Interleukin Research Articles

Impact of oral flora in tongue coating and saliva on oral cancer risk and the regulatory role of Interleukin-8

BackgroundOral flora and inflammatory factors play a crucial role in oral cancer, but the relationship between them and oral cancer has not been clearly established. MethodsOral flora served as exposure factor, oral cancer as outcome factor, and inflammatory factors as mediating factor. Mendelian randomization (MR) analysis was used to analyze the relationship between oral flora and oral cancer, and the potential mediating effect of inflammatory factors was explored through mediation analysis. Results29 kinds of oral flora in tongue coating and 22 kinds of oral flora in saliva were associated with increased risk of oral cancer. 18 species of oral flora in tongue coating and 25 species in saliva were associated with a reduced risk of oral cancer. Interleukin-8 (IL8) played a mediating role in the relationship between oral flora and oral cancer, and it was associated with an increased risk of oral cancer. Granulicatella, Streptococcus mitis, Saccharimonadaceae and Haemophilus in oral flora caused oral cancer indirectly through IL8. IL8 expression increased in oral cancer, which has good diagnostic value. IL8-related genes in oral cancer are closely associated with immune cell infiltration. What's more, IL8 has potential medicinal properties. ConclusionOral flora of tongue coating and saliva is closely related to oral cancer, and IL8 plays a mediating role in the causal relationship between oral flora and oral cancer.

Association of genetic variations of interleukin-6 polymorphism (rs1800795) with susceptibility to Hashimoto’s thyroiditis in West Algerian population

Aim: Hashimoto’s thyroiditis is a polygenic auto-immune disease with a complex etiopathogenesis. It is more common in females. An imbalance between pro-inflammatory and anti-inflammatory cytokines may play an important role in the disease pathogenesis. Numerous studies have been conducted to find an association between genetic polymorphisms and the development of Hashimoto’s thyroiditis. In this context, we proposed to study the impact of the interleukin-6 (IL-6) gene polymorphism (rs1800795) on the genetic susceptibility to Hashimoto’s thyroiditis. Methods: Polymorphism in IL-6 gene (rs1800795) was assessed in a case-control study involving a population of Western Algeria with 81 Hashimoto’s thyroiditis patients and 211 unrelated healthy subjects, matched in age and sex. The DNA was extracted by a magnetic bead-based technique. The genetic study was performed by molecular biology: real-time PCR using TaqMan single nucleotide polymorphism (SNP) genotyping assay with Applied Biosystems 7500 device. Results: Results showed that the GG and GC genotypic distribution is similar between patient and control groups with a higher frequency of the GG genotype (80.25% in patients and 78.67% in controls vs. 19.75% of patients and 20.38% of controls with the GC genotype). The CC genotype is absent in patients and present in only 02/211 healthy subjects. The frequency of the polymorphic G allele was similar in the two groups, with 90.1% and 88.8% in patients and controls respectively (P > 0.05). Conclusions: This study reports no significant difference in IL-6 (-174 G/C) gene polymorphism at the allelic or the genotypic level between Hashimoto’s patients and the control group (P > 0.05). No association between the SNP IL-6 rs1800795 and susceptibility to Hashimoto’s thyroiditis in Western Algerian population.

Interleukin 15-Presenting Nanovesicles with Doxorubicin-Loaded Ferritin Cores for Cancer Immunochemotherapy.

Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non-specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin-loaded ferritin (Dox-Fn) are reported. The DoxFILN significantly enhances the densities and activities of intratumoral CTLs and NK cells. Mechanistically, DoxFILN undergoes deshelling in the acidic tumor microenvironment, releasing Dox-Fn and membrane-bound IL15c. Dox-Fn selectively target transferrin receptors on cancerous cells, facilitating intracellular Dox release and inducing immunogenic cell death. Concurrently, membrane-bound IL15c recognizes and activates IL15 receptor β/γc heterodimers, leading to a remarkable increase in the proliferation and activation of CTLs (16-fold and 28-fold) and NK cells (37-fold and 50-fold). The IL15-displaying nanovesicle introduced here holds promise as a potential platform for immunochemotherapy in the treatment of cancer.

ANTIVIRAL IL-33-STUMULATED GROUP 2 INNATE LYMPHOID CELLS (CD-90 AND CD-117) FROM MOUSE LUNGS

This article represents not only a significant scientific value, but also a great teaching and instruction value for researchers and motivated students to improve the skill spectrum in flow cytometry. This article provides step-by- step procedure description and results based on in vivo studies on murine lung tissue, cell of interest isolation with dual protocols for flow cytometry method as well as IL-33 impact in dynamics. The newly described innate lymphoid cells of group 2 (ILC2) play an important role in type 2 immune reactions, epithelial repair in mucosal tissue and metabolic homeostasis. ILC2 releases large amounts of type 2 cytokines such as interleukin 4 (IL-4), IL-5 and IL-13, which stimulate type 2 immunity, such as protection against worms. However, without strict regulation, the level of ILC2 can cause undesirable type 2 immune pathologies, including allergic inflammation of the respiratory tract, hypersensitivity of the respiratory tract and atopic dermatitis. Viral infections of the respiratory tract, which are typical triggers of type 1 immune reactions, often lead to type 2 pulmonary immune pathologies, such as asthma and its exacerbations. Interestingly, pulmonary virus infections induce the release of IL-33 with subsequent induction of ILC2-mediated type 2 pulmonary immunopathology, which is independent of the adaptive immune system.

Necroptosis contributes to deoxynivalenol-induced liver injury and inflammation in weaned piglets

BackgroundThe aim of this study was to investigate the role of necroptosis in deoxynivalenol (DON)-induced liver injury and inflammation in weaned piglets.MethodsIn Exp. 1, 12 weaned piglets were divided into 2 groups including pigs fed basal diet and pigs fed diet contaminated with 4 mg/kg DON for 21 d. In Exp. 2, 12 weaned piglets were divided into 2 groups including control piglets and piglets given a gavage of 2 mg/kg body weight (BW) DON. In Exp. 3, 24 weaned piglets were used in a 2 × 2 factorial design and the main factors including necrostatin-1 (Nec-1) (DMSO or 0.5 mg/kg BW Nec-1) and DON challenge (saline or 2 mg/kg BW DON gavage). On 21 d in Exp. 1, or at 6 h post DON gavage in Exp. 2 and 3, pigs were killed for blood samples and liver tissues. Liver histology, blood biochemical indicators, and liver inflammation and necroptosis signals were tested.ResultsDietary or oral gavage with DON caused liver morphological damage in piglets. Dietary DON led to hepatocyte damage indicated by increased aspartate transaminase (AST) activity and AST/alanine aminotransferase (ALT) ratio, and DON gavage also caused hepatocyte damage and cholestasis indicated by increased AST and alkaline phosphatase (AKP) activities. Dietary DON caused liver necroptosis indicated by increased protein abundance of total receptor interacting protein kinase 3 (t-RIP3) and total mixed lineage kinase domain-like protein (t-MLKL). Moreover, DON gavage increased mRNA expression of interleukin (IL)-6 and IL-1β in liver. DON gavage also induced liver necroptosis demonstrated by increased protein abundance of t-RIP3, phosphorylated-RIP3 (p-RIP3), t-MLKL and p-MLKL. However, pretreatment with Nec-1, a specific inhibitor of necroptosis, inhibited liver necroptosis indicated by decreased protein expression of t-RIP3, p-RIP3, t-MLKL and p-MLKL. Nec-1 pretreatment reduced liver morphological damage after DON gavage. Pretreatment with Nec-1 also attenuated liver damage induced by DON indicated by decreased activities of AST and AKP. Furthermore, Nec-1 pretreatment inhibited liver mRNA expression of IL-6 and IL-1β after DON challenge.ConclusionsOur data demonstrate for the first time that necroptosis contributes to DON-induced liver injury and inflammation in piglets.

Improving dexamethasone drug loading and efficacy in treating rheumatoid arthritis via liposome: Focusing on inflammation and molecular mechanisms.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 0.46% of the global population. Conventional therapeutics for RA, including disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, frequently result in unintended adverse effects. Dexamethasone (DEX) is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties. Liposomal delivery of DEX, particularly when liposomes are surface-modified with targeting ligands like peptides or sialic acid, can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity. This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA. Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models, reduces joint inflammation and damage, and alleviates cartilage destruction compared to free DEX. The liposomal formulation also shows better hemocompatibility, fewer adverse effects on body weight and immune organ index, and a longer circulation time with higher bioavailability. The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) and B-cell-activating factor (BAFF), which are key players in the pathogenesis of RA. Additionally, liposomal DEX can induce the expression of anti-inflammatory cytokines like interleukin-10 (IL-10), which has significant anti-inflammatory and immunoregulatory properties. The findings suggest that liposomal DEX represents a promising candidate for effective and safe RA therapy, with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.

Clinical characteristics and predictive indictors of macrolide-unresponsive Mycoplasma pneumoniae pneumonia in children: a retrospective study

IntroductionMacrolide-unresponsive Mycoplasma pneumoniae pneumonia (MUMPP) cases have been rapidly increasing. The primary reason for this increased incidence is the pathogen's acquisition of resistance through mutations in 23S rRNA genes. Due to the unfeasibility of testing for macrolide susceptibility at the time of admission, this study aimed to assess the clinical features of pediatric MUMPP, using insights from laboratory tests and patterns of chest radiographic resolution.Material and methodsWe conducted a retrospective review of 161 patients with M. pneumoniae pneumonia (MPP) between January 2023 and December 2023. These patients were categorized into two groups based on their responsiveness to macrolides: 72 patients were in the MUMPP group, and 89 patients were in the macrolide-sensitive Mycoplasma pneumoniae pneumonia (MSMP) group.ResultsMUMPP patients experienced a longer duration of fever and hospital stay. A higher proportion of MUMPP patients had shortness of breath, transcutaneous blood oxygen saturation (SpO2) lower than 94%, bilateral lobar infiltrates, lobar pneumonia and pleural effusion. The serum level of serum ferritin (SF), interleukin-6(IL-6), D-dimer, lactate dehydrogenase to albumin rate (LAR), and neutrophil to lymphocyte rate (NLR) were higher in MUMPP group.ConclusionsOur findings revealed that patients with MUMPP exhibit more severe initial radiographic indicators and clinical course compared to those with MSMP. Therefore, it is crucial to promptly administer alternative therapeutic agents besides macrolides for the management of MUMPP.

Clinical Outcomes and Cytokine Profile of Standard and Short Implant-supported Prostheses in Diabetics Treated for Periodontal Disease: A 5-year Study.

The present cross-sectional study aimed to assess the clinico-radiographic parameters as well as salivary levels of receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-α) around standard and short dental implants (SDIs)-supported fixed partial denture in partially dentate type-II diabetes mellitus (T2DM) patients treated for periodontitis. The study comprised 4 groups: group 1 included T2DM patients with standard implants (n = 20); group II included non-T2DM patients with standard implants (n = 20); group III included T2DM patients with SDIs (n = 20); and group IV included non-T2DM patients with SDIs (n = 20). Participants eligible for the study included medically diagnosed T2DM patients with glycated hemoglobin (HbA1c) levels ≥ 6.5%, and non-T2DM participants with HbA1c levels between 4.0% and 5.0%. All had undergone previous periodontal therapy and had at least one standard implant and one SDI in the posterior maxillary or mandibular region. Exclusions were subjects with systemic conditions other than T2DM, recent use of steroids or antimicrobials, pregnancy or lactation, edentulism, misaligned dentition, or alcohol/tobacco use. Treatment involved non-surgical periodontal therapy, implant placement, and prosthetic procedures, with assessments including clinical (plaque index [PI], bleeding on probing [BOP], probing depth [PD]), radiographic (crestal bone loss [CBL]) parameters, and salivary cytokine levels including RANKL, OPG, IL-6, and TNF-α. The study groups, each comprising 20 participants, showed no significant differences in demographics, restoration type, T2DM duration, family history, body mass index, or brushing routine (p>0.05). At baseline and 5-year follow-up, T2DM participants exhibited poorer periodontal parameters compared to non-T2DM, with higher PI (baseline: 62.2 ± 5.8% vs 29.6 ± 3.7%; 5-year follow-up: 69.2 ± 6.1% vs 32.8 ± 3.8%), BOP (baseline: 30.5 ± 3.2% vs 18.2 ± 2.6%; 5-year follow-up: 35.5 ± 3.9% vs 20.5 ± 2.5%), PD (baseline: 5.5 ± 1.1 mm vs 3.1 ± 0.9 mm; 5-year follow-up: 4.2 ± 0.8 mm vs 2.4 ± 0.7 mm), and CBL (baseline: 4.4 ± 0.4 mm vs 2.0 ± 0.2 mm; 5-yearfollow-up: 4.9 ± 0.5 mm vs 2.3 ± 0.3 mm), regardless of implant type. Salivary cytokine levels (RANKL, OPG, IL-6, TNF-α) were consistently higher in T2DM groups than non-T2DM across both implant types. Participants with SDIs showed comparable clinico-radiographic outcomes and salivary levels of cytokines to standard implants. The application of SDI-supported rehabilitation in T2DM and non-diabetics showed comparable clinico-radiographic outcomes and salivary levels of cytokines to standard dental implants. Furthermore, T2DM patients exhibit poorer periodontal health and elevated inflammatory markers in patients with standard implants and SDIs.

Handgrip strength is independently associated with physical quality of life in patients undergoing maintenance hemodialysis: a cross-sectional study

ObjectiveWe aimed to identify the association between Health-related quality of life (HRQoL) and muscle strength in patients undergoing maintenance hemodialysis (MHD).MethodsIn this cross-sectional study from March 2021 to December 2021, 110 MHD patients with a mean age of 63.9 ± 13.0 years and a median dialysis vintage of 25.5 (12.0–52.3) months, were enrolled at a hemodialysis center in Guangzhou city, China. HRQoL was assessed using the Short Form 36 Health Survey (SF-36) and converted into the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The groups were assigned according to the mean score of PCS and MCS, and those with higher PCS/MCS scores (high-PCS/MCS) were compared with those with lower PCS/MCS scores (low-PCS/MCS). Independent factors were evaluated using multivariate analysis. Muscle strength was estimated by handgrip strength (HGS).ResultsThe mean HGS was 23.7 ± 9.60 kg in men and 14.3 ± 5.30 kg in women. Compared to the high-PCS group, the low-PCS group had older age, higher levels of creatinine, total cholesterol, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), and had lower HGS (all p < 0.05). After adjusting for confounding factors in different models, the five-model multivariate binary logistic regression analyses revealed that HGS was the only independent factor in PCS domain, but not in MCS.ConclusionHGS may be an independent factor of poor HRQoL in MHD patients, particularly in relation to physical health. The management of muscle strength may improve the HRQoL in MHD patients.Clinical trial registrationThe study was registered at https://www.chictr.org.cn/ as ChiCTR2100053790.

Observation on the therapeutic effect of probiotics on early oral feeding in the treatment of severe acute pancreatitis

ObjectivesTo evaluate the clinical efficacy of probiotics and early oral feeding in patients with severe acute pancreatitis.MethodsA prospective, randomized, controlled trial was conducted involving 66 patients, who were randomly divided into a control group (n = 32) receiving standard enteral nutrition and an observation group (n = 34) receiving additional Bifidobacterium quadruplex live bacterial tablets. Serum inflammatory markers, including white blood cells (WBC), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP), were measured on days 1, 3, and 7 post-admission. Abdominal pain scores, the computed tomography severity index (CTSI), and the Bedside Index for Severity in Acute Pancreatitis (BISAP) scores were also assessed. Additionally, defecation time and the total duration of hospitalization were compared between the two groups.ResultsInflammatory markers declined in all groups by the third day post-admission, with the observation group exhibiting a significantly greater reduction compared to the control group (p < 0.05). Similarly, from the first day to the third day, both groups experienced a decrease in abdominal pain scores, CTSI, and BISAP scores, with the observation group showing a significantly more pronounced decrease in BISAP scores compared to the control group (p < 0.05). By the seventh day of admission, inflammatory markers continued to decline in all groups compared to the third day, except for TNF-α levels, and the observation group demonstrated a significantly greater decrease compared to the control group (p < 0.05). Abdominal pain scores, CTSI, and BISAP scores also decreased further in both groups compared to the third day, with the observation group again showing a significantly greater improvement than the control group (p < 0.05). Additionally, the observation group had a significantly shorter time to bowel movement resumption (38.23 ± 2.31 h vs. 43.43 ± 2.75 h, p = 0.013) and total hospital stay compared to the control group (10.97 ± 0.35 days vs. 13.40 ± 0.50 days, p < 0.001).ConclusionEarly oral ingestion combined with probiotics can reduce the levels of inflammatory factors, improve abdominal pain symptoms, alleviate pancreatic edema and shorten defecation time and hospital stay in patients with severe acute pancreatitis.

The Mitochondrial Fusion Promoter M1 Mitigates Cigarette Smoke-Induced Airway Inflammation and Oxidative Stress via the PI3K-AKT Signaling Pathway.

This study investigated the efficacy and underlying mechanism of the mitochondrial fusion promoter M1 in mitigating cigarette smoking (CS)-induced airway inflammation and oxidative stress both in vitro and in vivo models. Cigarette smoke extract (CSE)-treated airway epithelial cells (BEAS-2B) and CS-exposed mice were pretreated with M1, followed by the measurement of proinflammatory cytokines, oxidative stress, mitochondrial fusion proteins (MFN2 and OPA1) and fission proteins (DRP1 and MFF). Molecular pathways were elucidated through transcriptomic analysis and Western blotting. M1 pretreatment in CSE-treated cells significantly reduced the release of inflammatory cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α); reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels; increased superoxide dismutase (SOD) activity; protected mitochondrial function by increasing the expression of mitochondrial fusion proteins (MFN2 and OPA1) and decreasing the expression of mitochondrial fission proteins (DRP1 and MFF). M1 attenuated CS-induced lung histologic damage and mucus hypersecretion in mice, relieved high oxidative stress and reduced the release of IL-6 and IL-8 in BALF. Similarly, it also protected mitochondrial function by regulating the CS-induced imbalance of mitochondrial dynamic proteins. Transcriptome sequencing and Western blotting showed that M1 inhibited CSE- or CS-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway. M1 plays a protective role in inflammation, oxidative stress and mitochondrial dynamics dysfunction caused by CS by inhibiting the PI3K-AKT signaling pathway; thus, it has therapeutic potential for the treatment of CS-induced airway disorders.

IL33-induced neutrophil extracellular traps (NETs) mediate a positive feedback loop for synovial inflammation and NET amplification in rheumatoid arthritis.

This study investigated the mechanisms driving the induction and sustained presence of neutrophil extracellular traps (NETs) in the synovial microenvironment of rheumatoid arthritis (RA). Synovial tissue and fluid samples were collected from patients with RA and osteoarthritis (OA), and NET levels and cytokine concentrations were measured using a cytometric bead array and enzyme-linked immunosorbent assay (ELISA). The ability of interleukin-33 (IL-33) to induce NET formation was evaluated using quantitative assays, immunofluorescence staining, live-cell imaging, and electron microscopy. Coincubation experiments of NETs with fibroblast-like synovial cells (FLSs) were conducted, and a modified Transwell migration assay was designed to assess neutrophil migration. The role of IL-33 and NETs in RA progression was further investigated using a collagen antibody-induced arthritis (CAIA) mouse model. The results revealed an increase in NETs and IL-33 levels in the synovial fluid of RA patients, with a significant positive correlation between them. NET formation assays confirmed that IL-33 activates neutrophils to produce NETs and that neutrophils from RA patients exhibit increased responsiveness to IL-33 stimulation. Both in vitro and in vivo evidence has demonstrated that NETs stimulate FLSs to secrete IL-33 and the chemokine CXCL8 via Toll-like receptor 9, promoting further neutrophil recruitment and increasing NET production within the RA synovium. This study reveals a novel positive feedback loop involving NETs and FLSs that is mediated by IL-33 that increases NET accumulation in RA. Targeting IL-33 or NET formation and amplification may offer new therapeutic strategies for managing RA.

Основные противовоспалительные цитокины и интерлейкин 6 у больных ревматоидным артритом: взаимосвязи и клиническое значение

In the pathogenesis of rheumatoid arthritis (RA), an important role is played by dysfunction between the production of the main anti-inflammatory interleukins (IL) IL-4, IL-10 and proinflammatory (IL-6) cytokines. Objective. Determination of IL-4, IL-6 and IL-10 concentrations in RA patients with advanced stage of the disease, assessment of the relationship between them, clinical indices of disease activity, the presence of rheumatoid factor (RF) and antibodies to cyclic citrullinated peptide (CCP). Material and methods. The study included 154 RA patients (41 males and 113 females) of middle age (56.0 (50.0; 64.0) years), disease duration (9.4 (3.0; 13.0) years), seropositive 129 (83.8 %) for IgM RF and/or 106 (68.8 %) ACPP with moderate or high (DAS28-ESR – 5.40 (4.65; 6.00)) disease activity. The concentration of IL-4, IL-6, IL-10 in the blood serum was determined by multiplex technology. Results. In patients with RA, the concentration of IL-4 did not differ significantly from the control, and for IL-6 and IL-10 it was significantly higher than in donors. High values of IL-6 were significantly more common (51.6 %) than IL-4 (12.33 %, p = 0.001) and IL- 10 (16.23%, p = 0.001). Reliable correlations were found between the hyperproduction of IL-4 and IL-6, IL-6 and IL-4, IL-10. For IL-4 and IL-10, such an association was not found. The concentration and frequency of increased IL-4, IL-6, IL-10 did not differ in patients positive or negative for IgM RF. The concentration of IL-4 was significantly higher in the group of patients seronegative for ACPA compared to seropositive ones, and the prevalence of high IL-4 values was also noted in this group. No such association was found for IL-6 and IL-10. The concentration of IL-6 significantly positively correlated with the indices (DAS28-ESR, CDAI, SDAI) of clinical activity of RA, and the level of IL-4 was positively associated with CDAI, SDAI, IgM RF and inversely with ACPA values. The concentration of IL-10 was associated with CDAI, SDAI, IgM RF. Conclusion. In patients with RA in the advanced stage of the disease, the production of IL-6 predominates over the production of IL-4 and IL-10. In the presence of interrelations between these cytokines, there are certain differences in the associations with clinical indices and laboratory indicators of disease activity, IgM RF and ACPA.

Concurrent intratumoural Treg cell depletion and CD8+ T cell expansion via a cleavable anti-4-1BB-interleukin-15 fusion protein.

Potent agonists of the inducible co-stimulatory receptor 4-1BB are too toxic for patients with advanced cancer. Here, on the basis of observations of a weak agonist of 4-1BB depleting regulatory T (Treg) cells within the tumour microenvironment without leading to substantial restoration of dysfunctional cytotoxic T cells (CTLs), we show that effective tumour control can be achieved via concurrent Treg cell depletion and CTL expansion through an anti-4-1BB antibody fused to interleukin-15 (IL-15) via a peptide sensitive to tumour proteases. In mouse models of advanced cancers, intraperitoneal injection of the bifunctional protein attenuated the activity of the interleukin mostly in the periphery of the primary tumour while allowing for the expansion of CTLs within the tumour microenvironment, led to more effective tumour inhibition and to lower systemic toxicity than treating the cancers with combinatorial treatment with unlinked anti-4-1BB antibody and IL-15, and reduced the resistance of tumours to checkpoint blockade. Concurrent eradication of Treg cells and activation of tumour-infiltrating lymphocytes may represent a general strategy for the effective control of advanced metastatic tumours.

Basophils: Regulators of lung inflammation over space and time.

In this issue of JEM, Schuijs et al. (https://doi.org/10.1084/jem.20240103) highlight a novel role for basophils during allergic immune responses to house dust mites (HDM). They reveal that interleukin-33 (IL-33)-activated basophils facilitate the recruitment and extravasation of Th2 cells into the lungs during a specific time frame via their interactions with pulmonary endothelial cells.

Protective Effects of Antcin H Isolated from Antrodia cinnamomea Against Neuroinflammation in Huntington's Disease via NLRP3 Inflammasome Inhibition.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. When the CAG repeat exceeds 36, it results in the accumulation of the mutant HTT (mHTT) protein in neurons and glial cells. Key pathological mechanisms in HD include excitotoxicity, energy dysfunction, impaired mitochondrial function, increased oxidative stress, and neuroinflammation. The NLRP3 inflammasome is a multimeric protein complex element of NLRP3, ASC, and caspase-1, which regulates interleukin (IL)-1β and IL-18 secretion. The NLRP3 inflammasome plays an important role in inflammatory reactions and is involved in the pathogenesis of several neurodegenerative diseases. We have previously demonstrated high NLRP3 inflammasome expression levels in the striatum of R6/2 mice (a transgenic HD mouse model). Systematic administration of an NLRP3 inhibitor (MCC950) to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, suggesting protective effects against HD. Antrodia cinnamomea is an indigenous medicinal fungus in Taiwan, which shows diverse medicinal and pharmacological activities, but its effects in HD are not well understood. Herein, we report that systematic administration of Antcin-H isolated from A. cinnamomea to R6/2 mice suppressed the NLRP3 inflammasome, IL-1β production, and reduced neuronal toxicity. Most importantly, oral administration of Antcin-H reduced disease progression by increasing neuronal survival, reducing neuroinflammation during an extended lifespan, and improving motor dysfunction in R6/2 mice. Taken together, our data suggest that Antcin-H has therapeutic potential for treating HD.

Health Implications of Proinflammatory Cytokine Activity at Different Levels of Fluoride Exposure: A Systematic Review.

The chronic intake of excessive fluoride (F-) (> 1.5 mg/L) affects several tissues, organs, and systems. This represents a worldwide issue due to the presence of the compound in nature, with drinking water being the main source of exposure. The underlying mechanisms by which F- is toxic are not completely understood, but proinflammatory cytokine activity is implicated in these events. The aim of this study was to perform a systematic review of the health implications of proinflammatory cytokine activity at different levels of F- exposure. The search for original studies in which the activity of proinflammatory cytokines was assessed under exposure to F- was performed using the PubMed, Scopus, Springer, EBSCO, and Google Scholar databases by applying the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered with PROSPERO (CRD42024546726). Sixteen studies were analyzed in the present review. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (β), IL-6, IL-2, IL-12, IL-17, IL-18, C-reactive protein, and transforming growth factor-β (TGF-β) were the proinflammatory cytokines identified in the included reports. Alterations in cytokine activity were observed in response to varying levels of F- exposure, implicating an increased risk of toxicity and damage to the evaluated structures by highlighting the role of inflammation in the progression of these processes. Hence, the activity of proinflammatory cytokines at different levels of F- exposure has important implications for health, where inflammation plays a relevant role in the underlying mechanisms related to the resulting toxicity.

<em>Influenzinum</em> and <em>Echinacea</em>: boosters of immune response in vitro

Background: Some homeopathic medicines are traditionally used in medical practice to strengthen immunity and reduce inflammation. In particular, Influenzinum is used in clinical practice for the prevention of influenza-like illness, the management of possible symptoms following an anti-influenza vaccination and post-infectious convalescence. Echinacea angustifolia is the best known for its beneficial effects on the immune system and infectious syndrome. During an infection (viral or bacterial), the innate immunity is the first body response. It is an immediate inflammatory reaction which involves, among other factors, phagocytosis and oxidative stress at the cellular level (1). Objectives: To evaluate in vitro the effect of homeopathic dilutions of Influenzinum 9CH and 15CH and Echinacea angustifolia 5CH on biological markers of cellular inflammation and phagocytosis in several cellular models. Results: In inflamed macrophages, Influenzinum 9CH significantly increases the production of IL-6 (Interleukin-6) and MCP-1 (Monocyte Chemoattractant Protein-1) by 26% and 34%, respectively, compared with placebo which help to eliminate pathogens. In inflamed endothelial cells, Influenzinum 9CH and 15CH significatly decrease ICAM-1(InterCellular Adhesion Molecule-1) production by 20% compared with placebo, limiting the vascular inflammation. Furthermore, Influenzinum 9CH and 15CH demonstrated an antioxidant effects by significantly decreasing total ROS (reactive oxygen species) in inflamed primary microglia cells. Moreover, Echinacea angustifolia 5CH significantly increases the phagocytosis by 15% in monocytes and 25% in microglial cells compared with water (placebo) in non-inflammatory conditions. Conclusions: We demonstrated that Influenzinum and Echinacea angustifolia have a biological action in cell models in vitro. In inflammatory conditions, Influenzinum 9CH and 15CH have (i) immunostimulant effect, (ii) anti-inflammlatory effect on vascular cells, (iii) antioxidant effect. Echinacea angustifolia 5CH stimulates phagocytosis. Overall, Influenzinum and Echinacea angustifolia have a boosting effect on various biological parameters of innate immunity.

Peli1 Deficiency in Macrophages Attenuates Pulmonary Hypertension by Enhancing Foxp1-Mediated Transcriptional Inhibition of IL-6.

The infiltration of macrophages into the lungs is a common characteristic of perivascular inflammation, contributing to vascular remodeling in pulmonary hypertension (PH). Peli1 (pellino E3 ubiquitin-protein ligase 1) plays a critical role in regulating the production of proinflammatory cytokines and the polarization of macrophages in various diseases. However, the role of Peli1 in PH remains to be investigated. The expression and biological function of Peli1 were investigated in both human and experimental models of PH. Peli1-deficient mice and bone marrow transplant mice were utilized to explore the roles of Peli1 in macrophages in vivo. Proteomic analysis and molecular biology techniques were used to uncover the underlying mechanisms. The upregulation of Peli1 in the lungs and alveolar macrophages was observed in hypoxia-treated mice. Peli1 knockout mice and myeloid Peli1-deficient mice significantly ameliorated hypoxia-induced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Mechanistically, Peli1 facilitated the ubiquitination and subsequent proteasomal degradation of Foxp1 (forkhead box p1), thereby alleviating its suppression of IL (interleukin)-6 transcription and contributing to macrophage activation. Furthermore, myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in hypoxia-induced PH mice. Our findings demonstrate that the Peli1-Foxp1-IL-6 pathway plays a crucial role in macrophage activation and recruitment during the development of PH, underscoring the potential of Peli1 as a therapeutic target for PH.

Therapeutic potency of kaempferol against Naja haje venom induced neurotoxicity, inflammation, biological activities, and antioxidant system damage: a pre-clinical antivenom evaluation.

Naja haje envenoming manifests organ system disorders leading to severe fatalities due to the venom's toxins. The neutralizing capacity of kaempferol has been reported against some medically significant snake venoms with exception of N. haje venom (NhV). This current study assessed the neutralizing profile of kaempferol against toxicities induced by NhV using in vitro and in vivo methods. In in vitro, NhV induced wide spectrum of toxic biological activities with substantial increase in hemorrhagic, anticoagulating, and hemolytic effects. Likewise in the in vivo study, the venom caused hematological disorders by inducing acute anemia, thrombocytopenia, and leucopenia in envenomed rats. Also, the venom caused detrimental effect on the antioxidant defense system of the brain through significant (P < 0.05) elevation of malondialdehyde (MDA), nitrite (NIT), and suppression of reduce glutathione (GSH) antioxidant, superoxide dismutase (SOD), catalase (CAT), and glutathione transferase (GST) enzymes. Additionally, the levels of neurotoxicity biomarkers, monoamine oxidase (MAO) and acetylcholinesterase (AChE), and pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were significantly (P < 0.0.5) enhanced by NhV in the brain of envenomed rats. Severe pathohistological effects were observed in brain tissues of the envenomed rats. However, kaempferol substantially (P < 0.05) inhibited the NhV-induced biological activities, normalized the hematological disorders, enhanced antioxidants system functions, and significantly (P < 0.05) suppressed the levels of neurotoxicity biomarkers and pro-inflammatory cytokines. Severe structural alterations observed in the brain tissues were ameliorated after kaempferol treatment. Further exploration of kaempferol could lead to the development of an alternative therapy for treatment of N. haje envenoming.