Decrease In IL-6 Research Articles

Effect of Whole-Body Electrical Muscle Stimulation Training on Inflammatory and Anti-inflammatory Cytokines in Overweight Men.

The aim of this study was to investigate the effects of whole-body electrical muscle stimulation (WB-EMS) training on inflammatory and anti-inflammatory cytokines in overweight men. We divided 30 participants into EMS and control groups. The training program for the EMS group comprised 20 WB-EMS sessions (7 weeks, three sessions per week). The results showed that EMS training caused significant increase in interferon γ (P<0.001) and interleukin 10 (IL-10; P<0.01) and significant decrease in IL-17 and IL-23 (P<0.05). Also, the lipid profile showed significant positive changes in the EMS training group. EMS training, a novel exercise method that uses electric stimulation, can affect the levels of various cytokines that are involved in inflammation and immunity. EMS training can have both beneficial and harmful effects on the body depending on the type and balance of involved cytokines.

Changes in serum levels of pro- and anti-inflammatory cytokines in women with papillomavirus infection before and after therapy”

Papillomavirus infections (PVI) are among the most common sexually transmitted diseases in the young population. A long, sluggish inflammatory process sufficiently worsens adequate preparation for normal pregnancy. Herpesvirus and Chlamydia infections are the most frequent associations with papillomavirus infection. Many authors believe that PVI may cause dysregulation of pro- and anti-inflammatory cytokines revealed in blood serum. Currently, there are no uniform standards for management and treatment of women with papillomavirus infection without pronounced clinical manifestations, in order to prevent morphofunctional disorders of genitourinary system leading to reproductive disorders. However, most authors believe that antiviral and immunomodulatory drugs are the main tool of therapy against expansion of pathogens in the body. The aim of our study was to compare changes in the levels of IL-17, IL-12 p70, IL-12 p40, IL-13 and TGF-p1 in blood serum of women with papillomavirus infection before and after therapy with Inosine pranobex (IP) and Solanum tuberosum (ST). We conducted a survey of 137 patients with papillomavirus infection treated with drugs containing Inosine pranobex and Solanum tuberosum as active substances. The levels of IL-17, IL-12 p70, IL-12 p40, IL-13, and TGF-p1 in blood serum were determined using specific reagents from RD Diagnostics Inc. (USA). Changes in pro- and anti-inflammatory cytokines before therapy were as follows: decreased levels were found for IL-12 p70, p40; increased values were revealed for IL-13, IL-17, and TGF-p1. After the courses of therapy, we have registered the following changes in PVI-infected patients treated with synthetic drug Inosine pranobex (IP): the levels of IL-12 p70, IL-12 p40 were increased, along with decrease in IL-13 and TGF-p1. Meanwhile, ST therapy was associated with increase in IL-12 p70, IL-12 p40, and a decrease in IL-13 and TGF-p 1. With IP therapy, patients with combined HPV + HV infection showed an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13, while TGF-p1 did not change. Following ST therapy, these patients exhibited higher IL-12 p70, IL-12 p40, decreased IL-13, whereas TGF-p 1 remained unchanged. In the group of women with HPV + Chlamydia infection, an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TGF-p1 was associated with IP therapy. An increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TGF-p 1 were shown after ST therapy. In all groups of patients, IL-17 remained at high levels after therapy without significant differences between the mentioned subgroups. In the groups of patients treated with IP. we have recorded a general normalization of immune disorders.

Features of the formation of early immunological tolerance during immunotherapy with allergens in patients with allergic rhinitis

BACKGROUND: The effectiveness of allergen-specific immunotherapy has been proven in studies. Studying the level and expanded spectrum of Th1, Th2, Treg and Breg cytokines against the background of allergen-specific immunotherapy, as well as allergen-specific IgG4 (asIgG4), is promising, which will clarify the mechanisms of the effectiveness of allergen-specific immunotherapy in patients with allergic rhinitis. AIM: To evaluate the clinical effectiveness of allergen-specific immunotherapy in patients with allergic rhinitis and to identify the most significant biomarkers of the formation of early immunological tolerance. MATERIALS AND METHODS: We examined 30 patients with allergic rhinitis aged 19 to 60 years who received allergen-specific immunotherapy. The clinical effectiveness was assessed using the validated Combined Symptom Medication Score (CSMS). All patients had their serum levels of IL-4, IL-13, IFN-γ, IL-12, IL-10, TGF-β, and asIgG4 of enzyme-linked immunosorbent assay recorded at baseline and 6 months after the start of allergen-specific immunotherapy. RESULTS: Allergen-specific immunotherapy has been demonstrated to be highly clinically effective in achieving control of allergic rhinitis. At baseline, the total CSMS score was 3.75 [3.33; 4.5], at the end of 6 months ― 1.83 [1.17; 2.67] (p=0.000002). When analyzing the dynamics of the cytokine profile and asIgG4, an increasing in the level of TGF-β (p=0.000002), IL-12 (p=0.000002) and asIgG4 (p=0.000003) was revealed, as well as a decreasing in the level of IL-4 (p=0.000024) 6 months after the start of allergen-specific immunotherapy. We did not register an increase in IFN-γ and the expected increase in IL-10 and decrease of IL-13. The correlation and principal component analysis showed that the clinical effect of allergen-specific immunotherapy was associated with an increase in TGF-β and IL-12, a moderate increase in asIgG4 with a decrease of IL-4. CONCLUSION: The results demonstrate the high clinical effectiveness of allergen-specific immunotherapy within 6 months from the moment of its initiation. Significant marker of the effectiveness of allergen-specific immunotherapy at the stage of early tolerance formation is TGF-β, which increasement was in correlation with an increased IL-12 with a decrease of IL-4. The increase in asIgG4 is less pronounced. The conducted correlation and principal component analysis showed the relationship of the discussed biomarkers with the CSMS, which may indicate in favor of their choice as potential biomarkers for assessing the effectiveness of allergen-specific immunotherapy.

The IBD Risk gene, PTPN2, Is Required for Commensal-associated Th17 Responses to Protect Against Pathobiont Colonization

Background/Aim: Inflammatory bowel disease (IBD) involves multiple factors including genetic susceptibilities, intestinal permeability, microbiome dysbiosis, and expansion of intestinal pathobionts such as adherent-invasive E. coli (AIEC). Mice lacking the IBD risk gene, Ptpn2, exhibit expansion of murine adherent-invasive Escherichia coli ( mAIEC strain, UCR-PP2). Internal transcribed spacer analysis of luminal and mucosal-associated bacteria also indicated a decrease in the protective commensal bacteria, segmented filamentous bacteria (SFB). SFB adherence to intestinal epithelial cells (IEC) induces Th17 cell secretion of IL-17 and IL-22 to promote mucosal defense. The goal of this study was to determine if constitutive whole-body, or IEC-specific Ptpn2 loss in mice modulates SFB abundance, adherence, and downstream production of protective Th17 cytokine in mice. Methods: All mice were housed in specific pathogen free (SPF) vivarium. Distal ileum (2-3 cm) was collected from whole body Ptpn2-wild-type (WT), heterozygous (Het) and Ptpn2 constitutive knockout (KO) mice [Balb/c]; or tamoxifen (TMX)-induced IEC specific Ptpn2 knockout mice ( Ptpn2ΔIEC) and TMX-treated control littermates ( Ptpn2fl/fl) [C57Bl/6]. Tissues were fixed and observed using the Hitachi TM4000 Scanning Electron Microscope (SEM) to visualize SFB. qPCR was used to quantify relative abundance of SFB in the Ileum tissue obtained from Ptpn2ΔIEC and Ptpn2fl/fl mice. Confirmed SFB-free C57Bl/6 mice (10 weeks old; JAX labs; Stock# 000664) were infected for four consecutive days by 109 mAIEC bacteria in PBS. Cytokine protein levels were quantified by Luminex Multiplex Array of whole tissue lysates from cecum, proximal and distal colon regions from 18-21day old WT, HET or KO mice. Immune cells were isolated from the cecum, colon, lamina propria, the mesenteric lymph nodes and the spleen of WT, HET and KO mice and analyzed by flow cytometry for IL-22+, and IL-17+ T cells. Results: SFB adherence to IECs in Ptpn2 constitutive KO mice was visibly decreased by SEM compared to WT and Ptpn2 Het littermates. SEM showed a dramatic decrease in SFB abundance in Ptpn2ΔIEC mice compared to control littermates ( Ptpn2fl/fl). This was confirmed by PCR analysis showing a significant decrease in SFB in Ptpn2ΔIEC mice (p&lt;0.05; n=8). The absence of SFB permitted mAIEC to colonize and cause mild disease in SFB-free mice (JAX; p&lt;0.01; n=8). SFB loss in whole-body Ptpn2-KO mice correlated with a decrease in IL-17+ CD4+ cells in the colon compared to Ptpn2-Het (p&lt;0.001; n=7) and Ptpn2-WT littermates (p&lt;0.05; n=5). Ptpn2-KO mice exhibited higher IL-22 levels in the distal colon (p&lt;0.01; n=3), and increased IL-22+CD4+ T-cells in the cecum, mesenteric lymph nodes and spleen compared to Ptpn2-WT and Het littermates (p&lt;0.001). Conclusion: Loss of the IBD risk gene Ptpn2 in mice, either constitutively or in IECs, reduces the abundance of SFB a commensal inducer of Th17 responses. Consistent with reduced SFB, IL-17+CD4+ T cells were reduced in whole-body Ptpn2-KO mice indicating a loss of SFB-induced Th17 maturation. Despite reduced IL-17, we observed increased IL-22 expression in Ptpn2-KO mice suggesting that loss of PTPN2 provokes a compensatory SFB/IL-17-independent increase in IL-22 production. These findings identify how loss of PTPN2 activity disrupts homeostatic commensal-mucosal immune crosstalk to facilitate IBD-relevant pathobiont colonization. This study was supported by grants NIH-2R01-DK091281, 1R01AI153314-01, R21AI152017, 1R01DK130373, and R01AI165490 (D.F.M.) from the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dietary phytochemicals as regulators of gut inflammation in the context of type 2 diabetes

Numerous disorders, including type 2 diabetes and even COVID-19, are linked to poor gut health and inflammation(1,2). In addition to impacting food digestion and absorption, gut inflammation worsens diabetes outcomes by causing gut microbial dysbiosis, disrupting tight junctions (allowing microbial metabolites to freely enter into circulation), and altering glucose absorption(3). ACE2 is a crucial regulator of gut health and has received much attention during the COVID-19 pandemic due to its role as a major viral entry protease. Studies have shown that the ACE2/Ang-(1-7)/Mas axis is important in managing inflammation and maintaining normal glucose metabolism(3). Dietary phytochemicals are plant bioactive compounds, with promising anti-inflammatory and anti-diabetic properties, and may affect these processes. In this work, we aimed to look at the link between inflammation, ACE2 and the glucose transporters, SGLT1 and GLUT2, and how phytochemicals could be used to normalise the changes brought about by inflammation in Caco-2/TC7 human intestinal epithelium cells. We first examined how gut inflammation, ACE2 and glucose transporters are related and proceeded to look at the effect of some chosen phytochemicals on regulating glucose transport via modulation of the ACE2/Ang(1-7)/Mas axis. This included genistein (an isoflavone from soyabeans), sulforaphane (an isothiocyanate found in Brassica, especially broccoli), apigenin (a flavone found in vegetables and herbs), and artemisinin (a sesquiterpene lactone used as a drug). The impact of phytochemicals on the SARS-CoV-2 viral entry receptors, ACE2 and TMPRSS2, was also examined as a secondary outcome. To induce inflammation, the Caco2/TC7 cells were co-stimulated with IL-1β (25 ng/mL) and TNF-α (50 ng/mL) for varying durations (24 h, 48 h, 72 h, 168 h) and changes in target gene expression (ACE2, SGLT1, GLUT2, TMPRSS2) were assessed by droplet digital PCR. IL-6 and IL-8 were assessed as markers of inflammation in the cell culture media by multiplex ELISA. Inflammation increased ACE2, TMPRSS2 and SGLT1 mRNA. ACE2 increased with cytokine exposure duration, coupled with an obvious decrease in IL-8, SGLT1 and TMPRSS2. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with decreases in SGLT1 (r = −0.99, p&lt;0.01) and IL-8 (r = −0.959, p&lt;0.05), implying ACE2 to play a crucial role in gut inflammation and postprandial glycaemia. After establishing the gut cell inflammation model, we compared the effect of the phytochemicals on our target genes in cells cultured in normal and pro-inflammatory environments. None of the tested phytochemicals were effective in reducing IL-8 secretion, while phytochemicals showed varying effects on the target genes. Genistein normalised the effects of inflammation on the target genes with less effect from the other tested phytochemicals. However, further research is required to assess the importance of genistein in vivo in the context of gut inflammation and type 2 diabetes.

296 Towards Nose-to-brain Inhibition of NFB: Activity of a Novel p65 Inhibitor in Glioblastoma and Feasibility of Intranasal Delivery With a Near-infrared Fluorescent HMC-Chitosan Nanoparticle

INTRODUCTION: Constitutive NFκB inflammatory signaling is a driving force of tumor progression, immune evasion, and therapeutic resistance in glioblastoma (GBM). CRL1101 is a novel small molecule inhibitor of RelA (p65), a transcription factor of NFκB-mediated gene expression. Previously, we have shown that heptamethine carbocyanine (HMC) conjugated nanoparticles target GBM tumor sites via organic anion transporter proteins. The activity of CRL1101 in GBM has not been explored. Poor blood-brain barrier (BBB) penetration and theoretical toxicities related to p65 inhibition pose challenges to its implementation in vivo. METHODS: GBM transcriptomic analysis was performed using Gene Profiling Interactive Analysis. In vitro cytotoxicity and migration assays were performed in U87 and GL261. Western blot was used to confirm the mechanism of CRL1101. Quantitative PCR was used to assess the relative expression of NFκB-regulated genes. HMC-chitosan-CRL1101 nanoparticles were synthesized by cross-linking chitosan with HMC and their uptake was visualized using immunocytochemistry. For survival analysis, we implanted GL261 cells into immunocompetent mice and treated intranasally with HMC-chitosan-CRL1101. RESULTS: RelA is overexpressed in GBM relative to normal brain tissue. CRL1101 alone effectively kills U87 cells (IC50 = 16.0 uM) and prevents migration in vitro (p &lt; 0.0001) by disabling the nuclear translocation of RelA. Treatment with CRL1101 was associated with a decrease in IL-8 (p = 0.01) and PD-L1 (p = 0.44) expression. HMC-chitosan-CRL1101 demonstrated an IC50 of 25.23 uM in U87. Near-infrared imaging confirmed intranasal delivery of HMC-chitosan-CRL1101 across the BBB in vivo. CONCLUSIONS: RelA-targeted NFκB inhibition with CRL1101 is a promising immunotherapeutic strategy in GBM. Intranasal nanoparticle delivery is a practical route to bypass the BBB and minimize systemic toxicities in mouse models of GBM, with expected survival benefit in vivo.

Abstract 2363: Enhanced T cell activation and cytotoxicity against AML via targeted anti-CD99-A192 ScFv-ELP nanoparticle treatment

Abstract CD99 is a transmembrane protein overexpressed in acute myeloid leukemia (AML), presenting a potential novel therapeutic target. Our previously developed anti-CD99-A192, comprising scFv and elastin-like polypeptides (ELPs), showed promising anti-leukemic activity by inducing apoptosis in AML cell lines and prolonging survival in AML xenograft models. Considering CD99's expression and role in T cell activation, we proposed that anti-CD99-A192 could have a dual function: targeting leukemic cells while activating T cells. Blood samples were obtained from 20 healthy donors, and peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with PHA and IL-2 cytokines to expand T cells for 72-96 hours. Post-expansion, T cells were treated with either anti-CD99-A192 or control anti-A192. Proliferation was evaluated via cell count and cell trace assays. The percentages of CD4+, CD8+, and CD25+ T cells, and the levels of T cell activation markers CD69 and CD38, were quantified by flow cytometry. Cytokine release profiles were assessed by the Proteome Profiler Human Cytokine Array Kit. The cytotoxic impact of the anti-CD99-A192-activated T cells on MV4-11Luc+ AML cells was measured in co-culture apoptosis and luciferase assays. Statistical comparisons utilized paired and unpaired T-tests with Holm-Sidak correction for multiple comparisons, and P value &amp;lt;0.05 was considered significant. T cells treated with anti-CD99-A192 displayed significant increased proliferation compared with untreated and anti-A192-treated groups at Day 5 (163.3% vs. 97% and 92.4%, p=0.042 and p=0.03, respectively). The percentage of CD4+, CD8+, and CD25+ cells remained unchanged across treated and control groups. Activation marker analysis revealed increase in % CD38+ cells in the anti-CD99-A192 group compared with the control (58.15% vs. 49.15%, p=0.0028). Among the cytokine panel, significant increases in IL-1β/IL-1F2 (11-fold change, p&amp;lt;0.001, adjusted p=0.006) and TNF-α (12-fold change, p=0.002, adjusted p=0.03) were observed, along with a marked decrease in IL-8 (70% reduction, p&amp;lt;0.001, adjusted p=0.001). GM-CSF (20-fold change, p=0.005, adjusted p=0.071) and IL-16 (2-fold change, p=0.003, adjusted p=0.051) levels also increased, though not significantly after adjustment. Co-culture assays showed greater apoptosis in MV4-11 cells at 18 hours (33.6% vs. 41.13%, p=0.015) and a reduction in viable leukemic cells at 18 hours (10.89% vs. 8.05%, p=0.034) and 48 hours (9.69% vs. 6.54%, p=0.065) in the anti-CD99-A192 compared with the control group, results were also validated by the luciferase assay (~32% reduction, p&amp;lt;0.001). Anti-CD99-A192 scFv-ELP nanoparticle stimulates T cell proliferation, elevates activation markers, and increases the release of pro-inflammatory cytokines. Anti-CD99-A192 culminates in heightened cytotoxicity against leukemic cells. Citation Format: Shephali Kadam, Atham Ali, Mateusz Pospiech, Sandra Onyemaechi, Yiting Meng, Kanaka Dhuri, Andrew Mackay, Houda Alachkar. Enhanced T cell activation and cytotoxicity against AML via targeted anti-CD99-A192 ScFv-ELP nanoparticle treatment [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 2363.

N-acetyl cysteine augments adipose tissue-derived stem cell efficacy on inflammatory markers and regulatory T cell system balance in an allergic asthma model

Background Allergic asthma is a destructive inflammatory process in the respiratory system. The anti-inflammatory and antioxidant effects of N-acetylcysteine (NAC) have been reported in patients with obstructive pulmonary disease. On the other hand, several studies have shown the modulatory effects of mesenchymal stem cells on the immune system and inflammatory responses. Accordingly, the purpose of the current study was to evaluate the effect of administration of adipose tissue-derived stem cells (ADSCs) plus NAC on regulatory T cell system balance in an allergic asthma model. Methods Eighty Sprague– Dawley rats were randomly divided into the following groups: Control, Plasmalite, Allergic asthma, Allergic asthma + ADSCs, NAC, Allergic asthma + NAC, Allergic asthma + ADSCs + NAC and Allergic asthma + Prednisolone. at the end of the experiment, arterial blood gas analysis, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokine concentration, total IgE and specific OVA-IgE levels, gene expression levels of CD4+-T cell subsets, pulmonary indicators, edema, and lung histopathology were evaluated in all groups. Results Administration of NAC plus ADSCs demonstrated a significant decrease in total WBC and eosinophil counts, which was in line with remarkable decrease in IL-17 and TNF-α concentrations and increases in IL-10 level compared with other treated groups. NAC plus ADSC treatment showed significant increases in Treg gene expression, although Th17 and Th2 expression significantly decreased compared with that in prednisolone- treated rats. Conclusion The results of the present study documented that the administration of ADSCs plus NAC has an inhibitory effect on the inflammation caused by allergic asthma in a rat model. The improvement of inflammatory indexes was significantly higher than that with prednisolone treatment.

Pelotherapy and pelotherapy combined with intravenous laser blood irradiation at the sanatorium-resort stage of treatment of patients with psoriasis vulgaris

To carry out a comparative analysis of the impact of different variants of sanatorium-resort treatment (SRT) - pelotherapy and pelotherapy in combination with intravenous laser blood irradiation (ILBI) - on the level of IL-17 and TNF-a, dermatological status, psychoemotional state and quality of life (QL) assessment of patients with psoriasis vulgaris. A naturalistic comparative study included 120 patients with psoriasis vulgaris, who were undergoing SRT: 57 patients in the pelotherapy group and 63 in the group of pelotherapy in combination with ILBI. The SRT effectiveness was assessed using the PASI index, the HARS and HDRS scales and the DLQI questionnaire. The dynamics of IL-17 and TNF-a plasma levels in blood plasma was studied. The study duration was 6 months 14 days. After 14 days of SRT, a decrease in IL-17 and TNF-a levels in blood plasma was statistically significant both in the pelotherapy group and in the group of pelotherapy in combination with ILBI, no statistically significant differences between the groups were found. Furthermore, the comprehensive use of pelotherapy in combination with ILBI has contributed to a more pronounced statistically significant decrease in the PASI index, the HARS and HDRS scales' total scores and an increase in the level of QL. The number of patients with clinical remission was statistically higher in the group of pelotherapy combined with ILBI compared to the pelotherapy group (87.3% versus 42.1%) six months after SRT. The advantage of comprehensive application of pelotherapy and ILBI in comparison with pelotherapy in patients with psoriasis vulgaris in SRT has been shown. The comprehensive application of pelotherapy and ILBI reduces the level of inflammatory biomarkers, improves dermatological and psychoemotional status, improves QL and is well tolerated by patients.

Immune Cells, Cytokines, and Gut Microbiota Landscape Along Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma (MM) Evolution

Introduction: Multiple myeloma (MM) is an incurable hematologic cancer characterized by abnormal plasma cell growth in the bone marrow (BM). It is preceded by two premalignant conditions: monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Understanding the transition from MGUS to MM is crucial for better risk stratification, early interventions, and targeted treatments. This study aims to gain insights into immunological changes and fecal microbiota variations along the MGUS to MM transition. Methods: To comprehensively evaluate the immune composition (myeloid/lymphoid T/B/NK subpopulations and immune checkpoint distribution) in both bone marrow (BM) and peripheral blood (PB), we designed six 10-color custom and two 8-color flow cytometry panels. We analyzed samples from 13 MGUS, 12 SMM, and 63 newly diagnosed MM patients. Additionally, we evaluated cytokine/chemokine abundance in BM and PB using a 48-plex Luminex plate on 72 samples from the same MGUS, SMM, and MM patients, along with 4 healthy donors (HD). Furthermore, we performed fecal microbiome profiling on samples from 3 MGUS, 6 SMM, and 9 MM patients to investigate potential relationships between bacterial composition and MM evolution. Statistical analysis was performed in R by using specific packages (such as FlowCT). Results: Through unsupervised analysis of T cells by flow cytometry, we identified a significant increase in circulating TEMRA CD8 T cells, mostly for CD57+ cells (mean, 7.5% for MGUS vs 20.1% for SMM vs 21.6% for MM; p&amp;lt;0.05) and a significant reduction in naïve CD8 T TIGIT+ cells (mean, 12.4% for MGUS vs 5.98% for SMM vs 4.16% for MM; p&amp;lt;0.001) and naïve CD8 T TIGIT+ TIM3+ (mean, 2.18% for MGUS vs 1.24% for SMM vs 1.17% for MM; p&amp;lt;0.001). Regarding CD4 T subsets, we observed a reduction in BM effector memory phenotype along disease evolution (mean, 7.07% for MGUS vs 4.54% for SMM vs 3.72% for MM; p&amp;lt;0.05). Interestingly, we confirmed the increase of BM CD4 T cells production of IL17 (mean: 6.7% for MGUS vs 22% for MM; p&amp;lt;0.05) in MM patients compared to those with MGUS. In the context of myeloid cell subsets, circulating non-classical monocytes expressing HLA-DR and CD11c (mean, 1.45% for MGUS vs 0.95% for SMM vs 0.69% for MM; p&amp;lt;0.05) as well as granulocytes (mean, 74.18% MGUS vs 73.86% SMM vs 65.59% MM; p&amp;lt;0.05) were found to be reduced along MM progression. No major differences were observed for other evaluated lineages. Regarding cytokines and chemokines, a concurrent decrease in GM-CSF, IFN-a2, IFN-g, IL-1b, IL-2, IL-2Ra, IL-3, IL-10, IL-13, and MCP-1/CCL2 levels within the BM plasma throughout MM progression was observed, thus supporting a global reduction in myeloid function as well as in T cell effector activity. Moreover, PDGF-BB, IFN-a2, IL-16, and IL-8 decrease was observed in PB plasma along MM progression. Lastly, while no differences were observed in term of alpha and beta diversity, we observed an overall increase in total abundance of fecal bacteria along MM evolution (maybe related to loss of myeloid/lymphoid control according to what previously described), with several bacterial genus significantly over-represented in MM patients, including Bariatricus, CAG-83, Alistipes, Bifidobacterium, Streptococcus, Ruminococcus D, Slackia A, and Coprococcus A, while others (such as Parabacteroides B) was found to be more represented in MGUS and SMM patients. The analysis of phyla abundance indicated Firmicutes D and Lactobacillales as more abundant in MM patients, while Actinobacteriota dominated in SMM patients, and Proteobacteria and Bacteroidota were more prominent in MGUS patients. Conclusions: Overall, this study demonstrated a progressive impairment of both myeloid and lymphoid compartment in term of cellular composition, cytokine production and release and control over gut microbiome. Recovering from T cell exhaustion and IL17 production remains a major challenge for these patients.

Poster 148: Preoperative Platelet Rich Plasma Injections Decreases Inflammatory and Chondrodegenerative Biomarkers in Patients with Acute Anterior Cruciate Ligament Tears and Reconstruction: A Pilot Study

Objectives: Post-traumatic osteoarthritis occurs at an alarming rate after ACL injury and surgery. The purpose of this study was to compare the effect of two, pre-operative PRP injections upon the progression of inflammatory and chondrodegenerative biomarkers to the natural progression before ACL reconstruction surgery. Our hypothesis was that pre-operative PRP injections would decrease the chondrotoxicity of the presurgery knee fluid. Methods: Participants were randomized to either a control or intervention group. Both groups received joint aspirations within the first 10 days following ACL injury (Time 1). In addition to joint aspiration at Time 1, the PRP group received a PRP injection at Time 1 and an additional PRP injection at a second visit 5-12 days after the initial visit. Synovial fluid samples were harvested in both groups at the time of ACL reconstruction (Time 2). ELISA was performed on all samples to detect cytokine levels of IL-1B, IL-10, IL-6, GM-CSF, IL-5, IFN-γ, TNF-⍺, IL-2, IL-4, and IL-8 Results: A total 24 participants were enrolled, final analysis was completed on 8 participants in the control group and 9 participants in the intervention group. The control group demonstrated a change in concentration (Δ1à2) between time 1 and time 2 that was not statistically significant for any cytokines p&gt;0.05, except for a statistically significant decrease in IL-8 (p=0.005). The intervention group demonstrated a decrease in all cytokine concentrations that was statistically significant for all cytokines p&lt;0.05, except for IL-8 (p=0.074). When comparing the control group to the intervention group at time 1, no significant difference was seen between cytokine concentrations (p&gt;0.05). Likewise, comparing the control group to the intervention group at time 2, no significant difference was seen between cytokine concentrations (p&gt;0.05). The magnitude of decrease was larger in the intervention group than the control group, but with comparison of means between groups there was not a statistically significant difference. The natural history for these biomarkers is a decrease but at a variable rate/amount. Preoperative intervention with PRP has the potential to consistently alter the concentration of chondrodestructive proteins. Conclusions: Intervention with aspiration and 2 injection series of PRP in the acute ACL injured knee resulted in greater reduction in effusion inflammatory markers than control. This may suggest a treatment modality to improve perioperative pain, function and possibly alter the course of post trauma arthritis in these patients, without the deleterious effect of steroid injection. Long term study and follow up is required to determine if intervention alters the natural history of post traumatic arthritis. [Table: see text][Table: see text]

Effect of intracanal cryotherapy on the inflammatory cytokine, proteolytic enzyme levels and postoperative pain in teeth with asymptomatic apical periodontitis: A randomised clinical trial.

to investigate the changes in the biomarker levels related to inflammation and tissue destruction in the periapical exudate of mandibular premolar teeth with asymptomatic apical periodontitis after receiving intracanal cryotherapy, to compare cryotherapy and control groups in terms of analgesic intake, interappointment, and postoperative pain, and evaluate the correlation between biomarker levels and interappointment pain. Mandibular premolar teeth of 44 patients aged 18-35 years, diagnosed with asymptomatic apical periodontitis, were root canal treated in two visits (registered as NCT04798144). Baseline periapical exudate samples were obtained, and the patients were assigned to either control or intracanal cryotherapy group according to the final irrigation with distilled water either at room temperature or 2.5°C. The canals were dressed with calcium hydroxide. In the second visit, the calcium hydroxide was removed with passive ultrasonic irrigation, and the periapical exudate was sampled again. IL-1β, IL-2, IL-6, IL-8, TNF-α, PGE2 and MMP-8 levels were determined with ELISA. Postoperative pain levels were recorded for six days following both visits using a visual analogue scale. Data were analysed using t-test, Mann-Whitney U, and correlation tests. There was a significant correlation between the pain scores reported after first visit and IL-1β and PGE2 levels (p < .05). IL-1β, IL-2, and IL-6 levels showed no significant difference in the cryotherapy group (p > .05), while they significantly increased in the control group (p < .05). There was a decrease in IL-8, TNF-α, PGE2 , and MMP-8 levels, however, the difference was not significant (p > .05). Pain scores were significantly lower in the cryotherapy group for the first three days (p < .05), except for 24th hours (p > .05). The positive correlation between interappointment pain and IL-1β and PGE2 levels might indicate that these biomarker levels can be used to predict the severity of postoperative pain. Intracanal cryotherapy was effective in reducing postoperative pain in the short term in teeth with asymptomatic apical periodontitis. Cryotherapy prevented an increase in IL-1β, IL-2, and IL-6 levels compared to the control group.

Abstract 2172: Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel

Abstract Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in pancreatic ductal adenocarcinoma (PDAC), and high tumor IL1RAP RNA expression is a negative prognostic marker1. Dimerization between IL1RAP and the IL-1 receptor is required for IL-1 signaling, and the IL-1 axis has been implicated in the tumor microenvironment and immune response to PDAC. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 anti-IL1RAP antibody, blocks IL-1α and IL-1β signaling. Preliminary efficacy from the clinical phase 1/2a trial CANFOUR, where PDAC patients (n=73) received nadunolimab with gemcitabine and nab-paclitaxel (GN), show median iPFS of 7.2 months (iRECIST; 95% CI 5.2-8.5), median OS of 12.7 months (10.0-19.1) with 59% of patients alive, and 1-year survival of 57%2. Methods: Patients with previously untreated, locally advanced or metastatic PDAC received nadunolimab at doses from 1 to 7.5 mg/kg, in combination with GN. The exploratory objective was to measure serum and tumor biomarkers related to treatment outcome. Pre-treatment tumor biopsies were assessed for IL1RAP expression by immunohistochemistry. Serum from all patients was analyzed for biomarkers by Meso Scale Discovery (MSD) and Olink. Results: IL1RAP was expressed on tumor and stromal cells in all biopsies analysed and IL1RAP-positive infiltrating immune cells were detected in biopsies from 94% of patients (n=38). The level of IL1RAP on tumor cells was associated with response (PR vs SD and PD; p=0.082). Patients with PR had a median IL1RAP H-score of 200, while patients with SD or PD as best response had a median H-score of 110. The data suggest a relationship between high IL1RAP expression and increased iPFS and OS. Reductions in serum biomarkers downstream of IL-1, detected by MSD, were also associated with response. Patients with the largest treatment-related decreases in IL-6 displayed a prolonged iPFS (p&amp;lt;0.023), while patients with a decrease in IL-8 showed prolonged iPFS (p&amp;lt;0.025) and OS (p&amp;lt;0.041). Patients with the most decreased CRP levels following treatment also showed extended iPFS (p&amp;lt;0.009) and OS (p&amp;lt;0.008). A reduction in other IL-1-related biomarkers, such as CXCL5, VEGFA, EGF, Angiopoietin 1 and TWEAK, was also detected by Olink post-treatment. Conclusions: Nadunolimab combined with GN shows promising iPFS and OS in 73 PDAC patients. In these patients, high tumor cell expression of IL1RAP, the molecular target for nadunolimab, correlated with response. Reduction of the downstream biomarkers IL-6 and IL-8, as well as CRP, were most pronounced in responding patients and correlated with efficacy. These data strongly suggest that nadunolimab interaction with IL1RAP is important for the treatment effects observed in the CANFOUR study. 1TCGA Database2Van Cutsem et al; ASCO 2022 Citation Format: Eric Van Cutsem, Joelle Collignon, Rikke Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Camilla Rydberg Millrud, Petter Skoog, Nedjad Losic, Susanne Magnusson, Annika Sanfridson, David Liberg. Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2172.

P001 Obefazimod upregulates miR-124 and downregulates the expression of some cytokines in blood and rectal biopsies of patients with moderate-to-severe ulcerative colitis.

Abstract Background The oral small molecule obefazimod (ABX464) has demonstrated efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC) in a randomized, placebo-controlled, 8-week phase 2b induction study1. We examined the effects of obefazimod on miR-124 and cytokines levels in blood (baseline, weeks 4 and 8) and rectal biopsies (baseline, week 8) of these patients. Methods Absolute quantification (QuantaSoft Pro) of the miR-124 copy number was performed by using droplet digital PCR technology on 644 rectal biopsy samples and 1104 whole blood samples from patients receiving obefazimod (25mg, 50mg or 100mg once daily) or placebo. A total of 15 cytokines (IL1b, IL13, IL17, IL6, IL10, IL23, MCP-1, IL34, CXCL-12, IL22, LIF, TGFb, GM-CSF, IFNg and TNFa) were examined by immunohistochemistry (IHC) on 208 rectal biopsies. For each cytokine, antibodies were tested for the chromogenic IHC detection on paraffin tissue sections; repeatability and reproducibility tests were conducted to validate protocols with robust signal. IHC signal was digitized and quantified with Halo® image analysis software. IL17 was also measured in blood samples using an ELLA immunoassay (Bio-Techne). Results The three tested doses of obefazimod (25mg, 50mg or 100mg once daily) significantly upregulated miR-124 in blood at week 1 (A) and 8 (B), and in rectal tissue at week 8 (C) (from p&amp;lt;0.001 to p&amp;lt;0.0001 vs. placeb The three doses of obefazimod significantly reduced IL17 levels in blood of patients at week 1, 4 and 8 (from p&amp;lt;0.01 to p&amp;lt;0.0001 vs. placebo). IHC protocols in rectal tissue were validated for 4 out of 15 cytokines: IL17, IL23, CXCL-12, INFg. Compared with baseline levels, an 8-week obefazimod treatment significantly down-regulated the expression of IL17 (at all doses, (from p&amp;lt;0.05 to p&amp;lt;0.001), IL23 (p&amp;lt;0.01 at 50mg, p&amp;lt;0.001 at 100 mg), and INFg (p&amp;lt;0.001 at 50 mg). Within obefazimod treated subjects, clinical responders showed higher reduction of IL-17A and IL-23 expression in rectal tissue than non-clinical responders at week 8 (reduction in MMS ≥2 points and ≥30% from baseline + decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1 point). No significant change was observed with CXCL-12. Conclusion The 8-week efficacy of obefazimod in patients with moderate-to-severe UC is associated with an increase in miR-124 expression in blood and tissue and with a decrease of IL17, IL23 and INFg in the colorectal tissue.

538. Human neutrophil gelatinase-associated protein (N-gal) and proinflammatory cytokines as biomarkers of disease severity in children with Hemolyitic Uremic Syndrom (HUS) and Shigatoxin-producing E.coli (STEC) infection.

Abstract Background Hemolytic Uremic Syndrome (HUS) is a complication of Shigatoxin-producing E.coli (STEC) infection which presents a characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Preliminary in vitro and experimental animal studies demonstrated that Shigatoxins (STXs) induce the secretion of proinflammatory cytokines. Human neutrophil gelatinase-associated protein (N-gal) has been reported as a marker of acute kidney injury. Dosing serum levels of IL-8, TNF-α, IL-6, IL-1β and N-gal in children with STEC-associated infection and HUS would allow to establish the role of these cytokines as biomarkers of renal injury and severity Methods Prospective study during 2017 – 2020 was performed; three groups of patients &amp;lt; 18 years were included: bloody diarrhea (BD), HUS requiring dialysis (HUSD) and HUS and no dialysis requirement (HUSND), all of them with presence of STX in stool. Blood samples were collected at diagnosis (t1) and at 7 days (t2). An immunoassay was used for detection of TNF-α, IL-1β, IL-6, and IL-8 (Bio-Plex Pro Human®, BioRad). An immunoassay (Anti-Lipocalin-2) was used for N-gal detection Results Forty-nine children were admitted; 22 (49%) were male. Median age was 24 (IQR 13-36) months. Fourteen patients with BD, 24 patients with HUS: 12 HUSD and 12 HUSND. Eleven healthy children (HC) were included. At diagnosis, higher IL-8 values were found in HUSD vs. BD (p=0.0004), HUSND (0.003) and HC (p= 0.0043). Higher TNF-α values were detected in HUSD vs. BD (P= 0.0001), HUSND (p= 0.0011) and HC (p= 0.0002). Higher TNF-α values were found in patients with BD vs HC (p= 0.0055). HUSD exhibited higher IL-6 values as compared with BD (p= 0.0145) and HC (0.0106). N-gal concentrations were higher in HUSD vs. BD (P= 0.0120), HUSND (P= 0.0166) and HC (p= 0.0049). A decrease in IL-8 was observed in HUSD between t1 and t2 (p=0.0357). (Figure 1) Conclusion Interleukin 8, IL-6, and N-gal may be considered as potential serological markers of renal damage and dialysis requirement. TNF-α concentrations are already increased in BD without HUS complications Disclosures All Authors: No reported disclosures.

Impact of elexacaftor-tezacaftor-ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF). Lung function (FEV1 ), body mass index (BMI) and microbiologic data were collected at initiation and 3-month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non-CF controls. Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r = 57.2, p < 0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n = 20) had significantly lower levels of circulating neutrophils,interleukin (IL)-6, IL-8, and IL-17A and higher levels of IL-13 compared to pwCF at baseline (n = 48). After 6 months of ETI, pwCF had significant decreases in IL-8, IL-6, and IL-17A levels and normalization of peripheral blood immune cell composition. In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.

Cytokine patterns in cystic fibrosis patients with different microbial infections in oropharyngeal samples.

Cytokines play a crucial role in the immune system's regulation by mediating protective responses to infections. anti-inflammatory and pro-inflammatory cytokines are in equilibrium. Therefore, any alteration in cytokine production or cytokine receptor expression might result in pathological illnesses and health issues. Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane regulator (CFTR) gene. Lung infection in these patients is related to chronic bacterial airway infection and inflammation, which is triggered by some inflammatory cytokines. Our goal was to compare the cytokine patterns in CF patient's serum and PBMCs caused by microbial pathogens that colonized their airways to controls. ELISA and Real-time PCR were used to determine the levels of IL-10, IFN-γ, IL-4, TGF-β, IL-8, and IL-17 in serum and PBMC cells. Blood parameters in both patients and healthy people were studied. An increase in IL-10, IFN-γ, IL-4 (p-v=0.03, 0.024 and 0.003) levels and a decrease in IL-17 (p-v=0.004) was found in Pseudomonas aeruginosa positive patients. There were no different in TGF-β and IL-8 (p-value=0.778 and 0.903) in this patients. IL-10, IFN-γ, and IL-4 (p-value=0.023, 0.001 and 0.002) levels were high in Staphylococcus aureus positive patients and TGF-β, IL-17, and IL-8 (p-value=0.085, 0.167 and 0.362) were not significantly different in the patient and control groups. IFN-γ and IL-4 levels were higher in patients without infection who had normal microbiota (p-v=0.002 and 0.024). In patients with P. aeruginosa, WBC and platelets increased, and MCH and MCV decreased. Patients with normal microbiota had less MCV. According to our research, patients with P. aeruginosa, S. aureus, and normal microbiota are exposed to cytokine alterations and changes in blood factors. The link between the CF patient's airway microbiota and the kind of generated cytokines might lead to the modulation of inflammatory cytokines alone or in combination with antibiotics, reducing disease-causing effects while avoiding drug resistance.

Changes of blood serum cytokine profile in the patients with papillomavirus infection before and after therapeutic pregravid preparation

Human papillomavirus is one of the most common sexually transmitted viruses. The state of the immune system is fundamental to the outcome of infectious processes of viral and bacterial genesis, thus determining the quality of pre-gravidar preparation. The purpose of present study was to perform a comprehensive analysis of pro- and anti-inflammatory cytokines in papillomavirus infection and to provide immunological assessment of therapeutic efficiency in women. Materials and methods: 137 patients with papillomavirus infection were observed, at the average age of 312.5 years old. The study consisted of 2 stages: stage 1 included analysis of humoral innate immunity in women of the main group, distributed according to etiological factor, i.e., G-I was with papillomavirus infection (PVI); G-II presented with papillomavirus and herpetic infection (PVI + HVI 1/2 type); G-III included the patients with papillomavirus and Chlamydia infection (PVI + Trash.). At Stage 2, we performed immunological analysis of the therapeutic efficiency for PVI: in G-IA group with papillomavirus infection (PVI) we used Inosine pranobex (n = 11); in the IB group, Solanum tuberosum was applied (n = 10); in G-II A group with papillomavirus and herpes infection (PVI+HVI 1/2 type), we used Valacyclovir + Inosine pranobex (n = 24); in G-IIB patients Valacyclovir + Solanum tuberosum were administered (n = 23); for G-IIIA group with papillomavirus and chlamydia infection (PVI + Trash.) Doxycycline + Inosine pranobex were used (n = 20); the patients from IIIB group were treated with Doxycycline + Solanum tuberosum (n = 19). Determination of levels of IL-17A, IL-12 p70, IL-12 p40, IL- 13 in blood serum was carried out using specific reagents from RD Diagnostics Inc. (USA). Results: Before therapy, an increase in IL-17 and IL-13 (p 0.05), and a pronounced deficiency of IL-12 p40 and IL-12 p70 (p 0.001) were observed in blood serum of the patients. After the course of therapy, a decrease in IL-13 and an increase in IL-12 p40 and IL-12 p 70 were found. The IL-17 level remained without dynamic changes. The applied therapeutic approaches had a positive effect in all studied groups of patients, regardless of the drug administered.

Cytokine system in the patients with type 2 diabetes mellitus non-infected with SARS-CoV-2

Diabetes mellitus (DM) is a common chronic non-communicable disease, being the most significant comorbidity in SARS-CoV-2 viral infection. The proportion of DM patients among those with COVID-19 is up to 25.0% in the Russian Federation. In presence of DM, clinical course of COVID-19 is characterized by greater severity and persistence of pulmonary damage, an increased need for immunosuppressive, glucocorticoid and combined antiviral therapy in COVID-19 patients, and with prolonged rehabilitation period. Pathogenetic effects of DM on severe course of the SARS-CoV-2 viral infection are being actively studied. The following factors were considered, e.g., negative impact of hyperglycemia on the course of infection; direct cytotoxic and indirect damage to pancreatic -cells with further activation of pro-inflammatory mechanisms; cumulation and progression of generalized inflammation common to DM and COVID-19 including impaired production of cytokines; influence of SARS-CoV-2 virus on the renin-angiotensin-aldosterone system causing inhibition of insulin secretion and increased insulin resistance. Chronic inflammation and impaired immune response may be among the main mechanisms of association between type 2 DM (T2DM) and COVID-19. It is important to identify systemic inflammatory disorders in patients with type 2 diabetes, which may be associated with greater disease severity, being of negative prognostic value. The aim of the present work was to investigate concentrations of some serum cytokines in the patients with type 2 diabetes not infected with SARS-CoV-2.&#x0D; The study included 20 patients with type 2 diabetes; the control group consisted of 11 clinically healthy volunteers. The serum concentration of 13 cytokines was assessed by multiplex analysis on a MAGPIX-100 immunoanalyzer using a Merck multiplex analysis kit (Germany), in accordance with the manufacturers instructions.&#x0D; Increased serum concentrations in T2DM patients were found, as compared with the control group for some key pro-inflammatory cytokines: CX3CL1, TNF, IFN, IL-8, IL-17A, MIP-1, and MIP-1. We have also revealed a decrease in serum concentrations of IL-4. Serum immunoregulatory cytokines in the T2DM were found to be changed in different directions: a decrease in IL-5, along with increase of IL-12p70 and IL- 17, whereas the serum contents of IL-2, IL-13 did not change.&#x0D; A comprehensive analysis of serum cytokine concentrations may increase clinical significance of assessing serum cytokine concentrations as prognostic and diagnostic markers, as well as therapeutic targets in type 2 DM, like as in SARS-CoV-2 infection.

Ambient air pollution and inflammation-related proteins during early childhood

Background and aimExperimental studies show that short-term exposure to air pollution may alter cytokine concentrations. There is, however, a lack of epidemiological studies evaluating the association between long-term air pollution exposure and inflammation-related proteins in young children. Our objective was to examine whether air pollution exposure is associated with inflammation-related proteins during the first 2 years of life. MethodsIn a pooled analysis of two birth cohorts from Stockholm County (n = 158), plasma levels of 92 systemic inflammation-related proteins were measured by Olink Proseek Multiplex Inflammation panel at 6 months, 1 year and 2 years of age. Time-weighted average exposure to particles with an aerodynamic diameter of <10 μm (PM10), <2.5 μm (PM2.5), and nitrogen dioxide (NO2) at residential addresses from birth and onwards was estimated via validated dispersion models. Stratified by sex, longitudinal cross-referenced mixed effect models were applied to estimate the overall effect of preceding air pollution exposure on combined protein levels, “inflammatory proteome”, over the first 2 years of life, followed by cross-sectional protein-specific bootstrapped quantile regression analysis. ResultsWe identified significant longitudinal associations of inflammatory proteome during the first 2 years of life with preceding PM2.5 exposure, while consistent associations with PM10 and NO2 across ages were only observed among girls. Subsequent protein-specific analyses revealed significant associations of PM10 exposure with an increase in IFN-gamma and IL-12B in boys, and a decrease in IL-8 in girls at different percentiles of proteins levels, at age 6 months. Several inflammation-related proteins were also significantly associated with preceding PM10, PM2.5 and NO2 exposures, at ages 1 and 2 years, in a sex-specific manner. ConclusionsAmbient air pollution exposure influences inflammation-related protein levels already during early childhood. Our results also suggest age- and sex-specific differences in the impact of air pollution on children's inflammatory profiles.