Higher Levels Of TNF-α Research Articles

Decreased mRNA expression level of FOXP3 correlate with TNF-α in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis patients: a case control study

Background: Forkhead box P3 (FOXP3), a transcription factor is thought to be the master regulator of regulatory T (Treg) cells in maintaining peripheral tolerance and autoimmunity. The number and functional capabilities have been reported to be low in several diseases including RA, which affects the immune regulatory action of Treg cells. Proinflammatory cytokines such as tumor necrosis factor α (TNF-α), are important in RA pathogenesis, but the influence on Treg cells is poorly understood. Methods: In the present study, the messenger RNA (mRNA) expressions of FOXP3 and TNF-α in a group of patients with RA (N=23) and a healthy control group (N=17) were studied in peripheral blood mononuclear cells (PBMCs). PBMCs were chosen as they are practical samples in which changes caused by disease or therapy can be conveniently monitored. Results: Expression of FOXP3 was lower (P<0.0001, 0.76 folds) and TNF-α gene expression was higher (P<0.0001, 2.28 folds) in RA patients when compared with the healthy control group. However, a statistically significant correlation could not be established between the FOXP3 and disease activity, but relative mRNA expression of FOXP3 and TNF-α showed a statistically significant correlation (P<0.0283) in RA patients when compared with the healthy control group. Conclusions: The results suggested that decreased expression of FOXP3 gene and increased level of TNF-α expression in the presence of rheumatoid factor antibodies (RF) may impair the activity of Treg cells with higher TNF-α levels when compared with patients who were negative for RF. Level of Evidence: Level II.

In Vitro 3D Staphylococcus aureus Abscess Communities Induce Bone Marrow Cells to Expand into Myeloid-Derived Suppressor Cells.

Staphylococcus aureus is the main causative pathogen of subcutaneous, bone, and implant-related infections, forming structures known as staphylococcal abscess communities (SACs) within tissues that also contain immunosuppressive myeloid-derived suppressor cells (MDSCs). Although both SACs and MDSCs are present in chronic S. aureus infections, it remains unknown whether SACs directly trigger MDSC expansion. To investigate this, a previously developed 3D in vitro SAC model was co-cultured with murine and human bone marrow cells. Subsequently, it was shown that SAC-exposed human CD11blow/− myeloid cells or SAC-exposed murine CD11b+ Gr-1+ cells were immunosuppressive mainly by reducing absolute CD4+ and CD8α+ T cell numbers, as shown in T cell proliferation assays and with flow cytometry. Monocytic MDSCs from mice with an S. aureus bone infection also strongly reduced CD4+ and CD8α+ T cell numbers. Using protein biomarker analysis and an immunoassay, we detected in SAC–bone marrow co-cultures high levels of GM-CSF, IL-6, VEGF, IL-1β, TNFα, IL-10, and TGF-β. Furthermore, SAC-exposed neutrophils expressed Arg-1 and SAC-exposed monocytes expressed Arg-1 and iNOS, as shown via immunofluorescent stains. Overall, this study showed that SACs cause MDSC expansion from bone marrow cells and identified possible mediators to target as an additional strategy for treating chronic S. aureus infections.

Timing of Tocilizumab and Corticosteroids Administration Under the Guidance of IL-6 in CAR-T Therapy for R/R Acute Lymphoblastic Leukemia

Background：Chimeric antigen receptor (CAR) T cells targeting CD19 have achieved great clinical responses in patients with relapsed or refractory acute B lymphoblastic leukemia (R/R B-ALL). However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity restrict it to further application. Tocilizumab against human interleukin-6 (IL-6) receptor is a common treatment for CAR-T cell therapy associated cytokine release syndrome. Corticosteroids are used when remission is not reached after the application of tocilizumab as well as neurotoxicity occurs, according to the guidance. However, their suitable timing still remains unclear when taking their efficacy and side effects into consideration.Methods:From January 2016 to July 2020, in our phase 1/2 clinical trials (NCT02965092、NCT04008251), 55 patients with R/R B-ALL were enrolled and injected with anti-CD19 CAR-T cells. Clinical laboratory tests on day 0、4、7、10、14、21、28 after infusion as well as endpoints、adverse events and treatment were recorded.CRS and neurotoxicity were graded according to American Society for Transplantation and Cellular Therapy (ASTCT)，and infection severity was classified as mild, moderate, severe, life-threatening, or fatal. (Young et al. Biol Blood Marrow Transplant 2016; 22:359-70.)Patients were assigned to four cohorts based on the fold change of IL-6 and the use of Tocilizumab. We defined fold change as the ratio of peak before Tocilizumab given to baseline in Tocilizumab group and the ratio of peak within 28 days to baseline in non- Tocilizumab group. According to the statistics, two groups were separated into high level (fold change over 5) and low level (fold change below 5), respectively.Wilcoxon tests、Log-rank tests and Fisher's exact tests were used to analyze statistics in GraphPad Prism 9.Results:During the observation period of 28-day-postinfusion, the use of Tocilizumab or corticosteroids did not significantly reduce the response rate or increase infectious risk (P>0.99, P=0.052). Doing a median follow-up of 7 months, the use of corticosteroids was significantly associated with shorter overall survival (OS) and progression-free survival (PFS), while it did not appear when Tocilizumab was applied alone. In addition, significantly fold change of IL-6, IL-10 were observed among subjects suffering cytokine release syndrome before the use of Tocilizumab or corticosteroids and higher levels of TNF-α were observed in 3 subjects with mild neurotoxicity (P=0.0002, P<0.0001, P=0.0004).In high level group, patients treated with Tocilizumab had mild CRS limiting to grade 1-2, with shorter duration of CRS (median=5) than non-Tocilizumab (median=6) , though it is without significant difference (P=0.874).In low level group, the use of Tocilizumab is associated with shorter PFS（P=0.0275）as well as severe cytokine release syndrome. Two patients developed grade 4 CRS after infusing Tocilizumab，with apparently increased level of IL-10 (fold change=200) or IFN-γ (fold change=114.24).Neurotoxicity occurred in four patients in Tocilizumab group, and their IL-6 levels increased significantly after treatment, reaching an average peak of 1000pg/ml (157-22001.9). No neurotoxicity were observed in non-Tocilizumab group.Conclusion:Our study demonstrate that severe and persistent CRS could be avoided by applying Tocilizumab when IL-6 has increased over 5-fold from baseline. Tocilizumab is not recommended to use with little change of IL-6 because it fails to suppress the inflammatory response, and may trigger the activation of other cytokines and accelerate the progress of disease recurrence in patients.Although corticosteroids were associated with relapse, we still suggested that corticosteroids should be administrated to antagonize neurotoxicity with symptoms and significantly increased IL-6 levels after the infusion of Tocilizumab. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

TLT-1, a Potential Regulator of Inflammatory Pathogenesis in Obesity and Non-Alcoholic Fatty Liver Disease (NAFLD)

Background:Obesity, a nationwide health issue, has related medical costs ranging between $147-210 billion per year in United States and has been associated with a 3.5-fold increased risk of developing NAFLD. In obesity, platelets work in a pleotropic manner with vascular and immune cells to amplify the chronic inflammatory process. Interestingly, studies have demonstrated that platelet numbers and reactivity are increased in obese individuals. The emerging role of activated platelets during obesity induced inflammation introduces the novel concept of platelet targeted therapeutic interventions.Kopec et al, further supports the idea that the mechanism underlying the progression of obesity lies in a platelet mediated pro-inflammatory state, illustrating that there is extravascular fibrin(ogen) deposition, macrophages and inflammatory cytokines within white adipose tissue and liver of mice on western diet. Kopec et al uses a fibrinogen mutant mouse (Fiby390-396 ) which lacks the binding motif for Mac-1 and inhibits the ligand interaction with leukocytes, diminishing inflammation, reducing macrophage counts, reducing weight, protects mice from NAFLD and glucose dysmetabolism. Taken together, all evidence points towards a platelet/fibrinogen/leukocyte pathophysiological mechanism underlying the development of obesity.TREM-Like Transcript-1 (TLT-1) is a platelet specific receptor found in the a-granules of platelets and released to the surface upon platelet activation. TLT-1 is a type 1 receptor that, like the integrin a2bb3, binds fibrinogen and facilitates platelet aggregation . However, although TLT-1 may assist in clot formation and hemostasis to arrest bleeding in a non-inflammatory/nonimmune mediated setting, TLT-1's main association is with regulating inflammatory-derived bleeding. This is demonstrated by increased hemorrhage after inflammatory treatments such as lipopolysaccharide LPS in the treml1 -/- mice as compared to controls.Considering the emerging evidence in support of a platelet-fibrinogen receptor ligand interaction as a key mechanism underlying the development of obesity and that TLT-1, a platelet specific receptor binds fibrinogen and mediates leukocyte trafficking, our laboratory set out to determine whether TLT-1 could be implicated as the main culprit underlying this mechanism. When placed on a western diet, treml1 -/- mice are more prone to weight gain, based on these finding we hypothesize that: The TLT-1/Fibrinogen molecular interaction regulates metabolic inflammation in obesityAims:Evaluate the effects of western diet on obesity and NAFLD in the treml1 -/- mouse modelMethods:TLT-1 (treml1 -/-) - apolipoprotein E (apoe -/-) double null (AT-DKO;n=11) mice and control apoe +/-/treml1 +/- littermate controls (AT-Hets;n=20) were fed western diet for 20 weeks. Plasma samples were collected for adipokine, glucose, insulin, liver enzyme and lipid profiling. Mouse were perfused, liver and adipose tissue were collected for histological analysis.Results:Overall AT-DKO mice gained more weight compared to AT-Hets (12.94±1.90 vs 8.51±1.70 grams p=0.02). Plasma analysis demonstrates that the AT-DKO have higher levels of TNF-a (0.54±0.60 vs 0.118±0.17 pg/ml p=0.03), and IL-10 (2.50±1.40 vs 1.50±2.10 pg/ml p=0.004) compared to littermate controls. Histological analysis of livers illustrates increased lipid vacuoles and inflammatory foci in the AT-DKO mice as compared to controls, while preliminary data is not significant for these differences, liver damage in the AT-DKO was significantly greater as demonstrated by increased AST levels (166.21±91.00 vs 102±68.10 U/L p=0.02). Moreover, the AT-DKO mice had higher levels of ALT, direct bilirubin, cholesterol, pai-1 , triglycerides and lower IL-6 and Adiponectin (Table 1 data not significant). These findings suggest that in the absence of TLT-1 these mice are more prone to liver disfunction , hyperlipidemia and inflammatory alterations.Conclusions:Mutant AT-DKO mice are more prone to obesity and NAFLD compared to littermate controls, suggesting that TLT-1, a platelet gene, plays a surprising role in metabolism. Further investigation could adjudicate TLT-1 administration as a potential therapeutic intervention for prevention and amelioration of Obesity and related pathologies. The current state of this project will be reported here. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hypovitaminosis D Is Associated with Higher Levels of Inflammatory Cytokines and with HAM/TSP in HTLV-Infected Patients.

Recent studies have shown the effects of vitamin D on host response to infectious diseases. Some studies detected a high prevalence of hypovitaminosis D in HIV-infected patients, but scarce information exists for HTLV-1 infection. We conducted a cross-sectional study to evaluate the frequency of hypovitaminosis D in HTLV-1 patients and its relationship with their immune response in HTLV-infected patients and in age- and gender-matched controls at a Brazilian rehabilitation hospital. We compared vitamin D, interleukin-6 (IL-6), tumoral necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) levels across groups. Logistic regression was utilized to assess the association between hypovitaminosis D and cytokine levels. We enrolled 161 HTLV-infected subjects (129 HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 32 asymptomatic HTLV carriers) and equal number of HTLV-negative controls. We observed a significantly higher prevalence of hypovitaminosis D in patients with HAM/TSP than in HTLV asymptomatic carriers (p < 0.001), or controls (p < 0.001). HAM/TSP patients also had higher levels of IL-6 and IFN-γ than asymptomatic carriers. Patients with HAM/TSP and hypovitaminosis D had higher levels of TNF-α than asymptomatic HTLV carriers. These findings suggest hypovitaminosis D plays a role in HAM/TSP pathogenesis, and it needs to be evaluated in further studies.

High levels of TNF-α are associated with symptoms of depression in health professionals at a hospital

The current evidence indicates that inflammation is highly related to depression but not to anxiety in clinical samples. However, less understood is the relationship between inflammation and symptoms of depression and anxiety in a nonclinical sample. The aim of this study was to investigate the association between three inflammation markers and symptoms of depression and anxiety in a healthy sample without a history of psychiatric disorders. Symptoms of depression and anxiety were evaluated in 74 healthy adults (mean age = 42.3; SD = 11.8) using the Hospital Anxiety and Depression Scale. We assessed proinflammatory cytokines (TNF-α, IL-1β, and CRP), and morning cortisol levels using blood samples. TNF-α correlates positively with depressive symptoms, but there were no significant relationships between anxiety scores and inflammation markers. Importantly, TNF-α relates to symptoms of depression independently of anxiety scores, age, body mass index, cortisol, and sex. Our results indicate that TNF-α is associated with depressive symptoms, independently of anxiety, age, body mass index, cortisol, and sex, even in a sample of hospital health professionals without diagnosis or psychiatric history. La evidencia actual indica que la inflamación está altamente relacionada con la depresión pero no con la ansiedad en población clínica. Menos comprendida es la relación entre la inflamación y los síntomas de depresión y ansiedad en población no clínica. El objetivo del estudio fue investigar la asociación entre 3 marcadores de inflamación y síntomas de depresión y ansiedad en adultos sanos sin diagnóstico ni antecedentes psiquiátricos. Se evaluaron los síntomas de depresión y ansiedad en 74 adultos sanos (edad media de 42,3 años; DE = 11,8) utilizando la Escala Hospitalaria de Ansiedad y Depresión. Se evaluaron las citocinas proinflamatorias (TNF-α, IL-1β y PCR) y los niveles de cortisol matutino utilizando muestras de sangre. El TNF-α se correlacionó positivamente con síntomas depresivos, pero no hubo relaciones significativas entre las puntuaciones de ansiedad y los marcadores de inflamación. Es importante destacar que el TNF-α se relaciona con síntomas de depresión, independientemente de las puntuaciones de ansiedad, edad, índice de masa corporal, cortisol y sexo. Nuestros resultados indican que el TNF-α se asocia a síntomas depresivos, independientemente de la ansiedad, edad, índice de masa corporal, cortisol y sexo en una muestra de profesionales de la salud de un hospital sin diagnóstico ni antecedentes psiquiátricos.

Role of tumor necrosis factor-α in the mortality of hospitalized patients with severe and critical COVID-19 pneumonia.

The coronavirus disease 2019 (COVID-19) is presently the most pressing public health concern worldwide. Cytokine storm is an important factor leading to death of patients with COVID-19. This study aims to characterize serum cytokines of patients with severe or critical COVID-19. Clinical records were obtained from 149 patients who were tested at the Sino-French New City Branch of Tongji Hospital from 30 January to 30 March 2020. Data regarding the clinical features of the patients was collected and analyzed. Among the 149, 45 (30.2%) of them had severe conditions and 104 (69.8%) of that presented critical symptoms. In the meantime, 80 (53.7%) of that 149 died during hospitalization. Of all, male patients accounted for 94 (69.1%). Compared with patients in severe COVID-19, those who in critical COVID-19 had significantly higher levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, and IL-10. Moreover, the passed-away patients had considerably higher levels of TNF-α, IL-6, IL-8, and IL-10 than those survived from it. Regression analysis revealed that serum TNF-α level was an independent risk factor for the death of patient with severe conditions. Among the proinflammatory cytokines (IL-1β, TNF-α, IL-8, and IL-6) analyzed herein, TNF-α was seen as a risk factor for the death of patients with severe or critical COVID-19. This study suggests that anti-TNF-α treatment allows patients with severe or critical COVID-19 pneumonia to recover.

Salivary cytokines levels, maternal periodontitis and infants' weight at birth: A cohort study in pregnant women with obesity.

Obesity and pregnancy may have synergistic effects on maternal periodontal tissues. In contrast, maternal obesity and periodontitis are antagonistic factors for the babies' weight at birth. This study evaluated, during pregnancy (T1) and after delivery (T2), periodontal parameters and salivary levels of cytokines in women with obesity, and the association of these outcomes with the baby's weight at birth. After matching by age, socioeconomic status and systemic health, the sample was composed of pregnant women with obesity (GO=25; BMI ≥30kg/m2) and normal BMI (GN=25; BMI between 18.5 and 24.99kg/m2), who were evaluated regarding: periodontal parameters; salivary levels of TNF-α, IL-1β and leptin (Luminex® assay); and babies' weight at birth. Mann-Whitney, Friedman, ANOVA; chi-square and Cochran's Q tests were applied (p<0.05). GO showed higher prevalence of periodontitis in T1 and T2 (p<0.001), with higher salivary levels of TNF-α (p=0.003) and IL-1β (p=0.009) in T1. IL-1β significantly decreased after delivery in GO. No intergroup differences for leptin levels were found, but both groups had a significant reduction of leptin levels between periods (p<0.001). GO had children with lower birth weight (p=0.022), being classified as low (<2,500g) or insufficient (2,500-2,999g) weight. It is suggestive that the inflammatory pattern caused by obesity and periodontitis, mainly related to high levels of TNF-α, impair the babies' weight at birth, resulting in more frequency of low/insufficient weight at birth.

Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients With Closed Abdominal Injury Complicated With Severe Multiple Abdominal Injuries.

ObjectiveWe aimed to evaluate the diagnostic value of soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and combined detection for sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries.Patients and MethodsOne hundred forty patients with closed abdominal injury complicated with severe multiple abdominal injuries who were diagnosed and treated from 2015 to 2020 were divided into a sepsis group (n = 70) and an infection group (n = 70).ResultsThe levels of sIL-2R, TNF-α, and PCT in the sepsis group were higher than those in the infection group (p < 0.05). The receiver operating characteristic (ROC) curve showed that the areas under the ROC curve (AUCs) of sIL-2R, TNF-α, PCT and sIL-2R+TNF-a+PCT were 0.827, 0.781, 0.821, and 0.846, respectively, which were higher than those of white blood cells (WBC, 0.712), C-reactive protein (CRP, 0.766), serum amyloid A (SAA, 0.666), and IL-6 (0.735). The AUC of the three combined tests was higher than that of TNF-α, and the difference was statistically significant (p < 0.05). There was no significant difference in the AUCs of sIL-2R and TNF-α, sIL-2R and PCT, TNF-α and PCT, the three combined tests and sIL-2R, and the three combined tests and PCT (p > 0.05). When the median was used as the cut point, the corrected sIL-2R, TNF-α, and PCT of the high-level group were not better than those of the low-level group (p > 0.05). When the four groups were classified by using quantile as the cut point, the OR risk values of high levels of TNF-α and PCT (Q4) and the low level of PCT (Q1) after correction were 7.991 and 21.76, respectively, with statistical significance (p < 0.05).ConclusionsThe detection of sIL-2R, TNF-α, and PCT has good value in the diagnosis of sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries. The high concentrations of PCT and TNF-α can be used as predictors of the risk of septic infection.

Evaluation of medullary cytokine expression and clinical and laboratory aspects in severe human visceral leishmaniasis.

Visceral leishmaniasis (VL) is a serious public health problem. The factors that can determine whether VL develops and progresses to severe form have not been fully identified, but a specific cellular immune response appears to play a key role. Therefore, understanding immunopathogenesis can be useful in preventing a serious clinical outcome. Bone marrow samples were collected from patients with severe VL (SVL) or non-severe VL (NSVL). Cytokine levels and parasitic load were analysed by RT-qPCR. There is a statistically significant difference in the leukocyte parameter in patients with SVL and NSVL compared with the control patients (p=.006 and p=.014, respectively). Urea, alanine transaminase and albumin parameters had a significant difference p=.036, p=.039 and p=.017, respectively, between SVL and NSVL. Although high levels of IFN-γ, IL-10, IL-6 and TNF-α were present in all groups of individuals with VL, they were not statistically associated with severity. In patients with active VL, IFN-γ and IL-10 were associated, respectively, with a reduction and increase in the parasite load, strong and significant positive association between IFN-γ and IL-10 (rho=.627 and p=.003). This study demonstrates that VL stimulates an non-dichotomized inflammatory response between Th1/Th2 and that bone marrow is an important tissue for immune regulation.

Comparative expression of pro-inflammatory and apoptotic biosignatures in chronic HBV-infected patients with and without liver cirrhosis

The interplay of immune mediators is paramount to optimal host anti-viral immune responses, especially against chronic hepatitis B virus (HBV) infection. Here, we investigated the dynamic changes in host immune responses in chronic HBV-infected individuals with and without liver cirrhosis by examining the signatures of apoptosis and plasma levels of pro-inflammatory cytokines, chemokines, and cytotoxic proteins. A total of 40 chronic HBV patients with and without liver cirrhosis were studied for plasma levels of immune mediators, and signatures of apoptosis in peripheral blood mononuclear cells (PBMCs). The intracellular concentrations of reactive oxygen species (ROS) in patients with chronic HBV with liver cirrhosis was relatively higher as compared to chronic HBV patients. The onset of apoptosis was sustained due to ongoing liver inflammation in concert with plasma TNF-α and IL-6 levels. Plasma VEGF was upregulated among chronic HBV patients with liver cirrhosis, whereas CCL2, CCL5 and granzyme B levels were down-regulated. High levels of ROS, IL-6 and TNF-α correlated with ongoing inflammation among chronic HBV patients with liver cirrhosis, which likely attributed to the expression of biosignatures of apoptosis and activation in immune cells.

Human induced pluripotent stem cell-derived macrophages ameliorate liver fibrosis.

With an increasing number of patients with degenerative hepatic diseases, such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metalloproteinases (MMPs) provide an attractive cellular therapy approach. Human induced pluripotent stem cells (iPSCs) are capable of efficiently generating a large-scale, homogenous population of human macrophages using fully defined feeder- and serum-free differentiation protocol. Human iPSC-macrophages exhibit classical surface cell markers and phagocytic activity similar to peripheral blood-derived macrophages. Moreover, gene and cytokine expression analysis reveal that these macrophages can be efficiently polarized to pro-inflammatory M1 or anti-inflammatory M2 phenotypes in presence of LPS + IFN-γ and IL-4 + IL-13, respectively. M1 macrophages express high level of CD80, TNF-α, and IL-6 while M2 macrophages show elevated expression of CD206, CCL17, and CCL22. Here, we demonstrate that treatment of liver fibrosis with both human iPSC-derived macrophage populations and especially M2 subtype significantly reduces fibrogenic gene expression and disease associated histological markers including Sirius Red, αSMA and desmin in immunodeficient Rag2-/- γc-/- mice model, making this approach a promising cell-based avenue to ameliorate fibrosis.

IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33.

Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), are consistent with regulatory functions in innate as well as adaptive immunity. Here, we tested whether the alarmin interleukin 33 (IL-33), which is secreted following inflammation or cell damage, could activate human MAIT cells. We found that MAIT cells stimulated with IL-33 produced high levels of IFNγ, TNFα and Granzyme B (GrzB). The action of IL-33 required IL-12 but was independent of T cell receptor (TCR) cross-linking. MAIT cells expressed the IL-33 receptor ST2 (suppression of tumorigenicity 2) and upregulated Tbet (T-box expressed in T cells) in response to IL-12 or IL-33. Electronically sorted MAIT cells also upregulated the expression of CCL3 (Chemokine C-C motif ligand 3), CD40L (CD40 Ligand), CSF-1 (Colony Stimulating Factor 1), LTA (Lymphotoxin-alpha) and IL-2RA (IL-2 receptor alpha chain) mRNAs in response to IL-33 plus IL-12. In conclusion, IL-33 combined with IL-12 can directly target MAIT cells to induce their activation and cytokine production. This novel mechanism of IL-33 activation provides insight into the mode of action by which human MAIT cells can promote inflammatory responses in a TCR-independent manner.

GUM FLUID BIOMARKERS IN PERSONALIZED DIAGNOSTICS OF INFLA MMATOR Y PERIODONTAL DISEASES

Aim of the study: To evaluate the diagnostic value of crevicular fluid immunoregulatory biomarkers in cases with inflammatory periodontal diseases. The study included a total of 97 patients aged 21 to 55 years with inflammatory periodontal disease (gingivitis — 22 patients; mild periodontitis — 31 patients; moderate periodontitis — 19) as well as 25 persons with healthy periodontium (the control group). A conventionally accepted clinical and instrumental examination revealed that all the patients with inflammatory periodontal diseases featured the most typical signs of periodontal issues: in the crevicular fluid — an increase in the levels of proinflammatory cytokines and chemokines (IL-1β, IL-6, IL-17, TNF-α), a decreased level of anti-inflammatory cytokine IL-1RA, and an increased concentration of vascular endothelial growth factor (VEGF). A ROC analysis showed that the increased content of VEGF, IL-8, IL-1β, IL-6 in the crevicular fluid is of a high diagnostic value in terms of detecting initial inflammation in the gum tissues, whereas the biomarkers pointing at periodontal destructive changes included high levels of VEGF, TNF-α and chemokines.

The role of soluble leptin receptor in the pathogenesis of coronary heart disease

Introduction. The participation of soluble leptin receptor (SLR) in the formation of hyperleptinemia and leptin resistance in patients with coronary artery disease (CAD) in combination with obesity is discussed. Aim. Study of the role of SLR in the pathogenesis of ischemic heart disease. Materials and methods. A cohort study of 744 patients was performed: 465 patients with CAD (56 years old, Q1=44; Q3=62), 270 patients without CAD (52 years old, Q1=44; Q3=56). Methods: EchoCG, heart computed tomography, coronary angiography. In the blood serum, the lipids, glucose, creatinine, uric acid, and c-reactive protein were assessed using a highly sensitive method (HF-CRP). Concentrations of SLR, leptin (LN), adiponectin (total and high molecular weight), fatty acid binding protein-4 (FABP-4) tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), serum insulin were determined by enzyme immunoassay. Results. The level of SLR in blood serum in men and women with CAD is lower than in men without CAD (p &lt;0.001). In CAD patients, obesity was associated with a low SLR level in the blood serum and a high free LN index. At a serum SLR concentration of &lt;7.5ng/ml in men with CAD, the incidence of obesity was higher simultaneously with signs of visceral obesity of the heart, the presence of atherosclerotic plaques in the common carotid arteries, high glycaemic levels, insulin, IL-6, and LN in serum, serum LN/adiponectin ratio and a high HOMA-IR index. Diabetes mellitus, visceral obesity, high levels of hs-CRP, TNF-α, FABP-4, serum insulin, and HOMA-IR index were more often detected in women with coronary artery disease with SLR &lt;10.2 ng/ml. In men and women with CAD, there were no differences in SLR concentration depending on the extent of coronary atherosclerosis. Conclusion. An increase in the free LN index indicates the disruption of connections in the leptin-receptor system and reflects the mechanisms of compensation for overcoming the resistance of peripheral tissues to leptin, which is confirmed by a noticeable negative relationship between the levels of SLR and leptin in the serum of men with coronary artery disease. A low concentration of SLR in patients with CAD is associated with obesity, pro-atherogenic and pro-inflammatory markers of cardiovascular diseases.

High Hemoglobin Glycation Index Is Associated With Telomere Attrition Independent of HbA1c, Mediated by TNFα.

The hemoglobin glycation index (HGI) is correlated with metabolic diseases and inflammation. Whether the HGI is associated with the aging process and how inflammation and oxidative stress affect the relationship remain unclear. We aimed to analyze links between the HGI and aging biomarkers, and to explore a potential role of inflammation and oxidative stress in the correlations. A cross-sectional study of 434 subjects with different glucose intolerances in a rural community was enrolled. The HGI was calculated as the difference between the measured and predicted hemoglobin A1c (HbA1c). The population was categorized into tertiles of the HGI. Telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) determined by polymerase chain reaction assay. Tumor necrosis factor (TNF) α and interleukin (IL) 6, 8-oxo-2'-deoxyguanosine (8-oxo-dG), superoxide dismutase (SOD) activities, and glutathione reductase (GR) were measured. Participants in the high HGI group were older and reported a shorter LTL, higher levels of TNFα, SOD activities, and HbA1c. Correlation analyses demonstrated that HGI was correlated with LTL (r = -0.25, P < .001) and TNFα (r = 0.19, P < .001) regardless of HbA1c levels. No relationship was found between HGI and mtDNAcn. HGI (β = -0.238, 95% CI -0.430, -0.046, P = .015) and TNFα (β = -0.02, 95% CI -0.030, -0.014, P < .001) were proved to be correlated with LTL independently, using multiple linear regression analysis. Ordinal logistic regression models showed that compared with subjects the high HGI group, the possibilities of a higher-level LTL was 5.29-fold in the low HGI group (OR 5.29, 95% CI (2.45, 11.41), P < .001), 2.41-fold in the moderate HGI group (OR 2.41, 95% CI 1.35, 4.30, P = .003) after controlling for confounding variables. Mediation analyses indicated that TNFα accounted for 30.39% of the effects of the HGI on LTL. HGI was negatively related to telomere attrition, independent of HbA1c. TNFα acted as a mediator of the relationship between HGI and LTL.

Progesterone-induced blocking factor-mediated Th1/Th2 balance correlates with fetal arrest in women who underwent in vitro fertilization and embryo transfer

The role of progesterone-induced blocking factor (PIBF)-mediated Th1/Th2 balance in delivery outcomes of in vitro fertilization and embryo transfer (IVF-ET) has not been fully elucidated. In this study, 73 infertile women with successful IVF-ET were enrolled (16 fetal arrests and 57 live births). PIBF and IL-4 levels were significantly lower in the fetal arrest group than in the live birth group (p < 0.05). TNF-α level and Th1/Th2 ratios were significantly higher in the fetal arrest group than in the live birth group (p < 0.05). High TNF-α level and Th1/Th2 ratios were risk factors for fetal arrest, whereas increased PIBF and IL-4 levels were protective factors (P < 0.05). Increased TNF-α/IL-4 exhibited relatively strong predictive value for fetal arrest (AUC, 0.855; sensitivity, 93.8%; specificity, 71.9%). In summary, the PIBF-mediated Th1/Th2 balance is closely correlated with delivery outcomes of IVF-ET. TNF-α/IL-4 may be a predictive marker of fetal arrest.

Severe Inflammatory Reactions in Mice Expressing a GFI1P2A Mutant Defective in Binding to the Histone Demethylase KDM1A (LSD1).

GFI1 is a DNA-binding transcription factor that regulates hematopoiesis by repressing target genes through its association with complexes containing histone demethylases such as KDM1A (LSD1) and histone deacetylases (HDACs). To study the consequences of the disruption of the complex between GFI1 and histone-modifying enzymes, we have used knock-in mice harboring a P2A mutation in GFI1 coding region that renders it unable to bind LSD1 and associated histone-modifying enzymes such as HDACs. GFI1P2A mice die prematurely and show increased numbers of memory effector and regulatory T cells in the spleen accompanied by a severe systemic inflammation with high serum levels of IL-6, TNF-α, and IL-1β and overexpression of the gene encoding the cytokine oncostatin M (OSM). We identified lung alveolar macrophages, CD8 T cell from the spleen and thymic eosinophils, and monocytes as the sources of these cytokines in GFI1P2A mice. Chromatin immunoprecipitation showed that GFI1/LSD1 complexes occupy sites at the Osm promoter and an intragenic region of the Tnfα gene and that a GFI1P2A mutant still remains bound at these sites even without LSD1. Methylation and acetylation of histone H3 at these sites were enriched in cells from GFI1P2A mice, the H3K27 acetylation being the most significant. These data suggest that the histone modification facilitated by GFI1 is critical to control inflammatory pathways in different cell types, including monocytes and eosinophils, and that a disruption of GFI1-associated complexes can lead to systemic inflammation with fatal consequences.

Quantitative Proteomics and Phosphoproteomics Reveal TNF-α-Mediated Protein Functions in Hepatocytes.

Increased secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), is often associated with adipose tissue dysregulation, which often accompanies obesity. High levels of TNFα have been linked to the development of insulin resistance in several tissues and organs, including skeletal muscle and the liver. In this study, we examined the complex regulatory roles of TNFα in murine hepatocytes utilizing a combination of global proteomic and phosphoproteomic analyses. Our results show that TNFα promotes extensive changes not only of protein levels, but also the dynamics of their downstream phosphorylation signaling. We provide evidence that TNFα induces DNA replication and promotes G1/S transition through activation of the MAPK pathway. Our data also highlight several other novel proteins, many of which are regulated by phosphorylation and play a role in the progression and development of insulin resistance in hepatocytes.

Different Profiles of Cytokines, Chemokines and Coagulation Mediators Associated with Severity in Brazilian Patients Infected with Dengue Virus.

The incidence of dengue in Latin America has increased dramatically during the last decade. Understanding the pathogenic mechanisms in dengue is crucial for the identification of biomarkers for the triage of patients. We aimed to characterize the profile of cytokines (IFN-γ, TNF-α, IL-1β, IL-6, IL-18 and IL-10), chemokines (CXCL8/IL-8, CCL2/MCP-1 and CXCL10/IP-10) and coagulation mediators (Fibrinogen, D-dimer, Tissue factor-TF, Tissue factor pathway inhibitor-TFPI and Thrombomodulin) during the dengue-4 epidemic in Brazil. Laboratory-confirmed dengue cases had higher levels of TNF-α (p < 0.001), IL-6 (p = 0.005), IL-10 (p < 0.001), IL-18 (p = 0.001), CXCL8/IL-8 (p < 0.001), CCL2/MCP-1 (p < 0.001), CXCL10/IP-10 (p = 0.001), fibrinogen (p = 0.037), D-dimer (p = 0.01) and TFPI (p = 0.042) and lower levels of TF (p = 0.042) compared to healthy controls. A principal component analysis (PCA) distinguished between two profiles of mediators of inflammation and coagulation: protective (TNF-α, IL-1β and CXCL8/IL-8) and pathological (IL-6, TF and TFPI). Lastly, multivariate logistic regression analysis identified high aspartate aminotransferase-to-platelet ratio index (APRI) as independent risk factors associated with severity (adjusted OR: 1.33; 95% CI 1.03–1.71; p = 0.027), the area under the receiver operating characteristics curve (AUC) was 0.775 (95% CI 0.681–0.869) and an optimal cutoff value was 1.4 (sensitivity: 76%; specificity: 79%), so it could be a useful marker for the triage of patients attending primary care centers.