and tissue regeneration. TNF itself is a key orchestrator of the cytokine cascade in many diseases and is often described as a “master regulator.” It engages in complex ligand-receptor interactions, making the study of these dynamics essential for the development of new therapeutic strategies.</div><div>This review summarizes the current experimental and computational tools used to study ligand–receptor interactions within the TNF superfamily, highlighting both their strengths and limitations. Particular attention is given to methods for analyzing protein–protein interactions, which are fundamental to deciphering the regulatory functions of this family. While traditional <em>in vitro</em>, <em>in vivo</em>, and <em>in situ</em> approaches have confirmed numerous authentic ligand–receptor pairs, <em>in silico</em> analyses reveal a much broader landscape of predicted interactions. These computational predictions do not represent experimentally validated binding events; rather, they indicate possible ligand–receptor compatibilities based on structural homology, interface similarity, and docking-derived binding energies. Such predictions suggest that the TNF interaction network may be more extensive than previously recognized, underscoring the need for systematic experimental validation to uncover additional biologically relevant interactions.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"198 ","pages":"Article 157100"},"PeriodicalIF":3.7,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880905","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 : 2025-12-30DOI: 10.1016/j.cyto.2025.157102
Yuxi Huang , Piaorong Zeng , Tianmin Liu , Mei Xu , Wenyi Tang , Fangyuan Cheng , Zhijuan Zhou , Bairong Chen , Kan Liu , TouKun Chong , Jian Chen
Background
Takotsubo syndrome (TTS) and sepsis often co-occur with poor outcomes, yet their underlying molecular mechanisms remain to be elucidated. Transcriptomic analysis is employed to detect diagnostic biomarkers and reveal shared pathophysiological mechanisms in sepsis-associated TTS.
Methods
Myocardial gene expression data (TTS, sepsis, and controls) from GEO were analyzed to identify shared differentially expressed genes. WGCNA and PPI networks were used for candidate gene selection. Key genes were further refined using random forest and LASSO algorithms. Immune cell infiltration was assessed using CIBERSORT. Myocardial injury and gene expression in rat models were evaluated using HE staining, TUNEL assay, immunohistochemistry, qPCR, and Western blotting. Clinical validation was conducted using plasma samples from the China TTS Registry. t-tests and ANOVA were conducted via GraphPad Prism 8 software. A P-value < 0.05 was considered statistically significant.
Results
Lipocalin-2 (LCN2) was recognized as an important biomarker through WGCNA, PPI network analysis, and machine learning algorithms, showing strong predictive performance. Its expression was significantly associated with neutrophil infiltration and myocardial injury in TTS. Consistent with the bioinformatics findings, the TTS-sepsis comorbidity model showed elevated mRNA and protein levels of LCN2 in myocardial tissue, accompanied by increased neutrophil infiltration and severe cardiac injury. Clinical validation confirmed elevated plasma LCN2 levels in patients with sepsis-associated TTS, correlating with neutrophil counts, NT-proBNP, and cTnI levels.
Conclusion
LCN2 is identified as a key inflammatory mediator linking neutrophil-driven inflammation to myocardial injury in sepsis-associated TTS, with dual potential as a diagnostic biomarker and therapeutic target.
{"title":"Shared inflammation in takotsubo syndrome and sepsis: Lipocalin-2 mediates neutrophil infiltration and cardiac damage","authors":"Yuxi Huang , Piaorong Zeng , Tianmin Liu , Mei Xu , Wenyi Tang , Fangyuan Cheng , Zhijuan Zhou , Bairong Chen , Kan Liu , TouKun Chong , Jian Chen","doi":"10.1016/j.cyto.2025.157102","DOIUrl":"10.1016/j.cyto.2025.157102","url":null,"abstract":"<div><h3>Background</h3><div>Takotsubo syndrome (TTS) and sepsis often co-occur with poor outcomes, yet their underlying molecular mechanisms remain to be elucidated. Transcriptomic analysis is employed to detect diagnostic biomarkers and reveal shared pathophysiological mechanisms in sepsis-associated TTS.</div></div><div><h3>Methods</h3><div>Myocardial gene expression data (TTS, sepsis, and controls) from GEO were analyzed to identify shared differentially expressed genes. WGCNA and PPI networks were used for candidate gene selection. Key genes were further refined using random forest and LASSO algorithms. Immune cell infiltration was assessed using CIBERSORT. Myocardial injury and gene expression in rat models were evaluated using HE staining, TUNEL assay, immunohistochemistry, qPCR, and Western blotting. Clinical validation was conducted using plasma samples from the China TTS Registry. <em>t</em>-tests and ANOVA were conducted via GraphPad Prism 8 software. A <em>P</em>-value < 0.05 was considered statistically significant.</div></div><div><h3>Results</h3><div>Lipocalin-2 (LCN2) was recognized as an important biomarker through WGCNA, PPI network analysis, and machine learning algorithms, showing strong predictive performance. Its expression was significantly associated with neutrophil infiltration and myocardial injury in TTS. Consistent with the bioinformatics findings, the TTS-sepsis comorbidity model showed elevated mRNA and protein levels of LCN2 in myocardial tissue, accompanied by increased neutrophil infiltration and severe cardiac injury. Clinical validation confirmed elevated plasma LCN2 levels in patients with sepsis-associated TTS, correlating with neutrophil counts, NT-proBNP, and cTnI levels.</div></div><div><h3>Conclusion</h3><div>LCN2 is identified as a key inflammatory mediator linking neutrophil-driven inflammation to myocardial injury in sepsis-associated TTS, with dual potential as a diagnostic biomarker and therapeutic target.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"198 ","pages":"Article 157102"},"PeriodicalIF":3.7,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877364","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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