Interleukin Research Articles

Enhancing neonatal sepsis detection: A comparative analysis of interleukin-6 and the BacT/ALERT blood culture system

One of the main causes of newborn mortality is neonatal sepsis, which has to be diagnosed quickly and precisely. Although the Bact/ALERT method for blood culture is commonly used, it is often slow, for early identification of sepsis, interleukin-6 (IL-6) provides a quicker substitute. : This study evaluates how well the BacT/ALERT system and IL-6 diagnose newborn sepsis, aiming to determine the most reliable and timely method for improving neonatal outcomes. A clinician at the National Institute of Medical Sciences & Research who admitted neonates to the neonatal intensive care unit (NICU) suspected 120 newborns of having sepsis. The inclusion criteria were satisfied by newborns between the ages of 0 and 28 days who showed clinical signs of sepsis. Exclusion criteria included infants with congenital anomalies or those who had received antibiotics before sampling. In this study of 120 neonates, IL-6 levels were elevated in 45% of the cases, with a sensitivity of 100%, specificity 86.84%, PPV 81.48% and NPV 100% for. 36.67% of samples had bacterial growth identified by the BacT/ALERT system. In just three hours, IL-6 produced results, which was far quicker than the BacT/ALERT method. IL-6 is a rapid, sensitive marker for neonatal sepsis, offering faster diagnosis than BacT/ALERT. Combining both methods may improve early detection and treatment outcomes. IL-6 offers rapid, high-sensitivity sepsis detection compared to BacT/ALERT, which, despite being slower, is crucial for pathogen identification. Combining both methods could enhance early diagnosis and treatment.

CD11b deficiency attenuates the ischemia/reperfusion-induced AKI-to-CKD process by regulatingmacrophage polarization.

Severe acute kidney injury (AKI) is a risk factor for the future development of chronic kidney disease (CKD), and macrophages are an essential cell group implicated in injury, repair, and fibrosis during this progress. However, the underlying mechanism of how macrophages participate in the development of the disease is largely unclear. CD11b (Integrin αM) is highly expressed in monocytes/macrophages and has been verified to mediate broad functions. We found that CD11b-knockout mice were protected from the ischemia/reperfusion-induced AKI-to-CKD process. Additionally, renal macrophages from the kidneys of CD11b-deficient mice presented an M2-like, anti-inflammatory phenotype. We demonstrated both invitro and invivo that enhanced alternative activation in CD11b-knockout macrophages is regulated by the interleukin (IL)-4/signal transducer and activator of transcription (STAT) 6 axis, which is mediated by the inactivation of the Src-family kinase (SFK) member Lyn. Importantly, the therapeutical administration of CD11b-neutralizing antibody can effectively prevent AKI-to-CKD progress. Thus, our study verifies that CD11b plays a critical role in limiting the alternative activation of macrophages and may be a potential therapeutic target during the AKI-to-CKD process.

Особенности секреции интерлейкина-6 и скорость окисления жиров у детей с конституционально-экзогенным ожирением с различным уровнем физической активности

Physical inactivity is accompanied by a decrease of skeletal muscle mass and is one of the main reasons for obesity. Interleukin-6 (IL-6) acts as a paracrine and endocrine regulator of the intensity of carbohydrate and fat metabolism during exercises. The purpose of this research was to evaluate the fat oxidation rate and serum IL-6 in children with simple obesity depending on the level of daily physical activity (PA). Methods used: a cross-sectional, single-center sampling study that included 53 children aged 12 to 18 y/o (27 boys/26 girls) with obesity (SDS BMI 3.0 [2.6;3.3]) divided into two groups depending on the level of daily PA was conducted. The maximal fat oxidation (MFO) was assessed during ergometric stress testing with gas analysis. The IL-6 was assessed by ELISA at baseline and after a single physical activity. The level of daily PA was determined using the IPAQ international questionnaire Results: basal IL-6 level in children with obesity and low PA was 1.18 [0.42;1.55] pg/ml and was statistically significantly increased compared to the group of children without physical inactivity, 0.57 [0.22;0.8] pg/ml (p=0.029). The values of IL-6 after physical activity in both boys and girls with obesity and physical inactivity were statistically significantly increased compared with the group of children with obesity and moderate/high PA (p=0.032 and p=0.012 for boys and girls, respectively). The MFO in children with a low level of PA was 0.33 [0.22;0.41] g/min and did not significantly differ statistically from the group of peers with moderate or high PA (0.31 [0.25;0.36] g/min; p=0.431). Conclusion: a sedentary lifestyle in obese children leads to an increase in both basal and stimulated IL-6 secretion and is not accompanied by a decrease in maximal fat oxidation.

Local cell therapy using CCL19-expressing allogeneic mesenchymal stem cells exerts robust antitumor effects by accumulating CD103+ IL-12-producing dendritic cells and priming CD8+ T cells without involving draining lymph nodes

BackgroundImmune checkpoint blockade is a promising anticancer therapy, whereas the presence of T cells in tumor sites is indispensable for its therapeutic efficacy. To promote the infiltration of T cells...

Immune Checkpoint Inhibitor Myopathy: The Double-Edged Sword of Cancer Immunotherapy.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

Association Between Peripheral Blood Regulatory T Cell Content with Inflammatory Stress Response and Immune Response in Children with Sepsis.

The study aims to analyze the correlation between Regulatory T(Treg) Cells and inflammatory stress response and immune response in sepsis patients. Sixty sepsis patients admitted between January 2021 and June 2023 were selected as the subjects and included in the observation group. During the same period, 80 healthy children who underwent physical examinations in the hospital were included in the control group. The Treg content, inflammatory mediators, and immune response biochemical indicators of two groups are compared. The Pearson correlation analysis verifies the correlation between Treg content and inflammatory stress response, and immune response. Treg content in the observation group exceeded that found in the control group (P < 0.05). Among the relevant biochemical indicators, Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Procalcitonin (PCT), and Hypersensitive C-reactive protein (hs-CRP) exceeded that found in healthy children (P < 0.05). The immunoglobulin IgA, IgM, and IgG in healthy children were below respective values in the control group (P < 0.05). The Pearson correlation data demonstrated that the peripheral blood Treg content in children with sepsis was positively related to inflammatory mediator indicators. It was negatively related with the immunoglobulin IgA, IgM, and IgG. In summary, when the Treg content in the peripheral blood of sepsis patients increases, it directly affects the body's inflammatory stress response and immune function.

Efficacy of biomarkers and imaging techniques for the diagnosis of traumatic brain injury: challenges and opportunities.

Concussion is a pervasive health issue in the present day. Increased prevalence in recent years has indicated a need to improve the current understanding of minor traumatic brain injury (mTBI). Effort has been devoted to understanding the underlying pathophysiology of TBIs, but some mechanisms remain unknown. Potentially lethal secondary effects of concussion include second impact syndrome and chronic traumatic encephalopathy (CTE), introducing long-term considerations for the management of mTBI. Post-concussion syndrome is another long-term consequence of concussion and may be influenced by both neuroinflammation and hormonal imbalances resulting from head trauma. Genetically mutated apolipoprotein E may also contribute to the severity and persistence of concussion symptoms, perhaps even acting as a risk factor for CTE. As it stands, the diagnosis of concussion is nuanced, depending primarily on subjective diagnostic tools that incorporate patient-reported symptoms and neurocognitive tests. Diagnostic tools provide some assistance in concussion diagnosis, but still lack accuracy and inherently leave room for uncertainty. To mitigate some of this uncertainty, considerable research has been devoted to the development of methods to diagnose concussions objectively. Biomarkers such as S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), neurofilament light protein (Nf-L), interleukin-6 (IL-6) and microRNAs (miRNAs) as well as imaging techniques including diffusion tensor imaging (DTI) and blood-oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) show great promise in this regard. This review aims to compile the relevant literature in these areas in the hopes of being used as a reference point for future research regarding concussions.

Exploring the Efficacy of Joint Lavage in Knee Osteoarthritis: A Focus on Cytokines, Degrading Enzymes, and Oxidative Stress.

This study aimed to assess the effectiveness of joint lavage in managing knee osteoarthritis (OA) by evaluating its effect on pain relief, inflammatory markers, cartilage-degrading enzymes, and oxidative stress. Seventy patients with Kellgren-Lawrence grade 2 or 3 knee OA were selected for this single-center study. Joint lavage was performed, and pain and function were measured using the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline and 24 weeks postintervention. Synovial fluid samples were collected at baseline, before lavage, and 24 weeks postintervention. Samples were stored at -80°C and analyzed in batches to minimize variability. At the time of analysis, the samples were thawed and evaluated for levels of proinflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), matrix metalloproteinase-3 (MMP-3), and total oxidant status (TOS), and oxidative stress index (OSI). Postintervention, VAS, and WOMAC scores significantly decreased (P < 0.001), with 100% achieving the minimal clinically important difference (MCID). Patient acceptable symptom state (PASS) rates varied: VAS (80%), WOMAC pain (50%), function (81.4%), and total (84.3%). Cytokine levels (IL-1β, IL-6, TNF-α) and MMP-3 significantly decreased (P < 0.001), along with TOS and OSI. Baseline TNF-α, IL-6, and IL-1β levels were significantly correlated with improvements in VAS and WOMAC scores. Moderate correlations were observed between reductions in IL-6/TNF-α and improvements in VAS/WOMAC. No significant associations were found between confounders and outcomes. Joint lavage resulted in marked pain relief and functional improvement while significantly reducing inflammatory markers, cartilage-degrading enzymes, and oxidative stress.

α-Pyrrolidinooctanophenone facilitates activation of human microglial cells via ROS/STAT3-dependent pathway.

Pyrrolidinophenone derivatives (PPs) are amphetamine-like designer drugs containing a pyrrolidine ring, and their adverse effects resemble those of methamphetamine (METH). Microglial activation has been recently suggested as a key event in eliciting the adverse effects against dysfunction of the central nervous system. The aim of this study is to clarify the mechanisms of microglial activation induced by PPs. We employed the human microglial cell line HMC3 to assess microglial activation induced by PPs and evaluated the capacities for proliferation and interleukin-6 (IL-6) production that are characteristic features of the activation events. The WST-1 assay indicated that viability of HMC3 cells was increased by treatment with sublethal concentrations (5-20µM) of α-pyrrolidinooctanophenone (α-POP), a highly lipophilic PP, whereas it was decreased by treatment with concentrations above 40µM. Treatment with sublethal α-POP concentrations up-regulated the expression and secretion of IL-6. Additionally, α-POP-induced increase in cell viability was restored by pretreating with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, and stattic, an inhibitor of signal transducer and activator of transcription 3 (STAT3), respectively, suggesting that activation of the ROS/STAT3 pathway is involved in the α-POP-induced activation of HMC3 cells. The increases in cell viability were also observed in HMC3 cells treated with other α-POP derivatives and METH. These results suggest that enhanced productions of ROS and IL-6 are also involved in microglial activation by drug treatment and that HMC3 cell-based system is available to evaluate accurately the microglial activation induced by abused drugs.

Cannabis use in youth is associated with chronic inflammation.

Markers of inflammation and cannabis exposure are associated with an increased risk of mental disorders. In the current study, we investigated associations between cannabis use and biomarkers of inflammation. Utilizing a sample of 914 participants from the Avon Longitudinal Study of Parents and Children, we investigated whether interleukin-6 (IL-6), tumor necrosis factor α (TNFα), C-reactive protein (CRP), and soluble urokinase plasminogen activator receptor (suPAR) measured at age 24 were associated with past year daily cannabis use, less frequent cannabis use, and no past year cannabis use. We adjusted for a number of covariates including sociodemographic measures, body mass index, childhood trauma, and tobacco smoking. We found evidence of a strong association between daily or near daily cannabis use and suPAR. We did not find any associations between less frequent cannabis use and suPAR. We did not find evidence of an association between IL-6, TNFα or CRP, and cannabis use. Our finding that frequent cannabis use is strongly associated with suPAR, a biomarker of systemic chronic inflammation implicated in neurodevelopmental and neurodegenerative processes is novel. These findings may provide valuable insights into biological mechanisms by which cannabis affects the brain and impacts the risk of serious mental disorders.

Development of a prediction nomogram for IgG levels among asymptomatic or mild patients with COVID-19

ObjectiveCOVID-19 has evolved into a seasonal coronavirus disease, characterized by prolonged infection duration and repeated infections, significantly increasing the risk of patients developing long COVID. Our research focused on the immune responses in asymptomatic and mild cases, particularly the critical factors influencing serum immunoglobulin G (IgG) levels and their predictive value.MethodsWe conducted a retrospective analysis on data from 1939 asymptomatic or mildly symptomatic COVID-19 patients hospitalized between September 2022 and June 2023. Spearman methods were used to test the correlation between serum IgG and age, immunoglobulin M (IgM), procalcitonin (PCT), interleukin-6 (IL-6), nucleic acid conversion time, and BMI. Univariate and multivariate logistic regression analyses identified independent key factors influencing serum IgG levels, which were integrated and visualized in a nomogram. Finally, receiver operating characteristic (ROC) curves were plotted to predict the model’s diagnostic performance by calculating the AUC.ResultsMild patients showed higher levels of IgG, IgM, and longer nucleic acid conversion times than asymptomatic patients, and a lower proportion of them had received ≥ 3 COVID-19 vaccine doses. Serum IgG was positively correlated with serum IgM and negatively correlated with age, PCT, IL-6, and BMI. Notably, it showed a moderate negative correlation with nucleic acid conversion time (r = -0.578, P &amp;lt; 0.001). Logistic regression results showed that younger age, lower IL-6 levels, ≥ 3 doses of vaccine, and no comorbidities were independent predictors of serum IgG levels ≥ 21.08 g/L. We used age, IL-6 levels, vaccine doses, and comorbidities to create a nomogram for predicting serum IgG levels, with the area under the ROC curve reaching 0.772.ConclusionAge, IL-6 levels, vaccination status, and comorbidities were independent predictors of serum IgG levels in asymptomatic or mild COVID-19 patients, facilitating risk stratification and clinical decision-making. Notably, receiving ≥3 doses of the COVID-19 vaccine was the most beneficial factor for elevated serum IgG levels.

Enhancing recovery and reducing inflammation: the impact of enhanced recovery after surgery recommendations on inflammatory markers in laparoscopic surgery—a scoping review

IntroductionThe relationship between the Enhanced Recovery After Surgery (ERAS) guidelines and inflammatory markers in laparoscopic surgery has garnered increasing attention. These recommendations are designed to minimize surgical stress and potentially improve recovery outcomes by modifying perioperative care.ObjectiveThis scoping review aims to evaluate the impact of ERAS recommendations on inflammatory markers in patients undergoing laparoscopic surgeries, identifying current research gaps and consolidating findings from existing studies.MethodsGuided by the Cochrane Handbook for Systematic Reviews and adhering to the PRISMA-ScR guidelines, this review analyzed studies from databases like PubMed, Scopus, and Cochrane Library. We included both randomized controlled trials and observational studies that assessed inflammatory markers such as C-reactive protein (CRP), white blood cells (WBC), and Interleukin-6 (IL-6) in laparoscopic surgery patients managed with ERAS recommendations.ResultsOut of 64 initial studies, 7 met the inclusion criteria, involving a total of 2,047 patients. Most of the studies focused on laparoscopic colorectal surgeries. Commonly assessed markers were CRP and WBC. The findings consistently showed that ERAS guideline could mitigate the inflammatory response, evidenced by reduced levels of CRP and IL-6, which correlated with fewer postoperative complications and expedited recovery.ConclusionERAS recommendations appear to beneficially modulate inflammatory responses in laparoscopic surgery, which suggests a potential for enhanced recovery outcomes. However, the evidence is currently limited by the small number of studies and inherent methodological biases. Further robust RCTs are required to strengthen the evidence base and refine these protocols for broader clinical application. Systematic Review Registrationhttps://osf.io/tj8mw/

Treatment of cancer-associated fibroblast-like cells with celecoxib enhances the anti-cancer T helper 1/Treg responses in breast cancer.

Tumor inflammation, as one of the hallmarks of cancer, has been the target for anti-cancer treatments. Celecoxib is a selective inhibitor of the enzyme cycloxygenase-2 (COX-2) and inhibits the production of PGE2, which is an important mediator of tumor inflammation produced by cancer cells and cells of the tumor microenvironment. In this study, we aimed at inhibiting COX-2 using celecoxib, expressed in cancer-associated fibroblast (CAF)-like cells isolated from breast cancer and evaluated the alterations in their cytokine profile and gene expression. CAF-like cells were isolated by explant culture from 13 breast cancer tissues. Simultaneously, peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood. CAF-like cells were treated with 10µM of celecoxib and expression of genes COX-2, smooth muscle actin-alpha (α-SMA), and production of prostaglandin E2 (PGE2), Interleukin 10 (IL10), and transforming growth factor beta1 (TGF-β1) was evaluated. Next, PBMCs were co-cultured with celecoxib-treated CAF-like cells and the expression of genes T-bet, Foxp3, GATA-3; production of cytokines IFN-ɣ, IL-10, IL-4, TGF-β1, and the mediator PGE2 were assessed by real-time-PCR and ELISA, respectively. Isolated CAF-like cells showed expression of fibroblast activation protein (FAP). Treatment with celecoxib was able to efficiently reduce the production of PGE2 and the expression of α-SMA in isolated CAF-like cells. Furthermore, PBMCs in co-culture with these cells showed enhanced Th1 phenotype including T-bet and IFNγ expression and decreased the phenotypical markers of regulatory T cells such as FoxP3 and IL-10 and TGF-β1 production. Our study shows the important role of COX-2 in CAFs by promoting immune suppression. Our results suggested that high expression of COX-2 in CAFs may serve as a new therapeutic, targeting CAFs in enhancing immune responses in breast cancer treatment.

Site-Specific Glyco-Tagging of Native Proteins for the Development of Biologicals.

Glycosylation is an attractive approach to enhance biological properties of pharmaceutical proteins; however, the precise installation of glycans for structure-function studies remains challenging. Here, we describe a chemoenzymatic methodology for glyco-tagging of proteins by peptidoligase catalyzed modification of the N-terminus of a protein with a synthetic glycopeptide ester having an N-acetyl-glucosamine (GlcNAc) moiety to generate an N-GlcNAc modified protein. The GlcNAc moiety can be elaborated into complex glycans by trans-glycosylation using well-defined sugar oxazolines and mutant forms of endo β-N-acetylglucosaminidases (ENGases). The glyco-tagging methodology makes it possible to modify on-demand therapeutic proteins, including heterologous proteins expressed in E. coli, with diverse glycan structures. As a proof of principle, the N-terminus of interleukin (IL)-18 and interferon (IFN)α-2a was modified by a glycopeptide harboring a complex N-glycan without compromising biological potencies. The glyco-tagging methodology was also used to prepare several glycosylated insulin variants that exhibit reduced oligomerization, aggregation, and fibrillization yet maintained cell signaling properties, which are attractive for the development of insulins with improved shelf-lives. It was found that by employing different peptidoligases, it is possible to modify either the A or both chains of human insulin.

Canine Adipose-Derived Mesenchymal Stromal Cells Reduce Cell Viability and Migration of Metastatic Canine Oral Melanoma Cell Lines In Vitro

Canine oral melanoma (COM) is a promising target for immunomodulatory therapies aimed at enhancing the immune system’s antitumor response. Given that adipose-derived mesenchymal stem cells (Ad-MSCs) possess immunomodulatory properties through cytokine release, we hypothesized that co-culturing Ad-MSCs and canine peripheral blood mononuclear cells (PBMCs) could stimulate interleukin (IL) production against melanoma cell lines (MCCLs) and help identify therapeutic targets. This study evaluated IL-2, IL-8, and IL-12 expressions in co-culture with MCCL, Ad-MSCs, and PBMCs and assessed the relationship between gene expression, cell viability, and migration. Using four experimental groups in a Transwell insert system to separate cell types, we found that Ad-MSCs can reduce MCCL migration and viability, though the effect may vary depending on each cell line’s susceptibility. Furthermore, Ad-MSCs modified IL expression profiles in co-cultured cells. Our findings suggest that Ad-MSCs could have therapeutic potential for COM by inhibiting cell migration and reducing viability. However, deeper insights into Ad-MSC interactions with the tumor microenvironment and melanoma-specific factors will be essential to optimize therapeutic efficacy.

Lentiviral Injection of Inter-α-Trypsin Inhibitor Heavy Chain 4 Promotes Female Spinal Cord Injury Mice Recuperation by Diminishing Peripheral and Central Inflammation.

Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) acts as a mediator of inflammation and extracellular matrix stabilization. The current study intended to delve into the impact of ITIH4 on locomotor performance, nerve injury, neuroinflammation, systemic inflammation, and the downstream pathway in spinal cord injury (SCI) mice. Overexpression lentivirus of ITIH4 (LV-ITIH4) and negative control lentivirus (LV-NC) were intravenously injected into adult C57BL/6 mice on 7days before SCI surgery. All mice were euthanized on day 28 after SCI surgery, and their blood samples and spinal cord tissues were collected. Decreased relative gene expression and protein levels of ITIH4 were observed in SCI mice. LV-ITIH4 improved the locomotor performance compared to LV-NC in SCI mice. In spinal cord of SCI mice, LV-ITIH4 reduced apoptosis and increased survival of neurons compared to LV-NC. By comparison with LV-NC, LV-ITIH4 also reduced relative gene expressions of interleukin (IL)-6 and tumor necrosis factor-α in spinal cord of SCI mice. Moreover, LV-ITIH4 reduced microglia M1 polarization compared with LV-NC in spinal cord of SCI mice. In the serum, LV-ITIH4 decreased the protein levels of IL-6 and IL-1β compared to LV-NC in SCI mice. LV-ITIH4 also inhibited the nuclear factor kappa-B (NF-κB) pathway compared to LV-NC in spinal cord of SCI mice. ITIH4 enhances locomotor performance in SCI mice, and it inhibits nerve injury, neuroinflammation, systemic inflammation, and the NF-κB pathway in SCI mice.

The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling.

Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGFβ-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGFβ-specific immunity in PC. Here, we explored the importance of IL-6 for TGFβ-specific immunity in PC. In a murine model of PC, coadministration of the TGFβ-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGFβ-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGFβ-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.

Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of SM17 in healthy volunteers: results from pre-clinical models and a first-in-human, randomized, double blinded clinical trial

BackgroundAlarmins mediate type 2 T helper cell (Th2) inflammation and serve as upstream signaling elements in allergic inflammation and autoimmune responses. The alarmin interleukin (IL)-25 binds to a multi-domain receptor consisting of IL-17RA and IL-17RB subunits, resulting in the release of Th2 cytokines IL-4, IL-5, IL-9 and IL-13 to drive an inflammatory response. Therefore, the blockage of IL-17RB via SM17, a novel humanized monoclonal antibody, offers an attractive therapeutic target for Th2-mediated diseases, such as asthma.MethodsWild-type mice were stimulated with house dust mite (HDM) extracts for evaluation of SM17’s pre-clinical efficacy in allergic asthma. The safety, pharmacokinectics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) doses of SM17 were assessed in a 2-part clinical study in healthy adult subjects. In Part A, 53 healthy participants were enrolled to receive a single IV dose of SM17 (2, 20, 70, 200, 400, 600, 1200 mg) or placebo. In Part B, 24 healthy subjects were enrolled to receive a single IV dose of SM17 every two weeks (Q2W; 200, 400, 600 mg) or placebo for a total of 3 doses.ResultsAnimal studies demonstrated that SM17 significantly suppressed Th2 inflammation in the bronchoalveolar lavage fluid and infiltration of immune cells into the lungs. In the Phase I clinical study, no drug-related serious adverse events were observed. Total SM17 exposure increased by approximately 60- to 188-fold with a 60-fold increase in dose from 20 to 1200 mg SM17. Upon administration of the third dose, mean accumulation ratios over 200-600 mg was 1.5 to 2.1, which confirms moderate accumulation of SM17. After Q2W dosing of SM17 over 4 weeks, total exposure increased in a dose-proportional manner from 200 mg to 600 mg SM17.ConclusionIn the pre-clinical studies, we demonstrated that SM17 is a potential therapeutic agent to treat allergic asthma. In the Phase 1 clinical trial, a single IV dose of SM17 up to 1200 mg and three Q2W doses up to 600 mg were well tolerated in healthy participants and demonstrated a favorable safety profile. The pre-clinical efficacy and clinical PK and immunogenicity results of SM17 support further clinical development.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT05332834.

Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages.

The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.

Intraperitoneal Treatment of Cambinol, a Synthetic SIRT1 and SIRT2 Inhibitory Compound, Exacerbates Brucella abortus 544 Burden in the Spleens of Institute of Cancer Research Mice

Our preliminary data using bone marrow-derived macrophages (BMDMs) collected from ICR mice treated with anti-sirtuin (anti-SIRT) 1 antibody showed that Brucella uptake was significantly attenuated. We then further investigated the effect of an inhibitor of SIRT1/2, cambinol, in the progression of Brucella. The in vitro results using RAW264.7 cells revealed that cambinol treatment had no effect on adhesion, uptake, intracellular survival and nitric oxide (NO) production during B. abortus infection, nor did it directly affect bacterial growth for up to 72 h. Finally, intraperitoneal treatment of 8-week-old female ICR mice infected with Brucella showed no differences in the total average weights of spleens and livers; however, the treated mice displayed higher Brucella colony-forming units (CFUs) from the spleens. Furthermore, the interleukin (IL)-10 serum level was observed to be lower in treated mice at 7 d post-infection, and none of the cytokines tested showed a change at 14 d post-infection. The overall findings showed that cambinol treatment had no effect on the proliferation of Brucella in RAW264.7 macrophages but exacerbated the splenic proliferation of the bacteria in mice and displayed reduced anti-inflammatory cytokine IL-10 at the first week of infection, suggesting that cambinol as an inhibitory of SIRT1/2 could be beneficial in the context of Brucella dissemination in animal hosts and that exploration of activating SIRTs could be an alternative treatment against Brucella infection.