Cytokine最新文献

Tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) has been reported to be upregulated in thyroid cancer (THCA). However, the role and mechanism of TNFRSF12A in THCA remain largely unknown. TNFRSF12A expression in THCA samples was analyzed using bioinformatics analysis. CCK-8, EdU incorporation assay, TUNEL, and caspase-3 activity assay was used to detect cell proliferation and apoptosis in THCA cells. Correlated genes of TNFRSF12A were identified using LinkedOmics database and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Western blot analysis was performed to determine proliferating cell nuclear antigen (PCNA), cyclin D1 (CCND1), Bax, and Bcl-2 expression and to analyze the effect of TNFRSF12A on mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) pathways. Results showed that TNFRSF12A was increased in THCA tissue samples and cells. KEGG analysis showed that correlated genes of TNFRSF12A were significantly enriched in MAPK and NF-κB signaling pathways. Moreover, TNFRSF12A knockdown inactivated the MAPK and NF-κB signaling pathways in THCA cells. TNFRSF12A silencing alone or combined with inhibitor of ERK (PD98059), JNK (SP600125), p38 (SB203580), or NF-κB (Bay 11-7082) impeded cell proliferation and reduced PCNA and CCND1 expression in THCA cells. Meanwhile, TNFRSF12A knockdown alone or combined with PD98059, SP600125, SB203580, or Bay 11-7082 facilitated cell apoptosis, increased caspase-3 activity, downregulated Bcl-2 expression, and upregulated Bax expression in THCA cells. TNFRSF12A knockdown alone or combined with PD98059, SP600125, SB203580, or Bay 11-7082 also decreased the expression levels of proinflammatory cytokines IL-1β, IL-6, and IL-8 in THCA cells. On the contrary, TNFRSF12A overexpression showed an opposite effect. Treatment with PD98059, SP600125, SB203580, or Bay 11-7082 reversed the effects of TNFRSF12A overexpression on cell proliferation, apoptosis, and proinflammatory cytokine expression. In conclusion, the effects of TNFRSF12A on proliferation, apoptosis, and proinflammatory cytokine expression in THCA cells were regulated by the MAPK and NF-κB pathways.

Inflammation, driven by various stimuli such as pathogens, cellular damage, or vascular injury, plays a central role in numerous acute and chronic conditions. Current treatments are being re-evaluated, prompting interest in naturally occurring compounds like kaempferol, a flavonoid prevalent in fruits and vegetables, for their anti-inflammatory properties. This study explores the therapeutic potential of kaempferol, focusing on its ability to modulate pro-inflammatory cytokines and its broader effects on inflammatory signaling pathways. Comprehensive reviews of in vitro and in vivo studies were conducted to elucidate the mechanisms underlying its anti-inflammatory and antioxidant actions. Kaempferol effectively inhibits the production of key inflammatory mediators, including cytokines and enzymes such as COX-2 and iNOS, while also targeting oxidative stress pathways like Nrf2 activation. The compound demonstrated protective effects in various inflammatory conditions, including sepsis, neurodegenerative disorders, cardiovascular diseases, and autoimmune conditions, by modulating pathways such as NF-κB, MAPK, and STAT. Despite its promise, kaempferol's clinical application faces challenges related to its bioavailability and stability, underscoring the need for advanced formulation strategies. These findings position kaempferol as a promising candidate for anti-inflammatory therapy, with the potential to improve patient outcomes across a wide range of inflammatory diseases. Further clinical studies are required to validate its efficacy, optimize dosage, and address pharmacokinetic limitations.

Neuroinflammation is a key factor in cognitive and behavioral changes seen in patients with non-CNS cancers, and cytokine levels in the blood are often used as a proxy for brain inflammation. However, this approach has yielded inconsistent results, and a common inflammatory signature remains elusive. To explore whether a blood-to-brain inflammatory signature exists across breast cancer types, we assessed cytokine and glial protein responses in the hippocampus, prefrontal cortex (PFC), and their relationship to serum cytokines in mice bearing three different mammary cancers (n = 40). While cytokine profiles in both serum and brain varied by cancer type, IL-1β and IL-4 were consistently altered across brain regions. In some cases, elevated serum IL-1α and IL-6 correlated with increased hippocampal IL-6. These findings support the use of blood cytokines to identify cancer patients at risk for cognitive and psychiatric comorbidities. However, our data also suggest that relying solely on serum cytokines may lead to under-diagnosis, as some mice exhibited brain cytokine elevations without changes in serum levels. This underscores the need for a broader range of inflammatory markers in blood to better identify at-risk patients. Brain region-specific differences in the cytokine response to mammary cancer highlighted the hippocampus as more vulnerable to cancer-induced inflammation than the PFC. We observed region-specific glial cell reactivity, however, only astrocyte and oligodendrocyte markers were correlated with cytokine changes within the hippocampus. Elevated serum IL-1α and IL-6 were correlated with reduced cortical astrocyte reactivity, suggesting that these cytokines can inform glial cell-specific changes in this region.

Background: Tumor cells within the tumor microenvironment (TME) release exosomes that influence macrophage phenotypes, either pro-tumorigenic or anti-tumorigenic. This mechanism, especially in head and neck squamous cell carcinoma (HNSCC), remains poorly understood. This study investigates the role of HNSCC exosomes in macrophage polarization.

Methodology: Exosomes were isolated from HPV16-positive (93VU147T, UDSCC2) and HPV-negative (OCT1) HNSCC cell lines. These exosomes were characterized for their potential to modulate macrophage polarization. Uptake of PKH-26 labeled exosomes by macrophages was monitored via confocal microscopy. Changes in macrophage polarization were assessed using quantitative real-time PCR and immunoblotting. Exosomal transcripts and proteome cargo was examined for polarization associated mediators.

Results: HPV-negative exosomes showed higher uptake by THP1 resting macrophages (M0). Exosomes from HPV-positive cells induced a mixed macrophage phenotype (M1 and M2), whereas HPV-negative exosomes favored M1 polarization. Immunoblotting analysis revealed that this polarization was driven by the activation of transcription factors STAT1, NF-κB, and AP1. Transcriptomic analysis of HNSCC exosomes revealed reads for AP1 (c-Jun, c-Fos, FosB, Fra1, Fra2) and NF-κB (p50/105, p52/100, RelA, RelB, c-Rel), along with their known upstream mediators MEK1--7, JNK1-3, JAK1-3, TYK2, IKKα, and IKKβ. Splice variants of macrophage polarization markers, including iNOS and TGFβ, were also identified, though none of the exosomal proteome component corresponded to these factors.

Conclusion: HPV-negative exosomes are efficiently internalized by macrophages, promoting M1 polarization likely via modulation of STAT1, NF-κB, and AP1 signaling. These findings provide novel insights into role of tumor exosomes in modulation of macrophage-mediated TME dynamics in HNSCC.

Objective: To investigate the interaction of inflammatory factors related to pulmonary infection and the TLR4/NF-κB signaling pathway in patients with spontaneous intracerebral hemorrhage (ICH).

Methods: A total of 325 critically ill ICH patients treated in our hospital from May 2021 to February 2024 were selected for this study. Based on whether the patient developed a pulmonary infection during treatment, they were divided into the infection group (n = 86) and the non-infection group (n = 239). The distribution characteristics of pathogens were observed, and changes in serum and defensin, hs-CRP, IL-4, TLR4 mRNA, and NF-κB mRNA were compared. Pearson correlation analysis was used to analyze the relationship between serum defensin, inflammatory factors, and the TLR4/NF-κB signaling pathway. A logistic regression model was used to construct a combined prediction model with defensin, hs-CRP, IL-4, HMGB1, TLR4 mRNA, and NF-κB mRNA. ROC curves were drawn to analyze the area under the curve (AUC), sensitivity, and specificity of defensin, hs-CRP, IL-4, HMGB1, TLR4 mRNA, NF-κB mRNA, and the six combined parameters for predicting pulmonary infection in critically ill ICH patients.

Results: In 86 ICH patients with pulmonary infection, 94 strains of pathogens were isolated, with 28 (29.79 %) Gram-positive bacteria, 58 (61.70 %) Gram-negative bacteria, and 8 (8.51 %) fungi. The levels of defensin, hs-CRP, IL-4, HMGB1, TLR4 mRNA, and NF-κB mRNA in the infection group were significantly higher than those in the non-infection group (P < 0.05). Pearson correlation analysis showed that defensin, hs-CRP, IL-4, and HMGB1 were positively correlated with TLR4 mRNA and NF-κB mRNA (P < 0.05). ROC curve analysis showed that the AUC values for defensin, hs-CRP, IL-4, HMGB1, TLR4 mRNA, NF-κB mRNA, and the six combined parameters for predicting pulmonary infection were 0.789, 0.778, 0.690, 0.792, 0.741, 0.750, and 0.870, respectively.

Conclusion: The main pathogens causing pulmonary infection in critically ill ICH patients are Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, and Streptococcus hemolyticus. Defensin, hs-CRP, IL-4, HMGB1, and other indicators are influenced by the TLR4/NF-κB signaling pathway in patients with secondary pulmonary infection.

T lymphocytes are among the immunological cells that make up the tumor microenvironment (TME), and they are essential in the growth of tumors and anti-tumor reactions. Regulatory T cells (Treg cells) are a subset of CD4+ T cells in the immune system that suppress the immune system. They are distinguished by their expression of the master transcription factor forkhead box protein P3 (FOXP3). Furthermore, Treg cells are essential for maintaining immunological homeostasis, inhibiting inflammation, and maintaining self-tolerance. In a variety of malignancies within the TME, Treg cells demonstrate notable flexibility and functional diversity. Highly plastic Treg cells can change into Th-like Treg cells in specific circumstances, which allow them to secrete particular pro-inflammatory cytokines. Interleukin 35 (IL-35) is a part of the immunosuppressive cytokines that belong to the IL-12 family. Treg cells release IL-35, which was elevated in the peripheral blood and TME of numerous cancer patients, implying that IL-35 in the TME may be an intriguing target for cancer therapy. In cancer, IL-35 is a two-edged sword; it promotes tumorigenicity in cancer cells while shielding them from apoptosis. Nonetheless, other investigations have mentioned its conflicting effects on cancer prevention. Herein, we provide an updated understanding of the critical mechanisms behind the anticancer immunity mediated by Treg cells plasticity, the role of IL-35, and tactics to strengthen the immune response against malignancies, outlining major clinical trials that used Treg cells/IL-35 therapies in the three main cancer types (lung, breast, and colorectal cancers).

Objective: Based on current evidence suggesting that bisphenol A (BPA) may contribute to obesity through the modulation of inflammatory markers, this study aims to investigate the correlation between BPA exposure and cellular inflammatory factors in preschool children.

Methods: A total of 155 preschool children aged 4-6 years were included. Urine and blood samples were collected. BPA exposure was detected by liquid chromatography-tandem mass spectrometry through urine samples. The levels of six inflammatory cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were determined by flow fluorescence technique. The correlation between urinary BPA exposure and cellular inflammatory factors was analyzed using Spearman's correlation and respectively stratified by gender and BMI.

Results: The detection rate of BPA in urine samples was 100 %. The median urinary BPA concentration was 0.48 μg/L(IQR:0.25-1.02 μg/L), and the creatinine-adjusted BPA concentration was 0.94 μg/g(IQR:0.57-1.66 μg/g). BPA level was negatively correlated with IL-10 (r = -0.172, P < 0.05). After stratification by gender, the negative association between BPA exposure and IL-10 was found in females (r = -0.257, P < 0.05), while no association was found in males. According to BMI stratification, BPA exposure in overweight/obese children was positively correlated with IL-6 (r = 0.354, P < 0.05).

Conclusions: Our study demonstrated that BPA exposure in preschool children was correlated with a decrease in levels of IL-10, and this effect was significantly expressed in girls. In addition, BPA exposure in overweight/obese children was correlated with increased levels of IL-6. However, the mechanism between BPA and inflammatory factors remains to be further explored.

Toll-like receptors (TLRs) are crucial for the detection of infections and activation of downstream signaling pathways that lead to the production of pro-inflammatory cytokines and interferons. Because of their strong immunostimulatory activity, TLRs are thought to be a "double-edged sword" for systemic treatment, even in the cancer field. To solve this, we have developed dextran-based TAM targeting activator conjugate (D-TAC) technology which successfully uses tumor-associated macrophages (TAMs) to deliver the TLR7 agonist DSP-0509. We have demonstrated that the anti-tumor effect of our best drug candidate 5DEX-0509R is dependent on the abundance of TAMs, which is consistent with their mechanism of action. In this study, we compared the anti-tumor effects of EIK1001 and 5DEX-0509R, and analyzed its unique immune reaction against tumors to evaluate whether 5DEX-0509R is suitable for further clinical study. 5DEX-0509R showed superior anti-tumor activity compared to EIK1001, an R848 sulfate currently in phase 2 trials, with comparable systemic cytokine profiles. 5DEX-0509R elicited unique CD4 T cell and B cell-dependent anti-tumor effects. We also found that 5DEX-0509R synergistically suppresses tumors with oxaliplatin by changing M2 macrophages that cause oxaliplatin to become resistant to antitumor M1 macrophages. In addition, 5DEX-0509R caused a rapid but not sustained cytokine elevation in both rats and dogs. We believe 5DEX-0509R is worth pursuing for clinical trials.

In the post-pandemic era, research on respiratory diseases should refocus on pathogens other than the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Respiratory pathogens, highly infectious to children, with to different modes of infection, such as single-pathogen infections and co-infections. Understanding the seasonal patterns of these pathogens, alongside identifying single infections and co-infections and their impact on the pediatric immune status, is crucial for clinical diagnosis, treatment, and prognosis in children. Our study found that from December 2023 to April 2024, the main co-infection combinations in children shifted from Mycoplasma pneumonia and influenza virus A (MP + IVA) to Bordetella pertussis and rhinovirus (BP + RhV). To explore the impact of these infections, two cohorts were established to analyze the effects of single and co-infections of four respiratory pathogens, MP, IVA, BP, and RhV, on the immune status of pediatric patients. Using multi-cytokine analysis, cytokines, such as PDGF-BB, that were differentially expressed between patients with single and co-infections were identified. Additionally, we observed that children with single-pathogen infections generally exhibited more severe conditions, as evidenced by higher overall cytokine expression than those with co-infections. Our findings provide an important theoretical basis for understanding the pathogenic mechanisms of single and co-infections of respiratory pathogens and clinically differentiating pediatric patients with various respiratory infections.

Background: Tuberculous pleural effusion (TPE) diagnosis still faces many difficulties and challenges. Some studies have shown that pleural interleukin -27 (IL-27) had a diagnostic potential for TPE. However, their findings are not always consistent. This study aimed to investigate the diagnostic accuracy of pleural IL-27 for TPE.

Methods: We prospectively enrolled 211 patients with undiagnosed pleural effusion. Effusion Mycobacterium tuberculosis (Mtb) culture, Ziehl-Neelsen staining, biopsy, and response to antituberculosis therapy were used to define TPE. The pleural IL-27 levels were determined by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic curve (ROC) with the area under the curve (AUC) was used to evaluate the diagnostic accuracy of IL-27 for TPE. In addition, we investigated the influence of age on the diagnostic performance of IL-27 by resampling patients with different upper age limits in the inclusion criteria.

Results: Among the 211 enrolled participants, 33 were TPE and 178 were non-TPE. The mean concentration of IL-27 in TPE patients was significantly higher than that of non-TPE patients. The AUC of IL-27 was 0.76 (95 %CI: 0.67-0.86). At the threshold of 500 pg/mL, the sensitivity and specificity of IL-27 were 0.26 (95 %CI: 0.20-0.33) and 0.91 (95 %CI:0.76-0.97), respectively. The AUC of IL-27 is 0.84 in patients with an upper age limit of 70. Still, it decreased to 0.76 in patients with an upper age limit of 75.

Conclusion: Age can affect the diagnostic performance of IL-27 for TPE.