High Levels Of Pro-inflammatory Cytokines Research Articles

Cytokines as markers of non-functional overstrain in rowing athletes

BACKGROUND: Regular high-intensity exercise, combined with other stressors and lack of adequate recovery time, can cause a sustained pro-inflammatory response, leading to systemic inflammation and immune dysregulation. AIM: The aim of this study is to establish the prognostic effectiveness of proinflammatory IL-1β, TNFα, IL-8, anti-inflammatory cytokine IL-4 and myokine IL-6 as markers of dysfunctional overstrain and overtraining in rowing athletes. MATERIALS AND METHODS: A total of 47 male athletes aged 18–22 years were examined, specializing in rowing, 1st category, candidates for master of sports. Of these, 28 were dynamic (4 times). The control group included 24 healthy donors, men aged 18–22 years. Cardiac overstrain was diagnosed based on 24-hour ECG data: identification of ventricular and supraventricular extrasystoles in the absence of organic changes in the heart. The content of cytokines in blood serum was determined using the Human Cytokine/Chemokine Magnetic Bead Panel 1 reagents (Merck, Millipore) on a MagPix device. The research results were processed using parametric statistics methods. RESULTS: Rowing athletes show an increase in pro-inflammatory cytokines, which can be both a consequence of adaptive changes and a sign of long-term systemic inflammation. Determination of IL-6, IL-8, TNFα may be useful for assessing the body’s adaptation to training loads. The greatest changes in the level of pro-inflammatory cytokines are observed during the competitive period, and it should be taken into account that an increase in the anti-inflammatory cytokine IL-4 occurs in response to high levels of pro-inflammatory cytokines and is a sign of good adaptation. CONCLUSIONS: The greatest importance in the diagnosis of non-functional cardiac overstrain in rowing athletes should be given to an increase in IL-1α and IL-6 and an increase in TNFα against the background of a decrease in IL-4.

The role of immune-inflammatory markers in children with complicated and uncomplicated malaria in Enugu, Nigeria

BackgroundThere is currently insufficient data regarding immune parameters and relationship with severity of malaria infection in Enugu, Nigeria where the economic and social costs of the disease and its management are extremely high. This study was conducted to determine the relationship between malaria severity and some immune-inflammatory markers among malaria-infected children in Enugu, Nigeria.MethodsThe study adopted a case control design. Eligible children were categorized into three groups — complicated, uncomplicated and healthy children. Pro-inflammatory cytokines –interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α); and anti-inflammatory cytokine — interleukin-10 (IL-10) were assayed using enzyme-linked immunosorbent assay (ELISA) technique, while immune cell ratios — neutrophil lymphocyte ratio (NLR) and monocyte lymphocyte ratio (MLR) were calculated from full blood count results.ResultsThe overall mean age of the participants was 7.3 ± 3.4 (range: 6 months − 12 years) and the male-female ratio was 1:1. There was no significant difference between the ages of the three groups (P = 0.44). The Mean levels of IFN-γ, TNF-α, and NLR were higher in complicated than uncomplicated malaria (266.9 ± 66.3pg/ml vs. 62.5 ± 6.4pg/ml, p < 0.001; 140.3 ± 30.0pg/ml vs. 42.0 ± 9.0pg/ml, p < 0.001; and 32.9 ± 16.2pg/ml vs. 17.8 ± 6.0pg/ml, p < 0.001, respectively); and higher in uncomplicated malaria than healthy children (62.5 ± 6.4pg/ml vs. 40.6 ± 9.1pg/ml, p < 0.001; 42.0 ± 9.0pg/ml vs. 105.7 ± 32.1, p < 0.001; 17.8 ± 6.0pg/ml vs. 18.7 ± 6.2pg/ml, p < 0.001, respectively). On the other hand, the mean level of IL-10 is higher in uncomplicated than complicated malaria (105.73 ± 32.06pg/ml vs. 40.60 ± 9.11pg/ml, p < 0.001). There was a positive correlation between NLR and IFN-γ (r = 0.815; p = 0.003), as well as NLR and TNF-α (r = 0.745; p = 0.002).ConclusionComplicated malaria is associated with higher levels of pro-inflammatory cytokines while uncomplicated malaria is associated with higher levels of anti-inflammatory cytokines. NLR correlates positively with pro-inflammatory cytokines, and could be useful in evaluation for the severity of malaria infection.

Correlation between Alzheimer's Disease and Gastrointestinal Tract Disorders.

Alzheimer's disease is the most common cause of dementia globally. The pathogenesis is multifactorial and includes deposition of amyloid-β in the central nervous system, presence of intraneuronal neurofibrillary tangles and a decreased amount of synapses. It remains uncertain what causes the progression of the disease. Nowadays, it is suggested that the brain is connected to the gastrointestinal tract, especially the enteric nervous system and gut microbiome. Studies have found a positive association between AD and gastrointestinal diseases such as periodontitis, Helicobacter pylori infection, inflammatory bowel disease and microbiome disorders. H. pylori and its metabolites can enter the CNS via the oropharyngeal olfactory pathway and may predispose to the onset and progression of AD. Periodontitis may cause systemic inflammation of low severity with high levels of pro-inflammatory cytokines and neutrophils. Moreover, lipopolysaccharide from oral bacteria accompanies beta-amyloid in plaques that form in the brain. Increased intestinal permeability in IBS leads to neuronal inflammation from transference. Chronic inflammation may lead to beta-amyloid plaque formation in the intestinal tract that spreads to the brain via the vagus nerve. The microbiome plays an important role in many bodily functions, such as nutrient absorption and vitamin production, but it is also an important factor in the development of many diseases, including Alzheimer's disease. Both the quantity and diversity of the microbiome change significantly in patients with AD and even in people in the preclinical stage of the disease, when symptoms are not yet present. The microbiome influences the functioning of the central nervous system through, among other things, the microbiota-gut-brain axis. Given the involvement of the microbiome in the pathogenesis of AD, antibiotic therapy, probiotics and prebiotics, and faecal transplantation are being considered as possible therapeutic options.

Macrophage-derived exosomes exacerbate postoperative cognitive dysfunction in mice through inflammation

This study investigated the impact of two-hit inflammation on postoperative cognitive dysfunction (POCD) in mice and the role of macrophage-derived exosomes in regulating this process. Mice models were used to mimic the state of two-hit inflammation, and cognitive function was assessed through behavioral experiments. Proinflammatory cytokine expression levels and blood-brain barrier (BBB)-associated functional proteins were measured using ELISA and Western blot, respectively. An in vitro macrophage inflammation two-hit model was created, and the role of exosomes was examined using the previously mentioned assays. Additionally, exosomes were injected into mice to further understand their impact in the two-hit inflammation model. Mice exposed to two-hit inflammation experienced impaired cognitive function, increased BBB permeability, and elevated levels of proinflammatory cytokines. Macrophages subjected to two-hit inflammation released higher levels of proinflammatory cytokines compared to the control group and other treatment groups. Treatment with an exosome inhibitor GW4869 effectively reduced the expression levels of proinflammatory cytokines in macrophages exposed to two-hit inflammation. Moreover, injection of macrophage-released exosomes into healthy mice induced inflammation, hippocampal damage, and cognitive disorders, which were mitigated by treatment with GW4869. In mice with two-hit inflammation, macrophage-released exosomes worsened cognitive disorders by promoting inflammation in the peripheral blood and central nervous system. However, treatment with GW4869 protected cognitive function by suppressing exosome release. These findings highlight the importance of two-hit inflammation in POCD and emphasize the critical role of exosomes as regulatory factors. This research provides valuable insights into the pathogenesis of POCD and potential intervention strategies.

IL-10 indirectly modulates functional activity of CD4+CD28null T-lymphocytes through LFA-3 and HLA class II inhibition.

Expansion of CD4+CD28null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4+CD28null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4+CD28null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4+CD28null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T-lymphocytes.

Inflammatory imbalance in tracheal aspirate of very preterm newborns is associated with airway obstruction and lung function deficiencies at school age: a cohort study

ObjectiveA low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more severe neonatal lung disease. The...

Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure.

CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8days (IQR: 3-13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7mg/dL to median post-treatment: 10.8mg/dL; - 47.8%; p < 0.001), procalcitonin (1.34 to 0.74pg/mL; - 44.6%; p < 0.001), interleukin-6 (385 to 131ng/mL; - 66.0%; p = 0.0182)-but also of platelets (72 to 31 G/L; - 56.9%; p = 0.0014) and fibrinogen (230 to 154mg/dL; - 33.0%; p = 0.0297) were detected. ICU survivors had a trend towards a stronger relative decrease in bilirubin (- 76.1% vs. - 48.2%), procalcitonin (- 90.6% vs. - 23.5%), and IL-6 (- 54.6% vs. - 17.8%) upon CytoSorb treatment. Moreover, no serious CytoSorb-attributed complications were detected. In conclusion, use of CytoSorb adsorber in ACLF patients results in a significant decrease in bilirubin and proinflammatory cytokines, while platelets and fibrinogen were also lowered. Prospective trials are warranted to investigate the impact of CytoSorb on clinical outcomes of ACLF patients with high proinflammatory cytokine levels.

The Effect of Virgin Coconut Oil on TNFα and Cytochrome P450 Aromatase Levels in Obese Female White Rats (Rattus norvegicus) Induced with a High-Fat Diet

Background: The high level of various proinflammatory cytokines due to adipocyte hypertrophy such as TNFα in obesity increases cytochrome-P450-aromatase, further inducing increased estrogen production, hypersecretion of Luteinizing Hormone and decreased Follicle Stimulating Hormone, resulting in impaired folliculogenesis, and chronic anovulation. Virgin Coconut Oil is rich in Medium Chain Fatty Acid and phytochemicals as anti-inflammatory. Aim: The aim of this study was to determine the effect of VCO on reducing TNFα and cytochrome-P450-aromatase levels in obese female white rats. Methods: Post test only control group, 24 rats were divided into 3 groups, namely: negative control group (K-), positive control group (K+), and treatment group (P). The K+ and P groups were induced using a high-fat diet for 10 weeks, then the P group was given VCO in weeks 7-10. On the first day of week 11, blood was taken from the orbital vein of the eyes of all rats for TNFα levels. Both examinations used ELISA kits. Data analysis used Shapiro Wilks normality test. The value of p&gt;0.05, followed by hypothesis testing using one-way annova and post hoc Bonferroni. Results: Mean TNFα in the K- group: 141.71±8.87, K+ group: 15.09±19.30, P group: 162,09±13,57. Mean cytochrome-P450-aromatase levels in the K- group: 9.00±0.77, K+ group: 12.22±1.69, P group: 10.58±0.97. The mean levels of one way ANOVA analysis showed that the administration of VCO can significantly reduce TNFα levels (p=0.001) and significantly reduce Cytochrome-P450-aromatase levels (p=0.001). Conclusion: VCO administration can reduce TNFα levels and cytochorme-P450-aromatase levels in obese female white rats. Keywords: TNFα, cytochrome-P450-aromatase, infertility, obesity

Cotargeting EBV lytic as well as latent cycle antigens increases T-cell potency against lymphoma

AbstractThe remarkable efficacy of Epstein-Barr virus (EBV)-specific T cells for the treatment of posttransplant lymphomas has not been reproduced for EBV-positive (EBV+) malignancies outside the transplant setting. This is because of, in part, the heterogeneous expression and poor immunogenicity of the viral antigens expressed, namely latent membrane proteins 1 and 2, EBV nuclear antigen 1, and BamHI A rightward reading frame 1 (type-2 [T2] latency). However, EBV lytic cycle proteins are also expressed in certain EBV+ malignancies and, because several EBV lytic cycle proteins are abundantly expressed, have oncogenic activity, and likely contribute to malignancy, we sought and identified viral lytic-cycle transcripts in EBV+ Hodgkin lymphoma biopsies. This provided the rationale for broadening the target antigen–specific repertoire of EBV-specific T cells (EBVSTs) for therapy. We stimulated, peripheral blood mononuclear cells from healthy donors and patients with EBV+ lymphoma with both lytic and latent cycle proteins to produce broad repertoire (BR) EBVSTs. Compared with T2 antigen-specific EBVSTs, BR-EBVSTs more rapidly cleared autologous EBV+ tumors in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice and produced higher levels of proinflammatory cytokines that should reactivate the immunosuppressive tumor microenvironment leading to epitope spreading. Our results confirm that lytic cycle antigens are clinically relevant targets for EBV+ lymphoma and underpin the rationale for integrating BR-EBVSTs as a therapeutic approach for relapsed/refractory EBV+ lymphoma (www.clinicaltrials.gov identifiers: #NCT01555892 and #NCT04664179), as well as for other EBV-associated malignancies.

The Role of α-Enolase on the Production of Interleukin (IL)-32 in Con A-Mediated Inflammation and Rheumatoid Arthritis (RA).

Interleukin (IL)-32 is produced by T lymphocytes, natural killer cells, monocytes, and epithelial cells. IL-32 induces the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8, and IL-32 expression is highly increased in rheumatoid arthritis (RA) patients. Enolase-1 (ENO1) is a glycolytic enzyme and the stimulation of ENO1 induces high levels of pro-inflammatory cytokines in concanavalin A (Con A)-activated peripheral blood mononuclear cells (PBMCs) and macrophages in RA patients. In addition, there are many reports that anti-ENO1 antibody is correlated with the disease progression of RA. It implies that ENO1 could regulate IL-32 production during inflammation related to the pathogenesis of RA. Therefore, we investigated the role of ENO1 in IL-32 production using Con A-activated PBMCs and RA PBMCs. IL-32 expression is increased by ENO1 stimulation using real-time PCR and ELISA. In addition, we confirmed that IL-32 production was decreased in Con A-activated PBMCs and RA PBMCs pre-treated with NF-κB or p38 MAPK pathway inhibitors. Taken together, these results suggest that ENO1 plays an important role in inflammation through the induction of IL-32 production by the activation of the NF-κB and p38 MAPK pathways.

Evodiamine Alleviates 2,4-Dinitro-1-Chloro-Benzene-Induced Atopic Dermatitis-like Symptoms in BALB/c Mice.

Evodiamine is an alkaloid found in Evodia fruits, a traditional Chinese medicine. Preclinical studies have demonstrated its anti-inflammatory and neuroprotective properties. The 2,4-dinitro-1-chloro-benzene (DNCB) was used to test the effects of evodiamine on a chemically induced atopic dermatitis-like model in BALB/c mice. Evodiamine significantly lowered serum immunoglobulin E levels, which increased as an immune response to the long-term application of DNCB. Several atopic dermatitis-like skin symptoms induced by DNCB, including skin thickening and mast cell accumulation, were suppressed by evodiamine therapy. DNCB induced higher levels of pro-inflammatory cytokines in type 2 helper T (Th2) cells (IL-4 and IL-13), Th1 cells (IFN-γ and IL-12A), Th17 cells (IL-17A), Th22 cells (IL-22), and chemokines (IL-6 and IL-8). These increases were suppressed in the lymph nodes and skin following evodiamine treatment. The results of our study indicate that evodiamine suppresses atopic dermatitis-like responses in mice and may therefore be useful in treating these conditions.

Targeted delivery of NO donor and ROS scavenger for synergistic treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by high level of reactive oxygen species (ROS) and proinflammatory cytokines, which facilitate the activation of the inflammatory signaling such as NF-κB pathway and exacerbate the development of inflammation. Herein, we designed a nanodrug by encapsulating the NO donor S-nitrosoglutathione (GSNO) into an emulsion and coating the surface with a polydopamine (PDA) layer to yield GSNO@PDA, which simultaneously scavenged the extra ROS and suppressed NF-κB signaling for potent RA treatment. To enhance the cellular uptake and NO generation efficiency, dextran sulfate (DS) and Cu2+ were anchored on the surface of GSNO@PDA to obtain the final formulation GSNO@PDA@DS. Our results demonstrated that GSNO@PDA@DS were successfully prepared and the modification of DS effectively boosted the cellular uptake of GSNO@PDA@DS. Moreover, GSNO@PDA@DS lowered cellular ROS and elevated intracellular NO, resulting in a decrease of M1 phenotype, inhibition of NF-κB pathway and down-regulation of proinflammatory cytokine tumor necrosis factor-α (TNF-α). Further in vivo studies confirmed that GSNO@PDA@DS significantly relieved symptoms and bone erosion by regulating the microenvironment of RA, highlighting the potential of GSNO@PDA@DS for RA therapy through ROS scavenging and NO-mediated suppression of inflammatory signaling.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer’s disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer’s disease, providing mechanistic insight into the biology of neuroinflammation.

Abstract 5588: Protein Arginine Methyltransferase 2 is involved in the control of inflammatory processes in acute myeloid leukemia

Abstract A direct link between chronic inflammation and development of Acute Myeloid Leukemia (AML) has been highlighted in the past few years, demonstrating an interconnection between marked inflammatory phenotype and aberrant myeloproliferation in AML patients. Treating AML patients exhibiting a higher inflammatory signature with anti-inflammatory molecules resulted in significant increase of overall survival. Protein Arginine Methyltransferases (PRMTs) are epigenetic factors known to regulate gene expression through methylation of histone tails. It has been previously reported that PRMT1, 4, and 5 inhibition exhibit anti-proliferative effects on AML models. In this study, we investigated the role of another PRMT, called PRMT2, in the development of AML through its regulatory roles in inflammatory pathways. We first determined from an AML cohort (The Leucegene project, IRIC, Montréal, QC, Canada) that patients with a low PRMT2 expression display an enrichment of proinflammatory pathways compared to patients with a high PRMT2 expression. Therefore, we hypothesized that PRMT2 could be a key regulator of inflammatory processes in AML. We thus used a PRMT2 knockout mouse model (Prmt2 KO) and a PRMT2 knockout human AML cell line to validate our hypothesis. Although we demonstrated no difference in the bone marrow progenitors or mature cell populations of Prmt2 KO mice compared to control, we observed that Prmt2 KO Bone-Marrow Derived Macrophages (BMDMs) are more sensitive to LPS stimulation and express higher levels of pro-inflammatory cytokines, supporting our previous findings for a role of PRMT2 in the negative regulation of inflammatory processes. PRMT2 depleted human AML cells displayed an increased pro-inflammatory signature due to overactivation of STAT3, which is caused by an enhanced activation of the NFkB signaling pathway, leading to an overproduction of IL6. Together, these findings demonstrate that PRMT2 is a key regulator of the control of inflammation in AML. Recognition of PRMT2 as a biomarker of inflammation in AML would help to adapt treatment possibly through the synergistic use of anti-inflammatory molecules with other cytotoxic drugs. Citation Format: Camille Sauter, Thomas Morin, Fabien Guidez, John Simonet, Cyril Fournier, Céline Row, Denis Masnikov, Baptiste Pernon, Anne Largeot, Aziza Aznague, Yann Herault, Guy Sauvageau, Marc Maynadie, Mary Callanan, Jean-Noël Bastie, Romain Aucagne, Laurent Levadny Delva. Protein Arginine Methyltransferase 2 is involved in the control of inflammatory processes in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5588.

Abstract 7469: Inflammation plays an important role in the progression of chronic myeloid leukemia

Abstract The development of Tyrosine Kinase Inhibitors (TKIs) resulted in a significant increase in the life expectancy of patients with chronic myeloid leukemia (CML). Nevertheless, TKIs still fail in a significant proportion of therapy-naïve patients, or their effectiveness is hampered by secondary resistance. It is therefore urgent to explore the underlying mechanisms in order to develop new therapeutic approaches to cure CML instead of controlling the disease with a lifelong TKI therapy. Using the ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML we show that BCR::ABL1 leads to the elevation of pro-inflammatory cytokines, known to be important in disease initiation and progression. This is supported by our data from CML patients, where we also observe higher levels of pro-inflammatory cytokines in the serum compared to healthy individuals. Furthermore, we demonstrate that BCR::ABL1 drives the expansion of bone marrow derived mast cells (BMMCs) and sensitizes them for FcεRI triggered degranulation. Interestingly, these BMMCs show differences in their lipid metabolism. Hence, sphingomyelin and lysophosphatidylcholine, both known to be involved in inflammation and cancer progression, are upregulated in BCR::ABL1-positive mast cells compared to their negative counterparts. By crossing in the Cpa3Cre mediated model for mast cell deficiency, we demonstrate for the first time that the lack of mast cells prevents the BCR::ABL1 induced upregulation of pro-inflammatory cytokines and also the development of splenomegaly. In addition, we were able to show that splenomegaly in CML patients is associated with high bone marrow mast cell counts and that an upregulation of pro-inflammatory cytokines in patient serum samples correlated with tryptase levels. In summary, our study identifies mast cells and their inflammatory cytokines as important factors in disease progression and suggests considering them as additional targets in CML therapy. Citation Format: Melanie Langhammer, Julia Schöpf, Timo Jaquet, Katharina Horn, Moritz Angel, Daniel Mohl, Simon Lagies, Corinna Spohr, Daniel Christen, Franziska Maria Uhl, Tiago Maié, Henrike Jacobi, Thorsten B. Feyerabend, Julia Huber, Marcus Panning, Cassian Sitaru, Ivan Costa, Robert Zeiser, Konrad Aumann, Heiko Becker, Till Braunschweig, Steffen Koschmieder, Bernd Kammerer, Khalid Shoumariyeh, Michael Huber, Mirle Schemionek-Reinders, Tilman Brummer, Sebastian Halbach. Inflammation plays an important role in the progression of chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7469.

IMMUNOLOGICAL ANALYSIS OF ORAL FLUID IN PATIENTS WITH GENERALIZED PERIODONTITIS

The objective of this study is to conduct an immunological analysis of oral fluid, specifically focusing on determining the interleukin status among patients with generalized periodontitis and underlying metabolic syndrome. Materials and methods. For immunological studies, 3 groups were formed: main group, comparative and control groups. The main group included 30 individuals with generalized periodontitis and metabolic syndrome, the comparison group included 30 people with generalized periodontitis without somatic pathology; 20 healthy individuals with intact periodontium made up the control group. The content of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and anti-inflammatory cytokines IL-4, TGF-β1 in the oral fluid of the subjects of the examination groups was determined by the method of solid-phase enzyme immunoassay using reagents of the company "Simko" (Ukraine).&#x0D; Results. According to average values obtained, the highest levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were found in individuals with periodontal pathology and metabolic syndrome. The value of the IL-1β content in the oral fluid of the main group was 1.1 times higher than the similar indicator of the comparison group, and 1.4 times higher than the indicator of the control group. The mean IL-6 content in the oral fluid of patients with metabolic syndrome was 1.3 times higher compared to individuals without the systemic disease. Interestingly, the disparity was more pronounced in healthy individuals, with IL-6 levels differing by 2 times.&#x0D; Conclusion. Patients with metabolic syndrome and periodontal pathology have significant disturbances in cytokine regulation. Cytokines are key factors in the formation of a local inflammatory reaction, therefore, an increase in the concentration of pro-inflammatory IL-1 β can be considered an immune response to the inflammatory process in periodontal tissues.

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes

RationaleHeterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating...

Inflammatory Response Associated with West Nile Neuroinvasive Disease: A Systematic Review.

West Nile virus (WNV) infection is a seasonal arbovirosis with the potential to cause severe neurological disease. Outcomes of the infection from WNV depend on viral factors (e.g., lineage) and host-intrinsic factors (e.g., age, sex, immunocompromising conditions). Immunity is essential to control the infection but may also prove detrimental to the host. Indeed, the persistence of high levels of pro-inflammatory cytokines and chemokines is associated with the development of blood-brain barrier (BBB) damage. Due to the importance of the inflammatory processes in the development of West Nile neuroinvasive disease (WNND), we reviewed the available literature on the subject. According to the 2020 updated PRISMA guidelines, all peer-reviewed articles regarding the inflammatory response associated with WNND were included. One hundred and thirty-six articles were included in the data analysis and sorted into three groups (in vitro on-cell cultures, in vivo in animals, and in humans). The main cytokines found to be increased during WNND were IL-6 and TNF-α. We highlighted the generally small quantity and heterogeneity of information about the inflammatory patterns associated with WNND. Further studies are needed to understand the pathogenesis of WNND and to investigate the extent and the way the host inflammatory response either helps in controlling the infection or in worsening the outcomes. This might prove useful both for the development of target therapies and for the development of molecular markers allowing early identification of patients displaying an inflammatory response that puts them at a higher risk of developing neuroinvasive disease and who might thus benefit from early antiviral therapies.

DOX-PLGA Nanoparticles Effectively Suppressed the Expression of Pro-Inflammatory Cytokines TNF-a, IL-6, iNOS, and IL-1β in MCF-7 Breast Cancer Cell Line.

Inflammation contributes to cancer pathobiology through different mechanisms. Higher levels of pro-inflammatory cytokines can lead to hyperinflammation and promote cancer development and metastasis. For cancer treatment, Doxorubicin (DOX) can be encapsulated into the poly-lactic-glycolic acid (PLGA) nanoparticles. This study aimed to investigate the impact of doxorubicin-loaded PLGA nanoparticles (DOX-PLGA NP) on the expression of pro-inflammatory genes TNF-α, IL-6, iNOS, and IL-1β in the MCF-7 cells. The DOX-PLGA NP was prepared by loading doxorubicin into PLGA and characterized using dynamic light scattering (DLS) and atomic force microscopy (AFM). The cytotoxic effect of the nanoparticles was determined by the MTT assay, and their impacts on the expression of pro-inflammatory genes were assessed by qRT-PCR. The encapsulation efficiency and loading capacity were 60±1.5 and 1.13±0.21 percent, respectively. The zeta potential and mean DOX-PLGA nanoparticle size were -18±0.550 mV and 172±55.6 nm, respectively. The 50% inhibitory concentration (IC50) of the DOX-PLGA NP on MCF-7 cell viability was 24.55 µg/mL after 72 hours of treatment. The qRT-PCR results revealed that the 20 µg/mL concentration of the DOX-PLGA NP significantly suppressed the expression of the pro-inflammatory genes TNF-α, IL-6, iNOS, and IL-1β compared to DOX alone (20 µg/mL). Additionally, the suppression effect of DOX-PLGA NP on the expression of these pro-inflammatory genes was dose-dependent. These results show that DOX-PLGA NP efficiently suppressed the expression of pro-inflammatory genes. Furthermore, encapsulation of DOX into PLGA nanoparticles significantly improved the effectiveness of DOX in suppressing pro-inflammatory genes in MCF-7 breast cancer cells.