Role Of IL-1β Research Articles

Comparison of Methods of Detecting IL-1β in the Blood of Alzheimer's Disease Subjects.

Interleukin (IL)-1β is a pro-inflammatory cytokine whose levels are increased in the brains of Alzheimer's disease (AD) patients. Despite the role of IL-1β in the pathology of AD, the fact that it is expressed at very low levels makes it a challenging cytokine to measure, hence limiting its potential use as a reliable biomarker. Moreover, being able to accurately and reliably measure the levels of IL-1 β in blood makes it possible to evaluate this cytokine as a potential biomarker of the inflammatory response in AD. In this study, we compared three quantification methodologies, Meso-Scale Discovery (MSD), both V-Plex and S-Plex versions, and Quanterix's SIMOA (Single-Molecule Array), to measure IL-1β in the serum of AD patients and age-matched controls. These assays are routinely used to measure IL-1β serum levels with high specificity and sensitivity in human AD patients, yet to the best of our knowledge, no study has compared all three techniques for their accuracy to measure IL-1β as biomarkers. Our findings indicate the two MSD assays can be used to measure IL-1β levels in AD and control serum, but the SIMOA assay showed the highest receiver operating characteristics (ROCs), with an area under the curve (AUC) of 0.9532, which can be compared to the AUC values for the V-Plex assay, 0.5660, and the S-Plex assay, 0.6632. Taken together, these data show that although all technologies are useful in the measurement of IL-1β in the blood, the SIMOA IL-1β 3.0 assay is more reliable and sensitive in measuring biomarkers of AD.

Role of IL-1β, IL-6, IL-10, IgG, IgA, PMN, Macrophage, and Cortisol on Psychological Stress Mechanisms in Periodontal Disorders

Role of IL-1β, IL-6, IL-10, IgG, IgA, PMN, Macrophage, and Cortisol on Psychological Stress Mechanisms in Periodontal Disorders

Airway IL-1β is related to disease severity and mucociliary function in bronchiectasis.

The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1β (IL-1β) release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated. To characterise the role of airway IL-1β in bronchiectasis, including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity. Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (high versus low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study the effect of IL-1β on cilia function. Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and an increased T-helper type 1, T-helper type 2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in vitro. A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β.

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β (IL-1β -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

Iron deficiency anemia in H.pylori pediatric patients and the role of IL-1β

Background Helicobacter pylori infection has long been recognized to be the cause of iron deficiency anemia (IDA). However, the data in this study shows that only some of children infected with Helicobacter pylori developed an IDA. The objective was to analyze the correlation between IL-1β levels with the incidence of IDA in children with Helicobacter pylori infection. Methods The study was a cross-sectional in which subjects with Helicobacter pylori infection were examined for IL-1β levels along with the incidence of IDA. The study was carried out for one full year period, started from January 2022 to January 2023, at the H. Adam Malik Hospital in Medan and its affiliation. The subjects in this study were pediatric patients who experienced abdominal pain and range between the ages of 2-18 years old. The entire samples were taken by using consecutive sampling. Subjects’ blood sampling were extracted for IL-1β examination (ELISA) and diagnostic tests of Iron Deficiency Anemia, while the diagnosis of H. pylori infection was done by endoscopy (CLO) Results The subjects consisted of 52 children in which 26 of them have Helicobacter pylori (+) and of those 26 children, 23 had IDA (prevalence ratio 11.5 (95% CI 3.015-43.864). There were indications that patients with H. pylori infection (+) is 11.5 times more likely to develop IDA. The cut-off point for IL-1β levels based on the freqtableuency of IDA in children with H. pylori infection is ≤ 1.3 pg/mL The sensitivity and specificity value of IL-1β levels in predicting IDA was 87% and 66.7% respectively. The positive and negative predictive value was 95.2% and 40% (respectively) with the accuracy level of 84.6 %. Conclusion There is a significant correlation between Helicobacter pylori infection and IDA. Interleukin-1β levels were significantly higher in children infected with H. pylori (+) in comparison to H. pylori (-).

Intestinal IL-1β Plays a Role in Protecting against SARS-CoV-2 Infection.

The intestine is constantly balancing the maintenance of a homeostatic microbiome and the protection of the host against pathogens such as viruses. Many cytokines mediate protective inflammatory responses in the intestine, among them IL-1β. IL-1β is a proinflammatory cytokine typically activated upon specific danger signals sensed by the inflammasome. SARS-CoV-2 is capable of infecting multiple organs, including the intestinal tract. Severe cases of COVID-19 were shown to be associated with a dysregulated immune response, and blocking of proinflammatory pathways was demonstrated to improve patient survival. Indeed, anakinra, an Ab against the receptor of IL-1β, has recently been approved to treat patients with severe COVID-19. However, the role of IL-1β during intestinal SARS-CoV-2 infection has not yet been investigated. Here, we analyzed postmortem intestinal and blood samples from patients who died of COVID-19. We demonstrated that high levels of intestinal IL-1β were associated with longer survival time and lower intestinal SARS-CoV-2 RNA loads. Concurrently, type I IFN expression positively correlated with IL-1β levels in the intestine. Using human intestinal organoids, we showed that autocrine IL-1β sustains RNA expression of IFN type I by the intestinal epithelial layer. These results outline a previously unrecognized key role of intestinal IL-1β during SARS-CoV-2 infection.

Cytokine Inhibitors Upregulate Extracellular Matrix Anabolism of Human Intervertebral Discs under Alginate Beads and Alginate-Embedded Explant Cultures.

We investigated the effects of the cytokine inhibitors IL-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor receptor-1 (sTNFR1) on the extracellular matrix metabolism of human intervertebral discs (IVDs) and the roles of IL-1β and TNF in the homeostasis of IVD cells. The 1.2% alginate beads and the explants obtained from 35 human lumbar discs were treated with cytokine inhibitors. Extracellular matrix metabolism was evaluated by proteoglycan (PG) and collagen syntheses and IL-1β, TNF, and IL-6 expressions after three days of culture in the presence or absence of IL-1Ra, sTNFR1, and cycloheximide. Simultaneous treatment with IL-1Ra and sTNFR1 stimulated PG and collagen syntheses in the NP and AF cells and explants. The IL-1β concentration was significantly correlated to the relative increase in PG synthesis in AF explants after simultaneous cytokine inhibitor treatment. The relative increase in PG synthesis induced by simultaneous cytokine treatment was significantly higher in an advanced grade of MRI. Expressions of IL-1β and TNF were upregulated by each cytokine inhibitor, and simultaneous treatment suppressed IL-1β and TNF productions. In conclusion, IL-1Ra and sTNFR1 have the potential to increase PG and collagen synthesis in IVDs. IL-1β and TNF have a feedback pathway to maintain optimal expression, resulting in the control of homeostasis in IVD explants.

Comprehensive Review: Unveiling the Pro-Oncogenic Roles of IL-1ß and PD-1/PD-L1 in NSCLC Development and Targeting Their Pathways for Clinical Management.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.

IL-1β-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance

Interleukin-1β (IL-1β) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1β in cancer is ambiguous or even contradictory. Here, we found that upon IL-1β stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1β-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1β expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1β-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1β and tumor cells by inhibiting NNT acetylation.

Modulating IL-1β and its receptors shapes spike-specific CD4 +T cell responses to mRNA vaccination

Abstract Augmenting and sustaining a durable immunity provided by COVID-19 mRNA vaccines is important. Thus, we characterized S protein-specific CD4 +T cells in healthy individuals who received COVID-19 mRNA vaccines utilizing single cell RNA-seq and mass cytometry. In humans, S protein-specific CD4 +T cells highly expressed IL-1 receptor (R) 1 and its decoy receptor IL-1R2. IL-1b promoted IFN-g expression by S protein-stimulated CD4 +T cells, which was furthered by adding anti-IL-1R2-blocking antibodies, supporting the functional implications of IL-1R1 and IL-1R2. Following the 2 nddose of vaccination, IL-1R1 expression increased while IL-1R2 expression decreased in S protein-specific CD4 +T cells. The expression levels of such cytokine receptors correlated with S-specific antibody production. Our findings provide novel insight into the role of IL-1β and its receptor system in developing COVID-19 mRNA vaccine-induced CD4 +T cell immunity. Supported by grants from NIH (1R01AG056728 and R01AG055362) and Quest Diagnostics.

IL-1β and Allergy: Focusing on Its Role in Allergic Rhinitis.

Allergic rhinitis (AR) is a chronic upper airway immune-inflammation response mediated by immunoglobulin E (IgE) to allergens and can seriously affect the quality of life and work efficiency. Previous studies have shown that interleukin-1β (IL-1β) acts as a key cytokine to participate in and promote the occurrence and development of allergic diseases. It has been proposed that IL-1β may be a potential biomarker of AR. However, its definitive role and potential mechanism in AR have not been fully elucidated, and the clinical sample collection and detection methods were inconsistent among different studies, which have limited the use of IL-1β as a clinical diagnosis and treatment marker for AR. This article systematically summarizes the research advances in the roles of IL-1β in allergic diseases, focusing on the changes of IL-1β in AR and the possible interventions. In addition, based on the findings by our team, we provided new insights into the use of IL-1β in AR diagnosis and treatment, in an attempt to further promote the clinical application of IL-1β in AR and other allergic diseases.

Dengue induces iNOS expression and nitric oxide synthesis in platelets through IL-1R.

Dengue is an arthropod-born disease caused by dengue virus (DENV), that may manifest as a mild illness or severe form, characterized by hemorrhagic fever and shock. Nitric oxide (NO) is a vasodilator signaling molecule and an inhibitor of platelet aggregation known to be increased in platelets from dengue patients. However, the mechanisms underlying NO synthesis by platelets during dengue are not yet elucidated. IL-1β is a pro-inflammatory cytokine able to induce iNOS expression in leukocytes and present in dengue patients at high levels. Nevertheless, the role of IL-1β in platelet activation, especially regarding iNOS expression, are not clear. We prospectively followed a cohort of 28 dengue-infected patients to study NO synthesis in platelets and its relationship with disease outcomes. We used in vitro infection and stimulation models to gain insights on the mechanisms. We confirmed that platelets from dengue patients express iNOS and produce higher levels of NO during the acute phase compared to healthy volunteers, returning to normal levels after recovery. Platelet NO production during acute dengue infection was associated with the presence of warning signs, hypoalbuminemia and hemorrhagic manifestations, suggesting a role in dengue pathophysiology. By investigating the mechanisms, we evidenced increased iNOS expression in platelets stimulated with dengue patients´ plasma, indicating induction by circulating inflammatory mediators. We then investigated possible factors able to induce platelet iNOS expression and observed higher levels of IL-1β in plasma from patients with dengue, which were correlated with NO production by platelets. Since platelets can synthesize and respond to IL-1β, we investigated whether IL-1β induces iNOS expression and NO synthesis in platelets. We observed that recombinant human IL-1β enhanced iNOS expression and dose-dependently increased NO synthesis by platelets. Finally, platelet infection with DENV in vitro induced iNOS expression and NO production, besides the secretion of both IL-1α and IL-1β. Importantly, treatment with IL-1 receptor antagonist or a combination of anti-IL-1α and anti-IL-1β antibodies prevented DENV-induced iNOS expression and NO synthesis. Our data show that DENV induces iNOS expression and NO production in platelets through mechanisms depending on IL-1 receptor signaling.

Macrophages promote growth, migration and epithelial-mesenchymal transition of renal cell carcinoma by regulating GSDMD/IL-1β axis.

Macrophages are highly enriched in renal cell carcinoma, and the inflammatory cytokines secreted by macrophages are remarkably associated with the survival rate of renal cell carcinoma. However, the relationship between gasdermin D (GSDMD) expression driven by macrophage and the invasion of renal cell carcinoma is not clear. The Caki-2 and 786-O cells were co-cultured with monocytes cells (THP-1) derived macrophages, then the bio function changes of Caki-2 and 786-O cells and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of IL-1β in Caki-2 and 786-O cells and macrophage interaction were investigated. Then, the animal model was used to confirm the role of communication of GSDMD with renal cell carcinoma in the tumor microenvironment. CD68 and GSDMD were overexpressed in human renal cell carcinoma. GSDMD contributed to the secretion of IL‑1β in macrophages and was associated with the proliferation rate of renal cell carcinoma cells. Furthermore, silencing GSDMD elicited renal cell carcinoma cells motility through epithelial-mesenchymal transition change. The in vivo study confirmed that GSDMD promoted tumor progression and GSDMD knockout impaired renal cell carcinoma growth and metastases. Finally, the interactions between macrophages and renal cell carcinoma cells promoted renal cell carcinoma proliferation and metastasis, possibly mediated by IL-1β. To our knowledge, this study showed that the GSDMD expressed by macrophages contributed to renal cell carcinoma cell growth, metastases, and epithelial-mesenchymal transition through regulating GSDMD/IL-1β axis and may be a novel therapeutic target and a potential biomarker for treating and diagnosing renal cell carcinoma.

The role of IL-1β during human immunodeficiency virus type1 infection.

Interleukin (IL)-1β is a key innate cytokine that is essential for immune activation and promoting the inflammatory process. However, abnormal elevation in IL-1β levels has been associated with unwanted clinical outcomes. IL-1β is the most extensively studied cytokine among the IL-1 family of cytokines and its role in pathology is well established. During the course of human immunodeficiency virus type 1 (HIV-1) infection, the level of this proinflammatory cytokine is increased in different anatomical compartments, particularly in lymphatic tissues, and this elevation is associated with disease progression. The aim of this review is to address the pathological roles play by IL-1β in the light of enhancing HIV-1 replication, driving immune cell depletion, and chronic immune activation. The role of IL-1β in HIV-1 transmission (sexually or vertically 'from mother-to-child') will also be discussed. Additionally, the impact of the available antiretroviral therapy regimens on the levels of IL-1β in HIV-1 treated patients is also discussed. Finally, we will provide a glance on how IL-1β could be targeted as a therapeutic strategy.

The role of IL-1β in the development of diabetes mellitus

Background. Currently, diabetes mellitus is the most common of all endocrine diseases with increasing tendency. The purpose of our research was to study the dynamics of serum levels of proinflammatory cytokine-IL-1β in streptozotocin-induced diabetes. Materials and methods. The experiments were performed on 88 white male Wistar rats weighing 170-210 g. Animals were divided into three groups: 1 - intact; 2 - control; 3 - experimental with a model of diabetes mellitus, which was reproduced by intraperitoneal injection of streptozotocin by “Sigma" company (USA), diluted in 0.1 M citrate buffer with a pH of 4.5, at a rate of 60 mg/kg body weight. The control group of animals received an intraperitoneal injection with an equivalent dose of 0.1 M citrate buffer solution with a pH of 4.5.
 All studies were performed under thiopental-sodium anesthesia at a rate of 60 mg/kg body weight. Serum levels of IL-1β were determined by enzyme-linked immunosorbent assay (ELISA) kit (Elabscience, USA) according to the manufacturer's instructions 14, 28, 42 and 70 days after streptozotocin injection. The STATISTICA 10 program was used for statistical processing of the obtained results. Results. Conducted biochemical analysis showed that in animals with streptozotocin-induced diabetes there was an increase in the content of proinflammatory cytokine IL-1β compared with similar indicators in the control group of animals at all stages of the experiment: after 14 days by 22.5%, after 28 days by 40.2%, after 42 days by 72.8% and after 70 days by 107.2%. Conclusion. The obtained results suggest that pro-inflammatory cytokine interleukin-1β plays one of the leading roles in the pathogenesis of streptozotocin-induced diabetes, as indicated by a significant increase in serum of this cytokine at all stages of the experiment.

Pseudomonas aeruginosa Elicits Sustained IL-1β Upregulation in Alveolar Macrophages from Lung Transplant Recipients

<h3>Purpose</h3> Clinical infection or colonization of the lung, specifically with <i>Pseudomonas aeruginosa</i> (<i>PsA</i>), is associated with increased incidence of lung allograft injury in lung transplant recipients (LTRs) and with an increase in BAL (bronchoalveolar lavage) pro-inflammatory cytokines. However, the effect of bacterial colonization on sustained innate immune activation and the mechanisms involved are not well understood. We sought to determine the mechanisms underlying persistent pro-inflammatory alveolar macrophage response to <i>PsA</i> stimulation. <h3>Methods</h3> We stimulated THP-1 derived macrophages and BAL-derived alveolar macrophages from LTRs with bacteria representative of infectious pathogens and upper respiratory commensals for up to 96 hours. Using a high dimensional flow cytometry panel, we evaluated macrophage responses including expression of costimulatory molecules (CD80, CD86, CD40); co-inhibitor molecules (B7-H1), pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β), and anti-inflammatory mediators (IL-10, IL-1RA, and TGF-β). <h3>Results</h3> We observed an upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) following stimulation by <i>PsA</i> compared to stimulation with other pathogens (<i>Staphylococcus aureus</i>) and oral-commensal bacteria (<i>Prevotella melaninogenica, Streptococcus pneumoniae</i>) in THP-1 macrophages. IL-1 β elevations were sustained for 96 hours after <i>PsA</i> exposure. Alveolar macrophages from LTRs undergoing surveillance bronchoscopy demonstrated elevated levels of IL-6 and showed a similar IL-1β responses to that observed in THP-1 macrophages when exposed to <i>PsA</i>. <h3>Conclusion</h3> <i>PsA</i> induces a sustained increase in IL-1β production in alveolar macrophages from LTRs. Given the prior described role of IL-1β in lung allograft injury and CLAD, further investigations are ongoing to determine clinical correlates of allograft injury with <i>PsA</i> and IL-1β.

Assessment of Stress Salivary Markers, Perceived Stress, and Shift Work in a Cohort of Fishermen: A Preliminary Work.

Due to work-related stress, today, work itself represents a daily challenge that must be faced in many occupations. While, in the past, the scientific community has focused on the helping professions, since, an increasing number of professions have since been investigated. Therefore, different approaches exist in order to assess this disorder, representing a scientific field wherein biological and psychological dimensions both need to be evaluated. In this paper, we consider three biological salivary markers: interleukin 1 beta (IL-1β), cortisol, and melatonin. The choice derives from recent contributions to the literature in which the interplay between these markers has been verified. Briefly, such interplay could explain how the central nervous, endocrine, and immune systems communicate with each other, supporting a holistic concept of person. In 30 marine fishermen from the Apulia region of Italy, perceived stress was measured using the Professional Stress Scale (PSS) and sleep disturbances were assessed through the Pittsburgh Sleep Quality Index (PSQI). Salivary markers were collected at 8:00 a.m. and 2:00 p.m. Those subjects reporting sleep disturbance and having altered scores in two PSS subclasses, home–work conflict and self-esteem, presented inverted salivary melatonin and cortisol nictemeral rhythms (with regard to melatonin levels at 8:00 a.m., those workers reporting values higher than the median showed 64.1% versus 48.6% home–work conflict with respect to cortisol levels, subjects having an inverted circadian rhythm showed 69.9% versus 52.5% home–work conflict, and these values resulted 47.7% versus 25.3% when the self-esteem was considered). As regards melatonin, PSQI score is statistically different in the two groups of subjects as identified by median melatonin at 8:00 a.m.; specifically, the subjects who had mean values higher than the median shared higher PSQI scores (10.8 versus 9.8). The same subjects reported more frequent home–work conflict and more sleep disorders. We found a negative correlation between IL-1β at 8:00 a.m. and Cortdiff (the difference between cortisol at 8:00 a.m.–cortisol at 2:00 p.m.), and that high IL-1β at 8:00 a.m. was associated with low Cortdiff. Based on our results we would like to propose this approach in health surveillance, in order to prevent mental and/or physical disorders, however our study is surely preliminary. The interesting perspectives and hypotheses cited in this paper, in which the roles of IL-1β and norepinephrine appear central and important, could remain hypothetical if not supported by more robust observation in order to produce, truly, new knowledge. In the future we will deepen this study with a larger sample, and if these results will be confirmed, this approach could allow preventing, not only mental and physical disorders, but also immuno-mediated diseases, and, perhaps, cancer.

Abstract PO-227: Role of IL-1β pathway in colon cancer progression and its therapeutic implications in African American colon cancer cell lines

Abstract Background: Colorectal cancer (CRC) is the third most common cancer and third cause of cancer-related death among African Americans (AA) in the US. When compared to Caucasian Americans (CA), AA patients present with higher incidence and mortality rates for CRC. Recent findings indicate that they have reduced response to the standard of care chemotherapeutic agent 5-Fluorouracil (5-FU) as well as lower frequency of MSI tumors, making them also less likely to respond to conventional immunotherapies. Previous results from human genomic analyses suggest that certain differences seen in AA patients might be due to a decreased antitumor immune response as well as an increased expression of genes involved in inflammatory processes, such as Interleukin-1β (IL-1β). Therefore, we aimed to investigate the role of IL-1β in promoting cell proliferation, cell migration, 5-FU resistance and activation of specific inflammatory pathways in novel AA colon cancer cell lines, and how these responses would compare to well established CA colon cancer cell lines. Methods: Our approach includes using MTS colorimetric assay and Transwell assay to examine the effects of IL-1β treatment on cell proliferation and migration. We performed Western Blot analysis to detect expression of phosphoproteins following treatment with IL-1β. We also investigated how IL-1β affects 5-FU resistance in AA and CA colon cancer cell lines in terms of cell viability. Finally, we tested the ability of IL-1 Receptor antagonist (IL-1Ra) to inhibit the effects of IL-1β on cell proliferation, protein expression, and 5-FU response. Results: Our MTS assay results indicated that cell proliferation in response to IL-1β differs between the AA and the CA colon cancer cell lines, with the AA colon cancer cells being more responsive. Whereas, the migration rate is increased after stimulation with IL-1β for both AA and CA colon cancer cell lines. Protein expression of Phospho-IkB-alpha is increased in AA but not CA colon cancer cell lines following IL-1β treatment, while Phospho-JNK expression was different between the cell lines following treatment. Importantly, our results show that 5-FU efficacy is decreased in the presence of IL-1β for both AA and CA colon cancer cell lines and that treating the cells with IL-1Ra appeared to reestablish 5-FU cell killing effect. IL-1Ra also suppresses the effects of IL-1β on cell proliferation and protein expression. Conclusions: Taken together, our results demonstrated a differential response to IL-1β for the AA colon cancer cell lines, suggesting a probable role played by the cytokine in driving inflammation-related cancer progression and reveals a possible new target to exploit in immunotherapy for this population. Citation Format: Marzia Spagnardi, Jenny Paredes, Jone Garai, Jovanny Zabaleta, Jennie Williams, Laura Martello-Rooney. Role of IL-1β pathway in colon cancer progression and its therapeutic implications in African American colon cancer cell lines [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-227.

Interleukin-1beta triggers the expansion of circulating granulocytic myeloid-derived suppressor cell subset dependent on Erk1/2 activation

Chronic inflammation contributes to cancer development and progression. Although interleukin-1beta (IL-1β) has been observed to be associated with an general immune suppression of T cell response and the immunosuppression strongly correlates with accumulation of myeloid-derived suppressor cells (MDSCs), the relationship and mechanism between MDSCs expansion and IL-1β expression remain ambiguous. Here, we showed that the concentration of IL-1β was highly correlated with G-MDSC subset, rather than mo-MDSC subset. Recombinant IL-1β increased the percentage of G-MDSCs in the blood of tumor-bearing mice, and IL-1Ra attenuated the accumulation of G-MDSCs in the tumor-bearing mice. In addition, the IL-1β-overexpressing B16F10 cells induced higher level of G-MDSCs compared with wild-type B16F10 cells. Moreover, we found that the accumulation of G-MDSCs induced by IL-1β was dependent on the activation of extracellular signal-regulated kinases 1 and 2 (Erk1/2). Collectively, these findings show a novel role of IL-1β in G-MDSCs accumulation by activating Erk1/2, which suggests that IL-1β elimination or Erk1/2 signaling blockade could decrease G-MDSCs generation and thereby improve host immunosurveillance.

Abstract MP32: Renal Tubular Epithelial Cell-derived IL-1β Triggers The Inflammatory Response That Induces Salt Sensitivity In Diabetes

Renal inflammation, and specifically interleukin (IL)-6, induces salt-sensitivity in diabetic mice by upregulating the epithelial sodium channel (ENaC). However, the origin of this inflammatory response is still unknown. We hypothesize that, during diabetes, tubular epithelial cells initiate renal inflammation by releasing IL-1β that further activates renal macrophages to produce IL-6 and impair kidney function. A primary culture of renal tubular epithelial cells from wild-type (WT) mice was exposed to either low (LG, 5mM) or high (HG, 15mM) glucose media. HG-treated cells released higher levels of IL-1β (28 ± 12 vs. 8 ± 4 pg/ml, P&lt;0.01) and have higher expression of NLRP3 (4 ± 1 fold increase, P&lt;0.001) and Caspase-1 (2.1 ± 0.2 fold increase, P&lt;0.001) compared to LG-treated cells. No effect was observed using mannitol as an osmotic control. Tubular cells were also co-cultured with bone marrow-derived macrophages. Flow cytometry analysis revealed that HG-treated tubular cells induced an M1-type polarization of macrophages. This effect was blunted when macrophages were obtained from IL-1 receptor KO mice (IL1RKO) confirming a role of IL-1β. Here, the percentage of M1 macrophages (CD45 + F4/80 + CD80 + ) of total macrophages (CD45 + F4/80 + ) decreased from 31 ± 4% to 10 ± 3% (P&lt;0.01). To evaluate whether IL-1β-mediated macrophage activation plays a role in vivo, 2-mo-old diabetic db/db mice (n=6) were transplanted with bone marrow from IL1RKO mice. In these mice, named db/db-IL1RKO, immune cells cannot respond to IL-1β. Db/db receiving wild-type (WT) bone marrow (db/db-WT) were used as control. No differences in body weight and hyperglycemia were observed after transplantation. At 7 months, mice were exposed to a high salt diet (NaCl 4% w/w) for 4 weeks. Db/db-IL1RKO did not develop salt-sensitivity (blood pressure was 110 ± 7 vs. 122 ± 9 mmHg, P&lt;0.05), have less renal IL-6 (138 ± 35 vs. 263 ± 28 pg/mg kidney, P&lt;0.05) and lower ENaC activity (0.4-fold decrease by amiloride test, P&lt;0.05) compared to db/db-WT. In conclusion, our data show that tubular epithelial cells are a major source of IL-1β under high glucose conditions. This cytokine promotes M1 macrophage polarization resulting in higher renal IL-6 levels which increases ENaC activity leading to salt sensitivity.