Plasma IL-6 Levels Research Articles

The risk of metabolic syndrome is associated with vitamin D and inflammatory status in premenopausal and postmenopausal Algerian women.

This first cross-sectional study examined whether vitamin D status and proinflammatory cytokines may be associated with metabolic syndrome (MetS) in Algerian women regarding their menopausal status. Fasting plasma glucose (FPG), lipids, insulin, 25(OH)D, PTH, adiponectin, resistin, TNFα, and IL-6 levels were assessed in 277 participants aged 18-74years. MetS was diagnosed according to NCEP-ATPIII criteria. The association of vitamin D deficiency, IL-6, and TNFα with components of MetS was analyzed by the logistic regression. Among a cohort of 277 participants, the prevalence of MetS in 115 premenopausal vs. 162 postmenopausal women was 54.02 vs. 68.1%. Cut-offs for vitamin D deficiency were 15.7 vs. 13ng/mL, 51.07 vs. 41pg/mL for IL-6 and 8.28 vs. 9.33 pg/mL for TNFα, respectively. 25(OH)D levels were positively correlated with adiponectin levels, while negatively with HOMA-IR in postmenopausal-MS + women. Adjustment for age and BMI reveals a significant association between vitamin deficiency and high FPG (OR: 2.92 vs. 2.90), TG (OR:2.79 vs. 3.51), BP (OR:2.20 vs. 1.92), and low HDL-c (OR:2.26 vs. 3.42), respectively. A significant association was also detected in postmenopausal women between IL-6 and high FPG (OR5.11, p = 0.03), BP (OR:3.13, p = 0.04), and low HDL-c (OR5.01, p = 0.02), while TNFα was associated with high BP in postmenopausal women (OR: 3.70, p = 0.01), and inversely with TG in premenopausal women (OR: 0.16, p = 0.04). This study highlighted that severe vitamin D deficiency increases MetS score and was closely associated with four components of MetS, more potently in postmenopausal women, probably related with estrogens. Abdominal obesity, as influential component of MetS, may be involved in enhancing vitamin D deficiency, and dysregulating some metabolic hormones such as adiponectin, resistin and insulin, that contributes in onset an inflammatory state, through the increase in IL-6 and TNFα levels. These findings need to be improved by expanding investigation to a large cohort of participants.

Multiplex interrogation of the NK cell signalome reveals global downregulation of CD16 signaling during lentivirus infection through an IL-18/ADAM17-dependent mechanism.

Despite their importance, natural killer (NK) cell responses are frequently dysfunctional during human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, even irrespective of antiretroviral therapies, with poorly understood underlying mechanisms. NK cell surface receptor modulation in lentivirus infection has been extensively studied, but a deeper interrogation of complex cell signaling is mostly absent, largely due to the absence of any comprehensive NK cell signaling assay. To fill this knowledge gap, we developed a novel multiplex signaling analysis to broadly assess NK cell signaling. Using this assay, we elucidated that NK cells exhibit global signaling reduction from CD16 both in people living with HIV-1 (PLWH) and SIV-infected rhesus macaques. Intriguingly, antiretroviral treatment did not fully restore diminished CD16 signaling in NK cells from PLWH. As a putative mechanism, we demonstrated that NK cells increased surface ADAM17 expression via elevated plasma IL-18 levels during HIV-1 infection, which in turn reduced surface CD16 downregulation. We also illustrated that CD16 expression and signaling can be restored by ADAM17 perturbation. In summary, our multiplex NK cell signaling analysis delineated unique NK cell signaling perturbations specific to lentiviral infections, resulting in their dysfunction. Our analysis also provides mechanisms that will inform the restoration of dysregulated NK cell functions, offering potential insights for the development of new NK cell-based immunotherapeutics for HIV-1 disease.

Serum Magnesium Levels in Patients with Chronic Kidney Disease: Is There a Relationship with Inflammation Status?

Magnesium (Mg2+) is a fundamental mineral that maintains cellular function, and low levels may be linked to inflammation in patients with chronic kidney disease (CKD). This cross-sectional study evaluated the correlation between serum Mg2+ levels and the inflammatory status in patients undergoing dialysis. Two hundred patients with CKD [150 undergoing hemodialysis (HD), 50 (18) years; BMI 24 (4.8) kg/m²; and 50 patients on peritoneal dialysis (PD), 54 (17.7) years; BMI, 27.5 (7.3) kg/m²] were included. Serum Mg2+ levels were evaluated using a colourimetric test and commercial kit. Inflammatory markers were assessed by ELISA and multiplex bead-based assay. Lipid peroxidation was evaluated using thiobarbituric acid-reactive substances. The median serum Mg2+ levels were 2.3 (0.5) mg/dL, and 21% of patients presented Mg2+ deficiency (< 2.07mg/dL or 0.85 mmol/L). We found no difference in Mg2+ serum levels between the two groups. A significant negative correlation was observed between serum Mg2+ levels and plasma hs-CRP (r =-0.17, p = 0.01), IL-8 (r =-0.35, p = 0.01), and MCP-1 (r =-0.31, p = 0.03) levels. Mg2+ serum levels were negatively correlated with inflammatory status in patients with CKD on dialysis.

Cigarette Smoking Contributes to Th1/Th2 Cell Dysfunction via the Cytokine Milieu in Chronic Obstructive Pulmonary Disease.

Dysregulation and pyroptosis of T-helper (Th) cells and inflammatory cytokines have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immune response mechanisms as a consequence of tobacco smoke exposure are not fully understood. We hypothesized that cigarette smoke-induced inflammation could be modulated through the cytokine milieu and T-cell nicotinic acetylcholine receptors (nAChRs). The proportions of peripheral blood Th1 and Th2 cells from patients with COPD, smokers without airway obstruction and healthy nonsmokers were analyzed using flow cytometry. The levels of plasma proinflammatory cytokines and their potential association with pulmonary function were also measured. The influence of cigarette smoke extract (CSE) on the conditioned differentiation of T helper cell subsets was further examined in vitro. Significantly higher Th1 cell and plasma IFN-γ and IL-18 levels but lower levels of Th2 cells were found in the peripheral blood from patients with COPD. The increased plasma levels of IFN-γ and IL-18 were negatively correlated with pulmonary function (FEV1% predicted value). Pyroptosis participates in COPD development probably through the activation of the NLRP3 inflammasome upon exposure to CSE. CSE does not directly induce the differentiation of T helper cells; however, under conditioned medium, CSE promotes Th1 development through α7 nAChR modification, while it does not substantially interfere with Th2 differentiation. The differences in the cytokine milieu play a key role in the effects of CSE on the immune response in patients with COPD.

Evaluating the plasma interleukin-1 beta and interleukin-8 levels in patients with chronic obstructive pulmonary diseases following treatment with allogeneic mesenchymal stem cell derived from umbilical cord tissues and platelet rich plasma

Chronic obstructive pulmonary disease (COPD) is a common disease which negatively affects living quality and longevity of patients. Unfortunately, current COPD treatments are not radical. COPD is characterized by persistent neutrophil infiltrations mediated by inflammatory cytokines including interleukin (IL)-1β and IL-8 in the airway. Mesenchymal stem cells (MSCs) have been proven to suppress inflammation, modulate the immune system and can be regenerative. Allogeneic MSCs have been used to treat COPD patients across the world and produced positive clinical outcomes. In this study, we evaluated plasma IL-1β and IL-8 concentrations in 10 stage-D COPD patients before being transplanted with allogeneic MSCs derived from umbilical cord tissues (UC-MSCs) activated by platelet-rich plasma (PRP) and at 4 follow- ups (after 1, 3, 7, 12 months), as well as determined their associations with COPD clinical and sub-clinical parameters. Plasma IL-1β and IL-8 concentrations were measured using Multiplex Immunoassay. We found that plasma IL-8 levels were significantly reduced from 3.2 to 1.9 pg/ml after 12 months of treatment which is accompanied by the notable decrease in C-reactive protein (CRP). Exacerbation episodes were significantly decreased from 3 to 1. Plasma IL-1β levels were positively correlated with IL-8 levels and white blood cell (WBC) levels. Parallel measurements of plasma IL-1β and IL-8 may help assess the disease progression of COPD patients after the treatment with UC- MSCs and PRP. Blockage of IL-1β or IL-8 could be a valid strategy for the prevention and control of COPD.

Abstract P2127: A Novel Arnt Dependent Hif2a Singling In Protecting Against Cardiac Microvascular Endothelial Barrier Dysfunction Following Myocardial Infarction

Rationale: Cardiac microvascular leakage and inflammation are triggered during myocardial infarction (MI) and contribute to heart failure. Hypoxia-inducible factor 2α ( Hif2α ) is highly expressed in endothelial cells (ECs) and rapidly activated by myocardial ischemia, but its impact in microvascular endothelial barrier function during MI is unclear. Objective: To test our hypothesis that the expression of Hif2α in ECs regulates cardiac microvascular permeability in infarcted hearts, which is through its binding partner aryl hydrocarbon nuclear translocator. (ARNT). Methods and Results: Experiments were conducted with mice carrying an inducible EC-specific Hif2α -knockout ( ecHif2α -/- ) mutation, with mouse cardiac microvascular endothelial cells (CMVECs) isolated from the hearts of ecHif2α -/- mice after the mutation was induced, and with human CMVECs and umbilical-vein endothelial cells transfected with ecHif2α siRNA. After MI induction, echocardiographic assessments of cardiac function were significantly lower, while measures of cardiac microvascular leakage (Evans blue assay), plasma IL6 levels, and cardiac neutrophil accumulation and fibrosis (histology) were significantly greater, in ecHif2α -/- mice than in control mice, and RNA-sequencing analysis of heart tissues from both groups indicated that the expression of genes involved in vascular permeability and collagen synthesis was enriched in ecHif2α -/- hearts. In cultured ECs, ec Hif2α deficiency was associated with declines in endothelial barrier function (electrical cell impedance assay) and the reduced abundance of tight-junction proteins, as well as an increase in the expression of inflammatory markers, all of which were largely reversed by the overexpression of ARNT. We also found that ARNT, but not Hif2α, binds directly to the IL6 promoter and suppresses IL6 expression. Conclusions: Endothelial HIF-2a protects from hypoxia-induced cardiac microvascular barrier dysfunction, promotes inflammation damage and represents a potential therapeutic target for cardioprotection, and prevention of fibrosis following acute ischemic injury.

High plasma IL-6 levels may enhance the adverse effects of mouse allergen exposure in urban schools on asthma morbidity in children

Few data on the relationships between environmental exposures, asthma morbidity, and systemic IL-6 inflammation exist. We sought to determine whether baseline plasma IL-6 level is associated with increased asthma morbidity in children exposed to mouse allergen in inner-city classrooms. Data from the longitudinal School Inner-City Asthma Studies of 215 children with asthma, aged 4 to 14 years and recruited from urban elementary schools, were analyzed. Given the unknown threshold of IL-6 risk levels and skewness of the distribution, the children were stratified into tertiles as follows: low baseline IL-6 level (<0.013 pg/mL), moderate baseline IL-6 level (0.013-0.302 pg/mL), and high baseline IL-6 level (>0.302 pg/mL). Relationships between plasma IL-6 level and body mass index (BMI) percentile, inflammatory markers, lung function, mouse allergen exposure, and asthma outcomes were assessed. Cross-sectional analysis demonstrated that increasing IL-6 level was associated with higher BMI percentile (P< .0001), C-reactive protein level (P= .0006), and blood neutrophil count (P= .0024). IL-6 was not associated with type 2 inflammatory markers, including blood eosinophil count, allergic sensitization, or fractional exhaled nitric oxide level. Longitudinal analysis showed that children with high IL-6 levels had a higher number of days with asthma symptoms than did those children with moderate (incidence rate ratio= 1.74 [95% CI= 1.10-2.77]; P= .0187) or low (incidence rate ratio=1.83 [95% CI= 1.21-2.77]; P= .0043) IL-6 levels. Children with high IL-6 levels who were exposed to increasing levels of mouse allergen exhibited lower ratios of FEV1 value to forced vital capacity than did children with moderate IL-6 levels (β= -0.0044 [95% CI= -0.0073 to -0.0015]; pairwise interaction P= .0028) or low IL-6 levels (β= -0.0042 [95% CI= - 0.0070 to -0.0013]; pairwise interaction P= .0039). Inner-city children with asthma and high plasma IL-6 levels are more likely to have an increased BMI, elevated C-reactive protein level, elevated blood neutrophil count, and greater asthma symptoms. High IL-6 level appears to increase susceptibility to the effects of classroom exposure to mouse allergen on lung function in urban children.

Differential effects of two phosphodiesterase 4 inhibitors against lipopolysaccharide-induced neuroinflammation in mice

BackgroundSeveral phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the pharmacological effects of two selective PDE4 inhibitors, roflumilast and zatolmilast, against lipopolysaccharide-induced neuroinflammation.ResultsIn BV-2 cells, the PDE4 inhibitor roflumilast reduced the production of nitric oxide and tumor necrosis factor-α (TNF-α) by inhibiting NF-κB phosphorylation. Moreover, mice administered roflumilast had significantly reduced TNF-α, interleukin-1β (IL-1β), and IL-6 levels in plasma and brain tissues. By contrast, zatolmilast, a PDE4D inhibitor, showed no anti-neuroinflammatory effects in vitro or in vivo. Next, in vitro and in vivo pharmacokinetic studies of these compounds in the brain were performed. The apparent permeability coefficients of 3 µM roflumilast and zatolmilast were high (> 23 × 10–6 cm/s) and moderate (3.72–7.18 × 10–6 cm/s), respectively, and increased in a concentration-dependent manner in the MDR1-MDCK monolayer. The efflux ratios were < 1.92, suggesting that these compounds are not P-glycoprotein substrates. Following oral administration, both roflumilast and zatolmilast were slowly absorbed and eliminated, with time-to-peak drug concentrations of 2–2.3 h and terminal half-lives of 7–20 h. Assessment of their brain dispositions revealed the unbound brain-to-plasma partition coefficients of roflumilast and zatolmilast to be 0.17 and 0.18, respectively.ConclusionsThese findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.

Evaluation of Plasma Levels of Interferon-Gamma, Interleukin-6, and Transforming Growth Factor-Beta in Under-Five Children with Malaria Parasitaemia

BACKGROUND: The interaction between the pro- and anti-inflammatory cytokines is known to play key roles in the immune response to infectious diseases. The pathogenesis of malaria parasitemia, including its progression to symptomatic manifestation, also seems to be strongly related to this interplay. AIM: The study evaluated the plasma levels of interferon-gamma (IFN-γ) and interleukin-6 (IL)-6, which are pro- inflammatory cytokines, and transforming growth factor-beta (TGF-β), which is an anti-inflammatory cytokine; in the 6–60 months age-group children, when infected with Plasmodium falciparum, to show their relevance in the development of immunity against malaria. METHODS: The study was a cross-sectional study involving children with uncomplicated malaria parasitemia. In the study, malaria parasitemia was confirmed by microscopy, using the Giemsa stain. The enzyme-linked immunosorbent assay (ELISA) method was used to evaluate the plasma levels of IFN-γ, IL-6, and TGF-β in the under-five children infected with P. falciparum, and their counterparts who were not infected with the parasite. RESULTS: The median plasma IFN-γ, IL-6, and TGF-β levels in participants with malaria parasitemia were 225.15 pg/ mL, 123.31 pg/mL, and 2091.02 pg/mL, respectively. The difference in the plasma levels of TGF-β in the infected and uninfected participants was statistically significant with a p &lt; 0.001. CONCLUSION: The findings in this work showed that malaria parasitemia in under-five children is associated with significant depression in the plasma level of TGF-β when compared to their uninfected counterparts.

Extracorporeal Photopheresis as a Possible Therapeutic Approach for Adults with Severe and Critical COVID-19 Non-Responsive to Standard Treatment: A Pilot Investigational Study.

Background: The optimal approach for adult patients hospitalized with severe and critical coronavirus disease 2019 (COVID-19), non-responsive to antiviral and immunomodulatory drugs, is not well established. Our aim was to evaluate feasibility and safety of extracorporeal photopheresis (ECP) in this setting. Methods: A prospective, single-center investigational study was performed between 2021 and 2022 at a tertiary referral center for COVID-19. Patients diagnosed with COVID-19 were screened, and cases with severe or critical disease fulfilling pre-defined clinical and biochemical criteria of non-response for >5 days, despite remdesivir, dexamethasone and immunomodulation (tocilizumab, baricitinib, ruxolitinib), were consecutively enrolled. After patient inclusion, two ECP sessions on two consecutive days per week for 2 weeks were applied. Patients were followed-up per protocol from study inclusion, and clinical, virological and radiological outcomes were assessed at the end of treatment (EOT) +28 days. Results: A total of seven patients were enrolled. At inclusion, four out of seven (57.1%) were admitted to the ICU, all patients had ongoing cytokine storm. Additionally, 3/7 (42.9%) had radiological progression on chest CT. At EOT+28 days, 2/7 (28.6%) patients died due to non-ECP-related causes. Among the survivors, no additional requirement for intensive care unit admission or radiological progression was observed, and invasive mechanical ventilation could be weaned off in 1/5 (20.0%). All patients achieved whole-blood SARS-CoV-2 RNAemia clearance, while 3/7 (42.9%) no longer showed detectable respiratory SARS-CoV-2 RNA. According to immune biomarker profiling, ECP mainly facilitated a decrease in plasma IL-6 and IL-17A levels, as well as the physiological regeneration of peripheral blood immunocyte subpopulations, notably CD8+/CD45RO+ memory T-cells. No safety signals were identified. Conclusions: ECP appears to be a safe and feasible option for adults hospitalized with severe or critical COVID-19 who do not respond to pharmacological interventions. Further trial data are warranted to assess its optimal use. Trial registration: ClinicalTrials.gov NCT05882331 (retrospectively registered).

U-shaped associations between glycated albumin and obesity and role of IL-10 in hyperacute ischemic stroke

ObjectiveThere is growing interest in the use of new biomarkers such as glycated albumin (GA). In contrast to glycated hemoglobin (HbA1c), GA showed an inverse correlation with prestroke obesity status, but data are limited for ischemic stroke (IS). Materials and MethodsWe explored the association between GA and body mass index (BMI) and investigated inflammatory cytokines to support the academic background. In total, 155 patients with hyperacute IS (HIS) between 2011 and 2019 were included. To identify the association between GA and BMI, patients were divided into four groups according to BMI quartiles. Levels of inflammatory cytokines, including IL-1β, IL-10, IL-6, TNF-α, and TNF-R1, were determined by ELISA using a ProcartaPlex multiplex immunoassay. ResultsThe mean age of the 155 patients was 68 ± 12 years, and 67.1% were men. The lowest BMI group had higher GA levels (GA 2 T and 3 T = 80%) (p-value=0.017), and these U-shaped associations were maintained only for small vessel occlusion etiology (p-value= 0.004). Plasma IL-10 levels were positively correlated with BMI and showed a U-shaped pattern (p-value= 0.001). ConclusionGA levels and BMI had U-shaped associations with HIS. IL-10, which acts as a protective cytokine for cardiovascular disease, may play a novel role in this association. Although GA is an emerging favorable clinical marker of cardiovascular outcomes, obesity status should be considered when interpreting these associations.

Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice.

Two independent experiments were performed with three groups each (sepsis control, sepsis, and sepsis with apoE23 treatment) to investigate the anti-inflammatory effect of apolipoprotein 23 (apoE23) in a mouse model of sepsis induced by S. typhimurium. Survival rates; plasma level variations in tumor necrosis factor (TNF)-α, interleukin (IL)-6, and lipopolysaccharide (LPS); S. typhimurium colony-forming units in the spleen tissue; and mRNA and protein expression levels of low-density lipoprotein receptor (LDLR), LDLR-related protein (LRP), syndecan-1, and scavenger receptor B1 were evaluated in the livers of mice from the three groups. Results found that the survival rate of septic mice treated with apoE23 was 100% within 48 h, while it was only 40% in septic mice without apoE23 treatment (P < 0.001). The plasma LPS, TNF-α, and IL-6 levels and the S. typhimurium load in mice in the apoE23-treated group were significantly lower than those in septic mice (P < 0.05). Moreover, apoE23 restored the downregulated expression of LDLR and LRP in the liver tissue of septic mice. So apoE23 exhibits an anti-inflammatory effect in the mouse model of S. typhimurium-induced sepsis. Further studies are required to understand the mechanisms underlying the anti-inflammatory effects of apoE23.

The role and regulatory mechanism of HIF-1α in myocardial injury in rats undergoing cardiopulmonary bypass

Background Hypoxia-inducible factor-1alpha (HIF-1α) is a transcription factor implicated in physiological and pathological responses to hypoxia. The present study aims to investigate the effect and mechanism of HIF-1α on cardiopulmonary bypass (CPB)-related myocardial injury, thereby conferring a theoretical basis for the clinical treatment of myocardial injury in CPB. Methods An experimental model of CPB was established in rats by surgery. Adenovirus-packaged overexpression vectors and antiagomiRNA were used to overexpress HIF-1α and NR4A1 or inhibit miR-124-3p expression in rat myocardial tissues, respectively. qRT-PCR and Western blot detected HIF-1α, miR-124-3p, and NR4A1 expression in myocardial tissues. The rat cardiac function was monitored through an echocardiogram. The rat plasma at different stages of CPB was collected, followed by the detection of IL-6, cTnT, CK-MB, and IL-1β. TUNEL staining measured apoptosis in myocardial tissues. ChIP assay analysed the enrichment of HIF-1α on the miR-124-3p promoter. The binding relationships between HIF-1α and miR-124-3p promoter sequence and between miR-124-3p and NR4A1 3'UTR sequence were confirmed by dual-luciferase reporter assay. Results HIF-1α expression had no significant change after CPB modelling. Overexpression of HIF-1α improved the cardiac function of CPB rats, decreased plasma IL-6, cTnT, CK-MB, and IL-1β levels, and reduced TUNEL-positive myocardial cells. HIF-1α was enriched on the miR-124-3p promoter and promoted miR-124-3p expression. miR-124-3p bound to NR4A1 3'UTR sequence and targeted NR4A1 expression. Inhibition of miR-124-3p or overexpression of NR4A1 partially reversed the ameliorative effect of HIF-1α overexpression on myocardial injury in CPB rats. Conclusion Overexpression of HIF-1α can improve myocardial injury in CPB rats via the miR-124-3p/NR4A1 axis.

Diagnostic value of mesenteric CTA combined with D-dimer level and inflammatory factor changes in severity of mesenteric artery embolism.

To investigate the value of mesenteric CTA combined with D-dimer (DD) level and inflammatory factor changes in evaluating the severity of mesenteric artery embolism. This is a retrospective study. The imaging data of mesenteric CTA and the levels of plasma DD and inflammatory factors in 120 patients with mesenteric artery embolism confirmed by DSA or surgery in Baoding No.1 Central Hospital were analyzed retrospectively from January 2021 to December 2022. The coincidence rate of CTA alone and CTA combined with DD and inflammatory factors with the results of surgery or DSA was compared and analyzed. The specificity, sensitivity and accuracy of CTA alone and CTA combined with DD and inflammatory factors in diagnosing superior mesenteric artery embolism were compared. The correlations of different severity of mesenteric artery embolism with DD and inflammatory factor levels were compared and analyzed. There was a significant difference in the coincidence rate between CTA diagnosis and CTA combined with DD and inflammatory factors diagnosis (p= 0.01). And the sensitivity and accuracy of the latter were significantly higher than those of the former (sensitivity, p= 0.01; accuracy, p= 0.00). The levels of plasma DD, TNF-a, CRP and IL-6 in the intestinal wall thinning group were significantly higher than those in the thickening group (p= 0.00). The above indexes increased significantly in the decreased intestinal wall enhancement group compared with the increased intestinal wall enhancement group (p= 0.00). DD, TNF-ɑ, CRP and IL-6 levels increased with the increase in stenosis severity. Mesenteric CTA combined with plasma DD and inflammatory factor levels can effectively determine the severity of mesenteric arterial embolism, and provide a scientific basis for early clinical diagnosis and treatment.

T-cell-derived TNF-α and a cluster of immunological parameters from plasma allow a separation between SARS-CoV-2 convalescent versus vaccinated elite athletes.

Guidelines for medical clearing after SARS-CoV-2 infection in elite athletes do not include T-cell immunity aspects despite its relevance in the course of COVID-19 disease. Therefore, we aimed to analyze T-cell-related cytokines before and after in-vitro activation of CD4+ T-cells. We sampled professional indoor sports athletes at medical clearing after SARS-CoV-2 infection obtaining clinical, fitness data, and serological data including CD4+ T-cell cytokines. All data were analyzed by principal component analysis and 2 × 2 repeated measures ANOVA. CD4+ T-cells were sampled for cell culture activation with anti-CD3/anti-CD28 tetramers. At medical clearing, CD4+ T-cells from convalescent athletes secreted increased levels of TNF-α 72h after in-vitro activation compared to vaccinated athletes. IL-18 levels in plasma were elevated and a cluster of parameters differentiated convalescent from vaccinated athletes by 13 parameters at the timepoint of medical clearing. All clinical data indicate infection is resolved, while increased TNF-α may reflect altered proportions of peripheral T-cells as a hangover of infection.

Distinct roles of IL-18 and IL-1β in murine model of macrophage activation syndrome

IL-18 and IL-1β play a central role in the pathogenesis of systemic juvenile idiopathic arthritis and its life-threatening complication, macrophage activation syndrome (MAS). This study aimed to clarify the role of IL-18 and IL-1β in the pathogenesis of MAS. We developed a mouse model to evaluate the role of each cytokine with Toll-like receptor 9 stimulation after continuous infusion with IL-18, IL-1β, and a combination of both for 7 days. The symptoms and laboratory findings were compared among the IL-18, IL-1β, and combination (IL-18+IL-1β) groups. Body weight was significantly decreased in the IL-1β and combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in the IL-18 group only. Decreased T-cell numbers, anemia, and thrombocytopenia were observed in the combination group. IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group. Hepatomegaly and splenomegaly in the IL-18 group were observed in a dose-dependent manner. TNF-α, CXCL9, and IL-12A mRNA levels were upregulated only in those mice with extremely elevated plasma IL-18 levels. IL-18 and IL-1β have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1β might be necessary to treat MAS.

Evaluation of plasma IL-21 as a potential biomarker for type 1 diabetes progression.

IL-21 is a multifunctional cytokine linked with the pathophysiology of several autoimmune diseases, including type 1 diabetes. In this study, our aim was to examine plasma IL-21 levels in individuals at different stages of type 1 diabetes progression. We measured plasma IL-21 levels, as well as levels of other key pro-inflammatory cytokines (IL-17A, TNF-α and IL-6), from 37 adults with established type 1 diabetes and 46 healthy age-matched adult controls, as well as from 53 children with newly diagnosed type 1 diabetes, 48 at-risk children positive for type 1 diabetes-associated autoantibodies and 123 healthy age-matched pediatric controls using the ultrasensitive Quanterix SiMoA technology. Adults with established type 1 diabetes had higher plasma IL-21 levels compared to healthy controls. However, the plasma IL-21 levels showed no statistically significant correlation with clinical variables, such as BMI, C-peptide, HbA1c, or hsCRP levels, evaluated in parallel. In children, plasma IL-21 levels were almost ten times higher than in adults. However, no significant differences in plasma IL-21 levels were detected between healthy children, autoantibody-positive at-risk children, and children with newly diagnosed type 1 diabetes. In conclusion, plasma IL-21 levels in adults with established type 1 diabetes were increased, which may be associated with autoimmunity. The physiologically high plasma IL-21 levels in children may, however, reduce the potential of IL-21 as a biomarker for autoimmunity in pediatric subjects.

8-LB: Adipocyte-Derived ANGPTL2 Regulates Abnormal Lipid Metabolism and Inflammation through PirB in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a disorder of glycolipid metabolism caused by diabetes mellitus, which leads to hemodynamic and inflammatory processes. The aim of this study is to investigate the mechanism of adipocyte-derived angiopoietin-like protein 2 (ANGPTL2) in promoting the progression of DKD. Patients with DKD were included, and plasma ANGPTL2 was detected by ELISA. Type 2 diabetic mouse model induced by HFD and STZ, systemic Angptl2 knockout mouse model and adipose-specific AAV-Angptl2 were constructed. HKC cells stimulated with high glucose and PA in vitro. ELISA was used to measure the levels of IL-6, IL-1β, TNF-α and ANGPTL2 in plasma. RT-qPCR and Western blot were used to detect PirB, lipid metabolism indicators and inflammation, and the proteomics of kidney was performed. HE, oil red O staining and inflammatory factor staining were used to evaluate the degree of renal lipid metabolism and inflammation. The plasma level of ANGPTL2 in DKD patients is significantly higher than that in normal controls. Compared with the normal mice, the DKD mice had increased lipid accumulation and severe inflammation in kidney tissues, with increased PirB, Cybb and pro-inflammatory factors, and decreased CD36 and FATP2 in kidney. Similarly, overexpression of adipose-derived ANGPTL2 in mice caused the same abnormal lipid metabolism and increased inflammation levels, while Angptl2 ko mice significantly improved lipid deposition and inflammation levels and fatty acid transport. Knockdown of ANGPTL2 in HKC cells also inhibited the reduction of CD36 and FATP2, the increase of its receptor PirB, and the increase of Cybb /Nox2-mediated inflammatory cytokines induced by high glucose and high lipid in HKC cells. Adipose-derived ANGPTL2 may play an important role in lipid metabolism and Cybb/ NOX2-regulated inflammatory through its receptor in DKD, suggesting that ANGPTL2 may serve as a potential treatment for preventing the progression of DKD. Disclosure R. Yin: None. L. Yang: None. D. Zhao: None. Funding National Natural Science Foundation of China (82170454)

Stimulatory effect of fluoxetine and desipramine, but not mirtazapine on C26 colon carcinoma hepatic metastases formation: association with cytokines.

Due to the high prevalence of depression among cancer patients, antidepressant medications are frequently administered as adjuvant treatment. However, the safety of such medications in the development of metastasis is unclear. In this study, we investigated the effects of fluoxetine, desipramine, and mirtazapine on the liver metastasis of murine C26 colon carcinoma (cc). Balb/c male mice were administered these antidepressants intraperitoneally (i.p.) for 14 days following intrasplenic injections of C26 colon carcinoma cells. Desipramine and fluoxetine, but not mirtazapine, significantly increased the number of tumor foci and total volume of the tumor in liver tissue. This effect was associated with a decrease in the ability of splenocytes to produce interleukin (IL)-1β and interferon (IFN)-γ and an increase in their ability to produce interleukin (IL)-10. Similar changes were observed in plasma IL-1β, IFN-γ, and IL-10 levels. The current study demonstrates that the stimulatory effect of desipramine and fluoxetine, but not mirtazapine, on experimental colon cancer liver metastasis is associated with a suppression of immune defenses against the tumor.

Association between low levels of anti-inflammatory cytokines during pregnancy and postpartum depression.

23 May 2023: This Accepted Article published in error. The article is under embargo and will publish in Early View shortly.