Pro-inflammatory Cytokines In Peripheral Blood Research Articles

919 granules improve postpartum depression through the regulation of abnormal peripheral blood IL-1β

Postpartum depression (PPD) has a significant impact on the physical and mental health of mothers, potentially leading to symptoms such as low mood, fatigue, and decreased appetite. It may also affect the healthy growth of the infant. The onset of PPD is closely related to abnormalities in inflammation and the immune system. PPD patients exhibit abnormalities in the proportion of peripheral blood immune cells, along with an increase in pro-inflammatory cytokines. Excessive pro-inflammatory cytokines in peripheral blood can disrupt the blood-brain barrier (BBB) by activating astrocytes and reducing transendothelial electrical resistance (TEER), allowing peripheral immune cells or cytokines to enter the brain and trigger inflammation, ultimately leading to the onset of depression. In addition, PPD lacks safe and effective treatment medications. In this study, we collected peripheral blood from both healthy postpartum women and those with PPD, conducted single cell RNA sequencing (scRNA-seq), and used an in-house analytical tool scSTAR to reveal that PPD patients exhibit elevated proportions of peripheral blood cDC2 and Proliferation B cells, which are significantly correlated with IL-1β. Additionally, animal experiments were designed to validate that 919 granules can improve PPD by modulating the levels of peripheral blood IL-1β, providing a potential therapeutic mechanism for PPD treatment.

The role of TLR4/NF-κB signaling pathway in sleep deprivation induced Meniere's disease

Objective:By detecting the levels of proteins in the Toll-like receptor-4/nuclear factor-κB （TLR4/NF-κB） signaling pathway and downstream proinflammatory cytokines in peripheral blood of patients with Meniere's disease （MD）, Pittsburgh Sleep Quality Index （PSQI） scores were collected to investigate the correlation between sleep disorders and MD and the role of TLR4/NF-κB signaling pathway in mediating sleep disorders inducing MD. Methods:Thirty-two MD patients and 20 family members of patients without middle ear and inner ear related diseases were selected. Basic data, PSQI and fasting peripheral blood of all subjects were collected. Enzyme linked immunosorbent assay.The levels of interleukin-1β（IL-1β）, tumor necrosis factor-α（TNF-α）, monocyte chemokine-1（MCP-1）, Toll-like receptor 4（TLR4） and nuclear factor-κB（NF-κB） in peripheral blood were detected by ELISA, and the data were statistically analyzed. Results:①PSQI score of MD group was higher than that of normal control group, and the difference was statistically significant（P<0.01）; The scores of every factors of PSQI in MD group were higher than those in normal control group, and the scores of factors 2, 4 and 6 were significantly different from those in normal control group. ②In the MD group, there were 18 patients with sleep disorders, with a prevalence rate of 56.25%, including 6 males with a prevalence rate of 50.00% and 12 females with a prevalence rate of 60.00%. ③The levels of five test indexes in MD group, sleep disorder group and non-sleep disorder group were higher than those in control group, and the levels of TLR4 and NF-κB in MD group were significantly different from those in control group（P<0.05）. The levels of IL-1β, TNF-α, TLR4 and NF-κB in sleep disorder group were significantly different from those in control group（P<0.05）. The levels of five test indexes in non-sleep disorder group were not statistically significant compared with those in control group. The levels of five test indexes in the MD sleep disorder group were higher than those in the MD group and the non-sleep disorder group, with no statistical significance. The levels of five test indexes in MD group were higher than those in non-sleep disorder group, with no statistical significance（P>0.05）. Conclusion:①Sleep disorders may be one of the important predisposing factors of some MD, and the effects of sleep disorders on MD are different between the sexes. ②Sleep disorders may activate TLR4/NF-κB signaling pathway to induce MD. The selection of TLR4/NF-κB signaling pathway related proteins and downstream pro-inflammatory factor inhibitors to intervene MD may provide a new idea for protecting the hearing balance function of MD.

The Importance of the Interleukin-8 Study in Chronic Obstructive Pulmonary Disease

Abstract Chronic obstructive pulmonary disease (COPD) is a preventable and treatable heterogeneous lung disease characterized by chronic respiratory symptoms such as dyspnea, cough, sputum production. The main pathophysiological changes occur in the airways, lung parenchyma, pulmonary blood vessels and are represented by chronic inflammation and structural changes. The inflammatory response is initiated by exposure to chronic irritants and amplifies with the severity of airflow. Smoking remains the most important risk factor, but chronic airflow limitation can also be objectified in non-smokers. Oxidative stress, the excess of pulmonary proteinases, the alteration of the lung microbiome and the presence of inflammatory mediators can contribute to the amplification of the inflammatory process. Lung inflammation that develops in patients with COPD leads to an increase in biomarkers that are associated with neutrophilic inflammation, such as MMP9, elastase, neutrophils in the bronchoalveolar lavage fluid, and proinflammatory cytokines in peripheral blood. Also, interleukin-8 (IL-8) contributes to neutrophil activation, but further research is needed to identify the role of IL-8, the benefits of anti-inflammatory therapy, also emphasizing the importance of progression in medicine.

The role of clinical parameters and cathepsin S gene expression in predicting the development of postoperative pain in patients with hip osteoarthritis

Objective : to evaluate the significance of clinical indicators, expression of pain syndrome genes cathepsin S and pro-inflammatory cytokines in peripheral blood for predicting the development of postoperative pain (POP) in patients with hip osteoarthritis (HOA) before total arthroplasty (TA). Material and methods. The study included 31 patients with stages III–IV of HOA (mean age 61.3±9.8 years) who underwent TA and 26 healthy volunteers (control group). Depending on the presence or absence of POP, patients were divided into two subgroups: with POP (1st subgroup, n=12) and without POP (2nd subgroup, n=19). Patients were examined before and 6 months after surgery. Prior to TA, the level of pain was determined in all patients using the visual analogue scale (VAS), as well as using the DN4 and PainDETECT neuropathic pain questionnaires. Functional status was assessed by the WOMAC index. The development of POP ≥ 30 mm according to VAS was assessed 6 months after TA. Total RNA was isolated from whole blood and used to evaluate gene expression for cathepsin S, interleukin 1 (IL1 ), tumor necrosis factor α (TNF α ), and cyclooxygenase 2 (COX2) by quantitative real-time polymerase chain reaction. Results and discussion . Complaints of pain persisted in 12 (38.7%) patients 6 months after TA. Before surgery, the expression of cathepsin S, IL1 , TNF α , and COX2 genes was significantly higher in patients of both subgroups compared to healthy controls. In addition, in patients with POP who were not satisfied with the outcome of TA, the rates of neuropathic pain according to the DN4 questionnaire and cathepsin S gene expression were significantly higher than in other patients. At the same time, there was no significant difference in the expression of genes of pro-inflammatory cytokines in patients of the studied subgroups before TA. Conclusion . The development of POP in patients with HOA may be partially associated with its perception mechanisms disturbance, and an increase in the expression of the cathepsin S gene in the peripheral blood prior to TA can serve as its prognostic biomarker.

Dysfunction of inflammation-resolving pathways is associated with postoperative cognitive decline in elderly mice

BackgroundPostoperative cognitive dysfunction (POCD) refers to a reversible, perioperative mental disorder. POCD increases the likelihood of postoperative complications and the risk for postoperative mortality, typically among elderly patients (age 65 or older). The importance of the cholinergic anti-inflammatory pathway (CAP) in resolving neuro-inflammatory and cognitive decline caused by sterile trauma has been recognized. We speculate that the POCD in elderly mice is associated with dysfunction of CAP. MethodsMice were assigned to several groups (n = 5 in each group): AM (adult mice) Sham, AM (adult mice) Surgery, EM (elderly mice) Sham, EM (elderly mice) Surgery, and EMP (elderly mice with PNU) Surgery. At 24 h after surgery, assessed the cognitive levels. Pro-inflammatory cytokines in peripheral blood and splenic monocytes (TNF-α, IL-6 and IL-10) were assessed by ELISA and qPCR. Levels of M2 macrophages in hippocampus were visualized by immunofluorescence. Detecting CD11b/c+α7 nAChR+ cells in the spleens with flow cytometry. ResultsAt postoperative 24 h, elderly mice exhibited significantly increased POCD compared with adult mice. The proinflammatory factor TNF-α and IL-6 were higher among elderly surgery mice (EM) compared with adult surgery (AM) and elderly-P surgery mice (EM-P); the anti-inflammatory factor IL-10 and M2 macrophages were lower among EM surgery mice compared with AM surgery and EM-P surgery mice. The CD11b/c+α7 nAChR+ population of splenocytes was reduced in the EM surgery mice. ConclusionsThe exaggerated and persistent cognitive decline and inflammatory response among elderly mice were associated with dysfunction of CAP, and these phenomena were reversed by α7nAch receptor agonists.

Systematic reviews of effects of Tripterygium Glycosides Tablets on pro-inflammatory factors in rheumatoid arthritis

To systematically evaluate the effects of Tripterygium Glycosides Tablets alone or in combination with methotrexate(MTX) and leflunomide(LEF) on the levels of pro-inflammatory cytokines in patients or animal models with rheumatoid arthritis(RA), and to provide reference for clinical application and related basic research, this study systematically searched databases of CNKI, VIP, WanFang, PubMed, Embase and Cochrane Library, collected relevant clinical or animal experimental studies, used risk assessment tools to evaluate the quality of research, and used Revman 5.3 software to conduct Meta-analysis or descriptive analysis of the outcome indicators included in the literatures. Of the 1 709 papers retrieved, 3 clinical studies and 12 animal experiments were included. The results showed that compared with MTX alone, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of peripheral blood TNF-α(SMD=-8.88,95%CI[-10.77,-6.99],P&lt;0.000 01),IL-1β(P&lt;0.000 01) and IL-6(SMD=-8.63, 95%CI[-10.57,-6.69], P&lt;0.000 01) in RA patients. Compared with LEF alone, the combination of Tripterygium Glycosides Tablets and LEF could not further reduce the expression levels of TNF-α(P=0.20), IL-1β(P=0.17), IL-6(P=0.31). In RA animal model, compared with model group, Tripterygium Glycosides Tablets could reduce the expression levels of peripheral blood IL-1β(SMD=-6.29,95%CI[-9.64,-2.93],P&lt;0.000 2)in peripheral blood(SMD=-1.39,95%CI[-1.77,-1.02],P&lt;0.000 01), joint fluid(P&lt;0.000 01) and paw plasma(P=0.02), and also reduce the expression levels of TNF-α in RA animal model group. Compared with MTX alone, Tripterygium Glycosides Tablets alone reduced the same levels of TNF-α(P=0.42) and IL-6(P=0.08) in joint fluid, while Tripterygium Glycosides Tablets combined with MTX could further reduce the levels of IL-6(P=0.000 1) in joint fluid; compared with LEF alone, Tripterygium Glycosides Tablets have the similar effects on reducing the expression levels of peripheral blood TNF-α(P=0.16), IL-1β(P=0.32), IL-6(P=0.12), while Tripterygium Glycosides Tablets combined with LEF could further reduce the expression levels of TNF-α(P=0.008), IL-1β(P=0.02), IL-6(P&lt;0.000 1) in peripheral blood. Therefore, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of pro-inflammatory cytokines in peripheral blood of RA patients. Tripterygium Glycosides Tablets alone could reduce the expression levels of pro-inflammatory cytokines in peripheral blood and local joint of RA animal models. Tripterygium Glycosides Tablets combined with MTX or LEF could further reduce the express levels of pro-inflammatory cytokines in peripheral blood of RA animal models. Due to the limitation of literature, this conclusion needs to be further validated.

Age-related dynamics of pro-inflammatory cytokines in equine bronchoalveolar lavage (BAL) fluid and peripheral blood from horses managed on pasture.

The objectives of this study were to evaluate the natural age-related variation and compare the level of pro-inflammatory cytokines in the peripheral blood and lower airways of horses. The mRNA expression of IL-1β, IL-6, IL-8 TNF-α TLR-4 in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMC) were studied by quantitative real time polymerase chain reaction (PCR) and differential cell count cytology from 44 horses of different ages. A significant age-related increase was found for the mRNA expression of IL-6, IL-8, TLR-4 and TNF-α in stimulated BAL cells and for TNF-α in stimulated PBMC. Furthermore, a significant decrease was found in the mRNA expression of IL-1β and TNF-α in stimulated BAL cells compared to stimulated PBMC. In conclusion, continued low antigen exposure of horses in the pasture environment could lead to a tight regulation of mRNA gene expression in the airway space compared to the peripheral blood and favour an age-related accumulation of mRNA genes.

Inflammation and osteoarthritis-related pain

Osteoarthritis (OA) is one of the major causes of chronic pain. Although OA has long been considered anon-inflammatory "wear and tear" disease leading to loss of articular cartilage, recent findings provide convincing evidence that inflammatory mechanisms play apivotal role in the pathophysiology of OA. In OA mononuclear cells (e. g. T‑cells and macrophages) infiltrate the synovial membrane and the levels of pro-inflammatory cytokines in peripheral blood and synovial fluid samples are elevated. Increased release of inflammatory mediators including interleukin (IL) IL-1β, IL-6, IL-8, IL-15 und tumor necrosis factoralpha (TNF‑α) induces the expression of proteolytic enzymes such as matrix metalloproteinases resulting in cartilage breakdown. Molecular and cellular interactions between the immune and nervous system are also involved in the development of OA-related pain. Inflammatory mediators including IL-6 und TNF‑α lead to peripheral sensitization of joint nociceptors and growth factors (e. g. NGF) trigger the expression of TRPV1 channels in primary afferents. Moreover, neuropeptides reduce the threshold of nociceptors of OA joints. The current review highlights the role of inflammatory mechanisms in OA-induced joint pain considering clinical signs of inflammation and major inflammatory pathways.

Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-β peptide (Aβ) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models. We observed that hucMSC-exosomes injection could repair cognitive disfunctions and help to clear Aβ deposition in these mice. Moreover, we found that hucMSC-exosomes injection could modulate the activation of microglia in brains of the mice to alleviated neuroinflammation. The levels of pro-inflammatory cytokines in peripheral blood and brains of mice were increased and the levels of anti-inflammatory cytokines were decreased. We also treated BV2 cells with hucMSC-exosomes in culture medium. HucMSC-exosomes also had inflammatory regulating effects to alternatively activate microglia and modulate the levels of inflammatory cytokines in vitro.

Histone deacetylase 2 is decreased in peripheral blood pro-inflammatory CD8+ T and NKT-like lymphocytes following lung transplant.

Immunosuppression therapy following lung transplantation fails to prevent chronic rejection in many patients, which is associated with lack of suppression of cytotoxic mediators and pro-inflammatory cytokines in peripheral blood T and natural killer T (NKT)-like cells. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) upregulate/downregulate pro-inflammatory gene expression, respectively; however, differences in the activity of these enzymes following lung transplant are unknown. We hypothesized decreased HDAC2 expression and increased HAT expression in pro-inflammatory lymphocytes following lung transplant. Blood was collected from 18 stable lung transplant patients and 10 healthy age-matched controls. Intracellular pro-inflammatory cytokines and HAT/HDAC2 expression were determined in lymphocyte subsets following culture using flow cytometry. A loss of HDAC2 in cluster of differentiation (CD) 8+ T and NKT-like cells in transplant patients compared with controls was noted (CD8+ T: 28 ± 10 (45 ± 10), CD8+NKT-like: 30 ± 13 (54 ± 16) (mean ± SD transplant) (control)). Loss of HDAC2 was associated with an increased percentage of CD8+ T and NKT-like cells expressing perforin, granzyme b, interferon gamma (IFN-γ) and TNF-α (no change in HAT expression in any lymphocyte subset). There was a negative correlation between loss of HDAC2 expression by CD8+ T cells with cumulative dose of prednisolone and time post-transplant. Treatment with 10 mg/L theophylline + 1 µmol/L prednisolone or 2.5 ng/mL cyclosporine A synergistically upregulated HDAC2 and inhibited IFN-γ and TNF-α production by CD8+ T and NKT-like lymphocytes. HDAC2 is decreased in CD8+ T and NKT-like pro-inflammatory lymphocytes following lung transplant. Treatment options that increase HDAC2 may improve graft survival.

Generation TNF-α, IL-1β in newly diagnosed patients with different clinical forms of pulmonary tuberculosis in the Astrakhan Region

Objective: To study the spontaneous production of proinflammatory cytokines (TNF-α and IL-1β) in newly diagnosed patients with different clinical forms of pulmonary tuberculosis, Russian population groups living in the Astrakhan region. Materials and Methods: on the basis of hospital № 1 "Regional Clinical TB Dispensary" Astrakhan, performed a comprehensive clinical and immunological examination of 60 patients newly diagnosed with pulmonary tuberculosis. Men 44 (73.3%), 16 women (26.7%). Age – from 18 to 56 years. Residents of the city of Astrakhan was 29 (48.3%), rural area – 31 (51.7%). The level of proinflammatory cytokines in peripheral blood was measured before the start of a specific treatment, using a firm "VECTOR-BEST" Russia reagent kits. Results. In a study comparing the two groups were formed: Ι – 31 patients with limited specific changes in lung tissue with a predominance of the productive component of inflammation; ΙΙ – 29 patients with bulky specific changes with the collapse of the lung tissue with a predominance of exudative inflammation component. In patients with disseminated tuberculosis patients Ι group serum TNF-α was detected in higher concentrations than patients ΙΙ group (8,16 ± 0,14 pg / ml vs. 4,01 ± 0,09 pg / ml; p &lt;0.05 ). The same trend was observed at infiltrative tuberculosis patients, comparison groups, p &lt;0.05. Development of IL-1β in serum, previously without a history of patients with tuberculosis compared groups is as follows: with disseminated - in group Ι concentration 10,11 ± 1,07 пг / мл vs. 8,91 ± 1,07 pg / ml in group ΙΙ, p&gt; 0.05; in infiltrative - in group Ι concentration 9,04 ± 0,94 pg / ml vs. 18,01 ± 1,04 pg / ml in group ΙΙ, p &lt;0.05; when Tuberculomas only Ι group concentration was 6,81 ± 0,21 pg / ml; at the cavernous and fibro-cavernous pulmonary tuberculosis concentration was 9,15 ± 1,09 pg / ml.Conclusion. High concentrations of interleukin-1b potentiate the development of exudative-necrotic component specific inflammation and destruction of the lung tissue.

Inflammation Induced Expression of Ybx1 Mediates Resistance to JAK-Kinase Inhibitor Therapy in Myeloproliferative Neoplasia

Myeloproliferative neoplasia (MPN) is a group of diseases which include polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) and is characterized by clonal proliferation of myeloid cells. In many cases there is also a striking inflammatory syndrome (CRP elevation, fever, elevation of pro-inflammatory cytokines in peripheral blood) in particular in advanced phases of the disease. Auto- and paracrine effects of pro-inflammatory cytokines may contribute to maintenance of the disease and aggravation of the inflammatory syndrome. Cold-shock proteins are multi-functional DNA/RNA-binding proteins and Ybx1 is the prototypic member. These proteins regulate the expression of a number of pro-inflammatory cytokines, as well as cytokine receptors, making them key players in the orchestration of inflammatory processes. Moreover, expression of Ybx1 is induced by cellular and oncogenic stress and mediates resistance to chemotherapy. As patients with MPNs may present with an inflammatory syndrome, we assessed for Ybx1 expression as a potential mediator of cytokine signaling.By immunohistochemistry we found expression of Ybx1 in primary human bone marrow (BM) biopsies derived from patients with MPN. In contrast, BM sections derived from healthy donors (or remission controls without any evidence for active disease) did not show any expression of Ybx1. Moreover, Ybx1 expression was increased in the cytoplasm of myeloid immune cells derived from the peripheral blood of MPN patients as assessed by flow cytometry. Lower levels of cytoplasmatic Ybx1 were detectable in healthy volunteers.Therefore, we hypothesized that inflammatory stimuli (e.g. secretion of pro-inflammatory cytokines) may contribute to Ybx1 expression and this may mediate resistance to JAK-kinase inhibitor therapy.To assess for a functional role of Ybx1 in MPN we used murine cell lines (32D and Ba/F3) transduced with mutated JAK2 (JAK2-V617F) or MPL-receptor (MPLW515L) as well as human cell lines harboring the respective mutations. Exposure of these murine cell lines to pro-inflammatory stimuli (e.g. pro-inflammatory cytokines) induced expression of Ybx1 as assessed by qPCR. As Ybx1-expression has been described to contribute to drug resistance, we aimed to assess for its function in the setting of JAK-kinase inhibitor therapy.Lentiviral knockdown of Ybx1 alone did neither affect proliferation nor induce apoptosis in JAK2V617F- and MPL-mutated murine cell lines. However, co-treatment with the JAK-kinase inhibitor ruxolitinib (RUX) after Ybx1 knockdown led to induction of apoptosis that significantly exceeded the amount of apoptotic cells (AnnexinV+, Caspase+) upon RUX-treatment alone. These effects could be re-capitulated in human leukemia cell lines (HEL and SETB2) harboring the JAK2V617F mutation.As knockdown of Ybx1 (to 40-50% of baseline) alone did not impair proliferation of murine cell lines in vitro, we asked whether reduction of Ybx1 would impair function of normal hematopoiesis. We used a straight knockout mouse model in which homozygous loss of Ybx1 is embryonically lethal. However, heterozygous animals are born without malformations. Ybx1+/- animals show regular steady state hematopoiesis with Ybx1 expression being reduced to 50%. When injected into lethally irradiated hosts, Ybx1+/- cells produced a stable chimerism during serial transplantations as compared to Ybx1+/+ controls.To assess for a role of Ybx1 in MPN development in vivo, we used a previously published JAK2V617F knock-in mouse model. By the use of a Vav1-Cre-recombinase, a PV-like phenotype was initiated in early hematopoiesis. Sorted LSK-cells from JAK2V617F-knockin-mice were infected with lentiviral Ybx1-shRNA constructs and injected into lethally irradiated hosts. Knockdown of Ybx1 led to a delay in disease onset, when compared to scrambled-shRNA controls. Co-treatment of recipient mice with JAK-kinase inhibitors is currently under way to recapitulate the synergy observed in cell culture models described above.Taken together, Ybx1 expression in MPN is induced by inflammatory stimuli and protects JAK2V617F or MPLW515L transformed cells from JAK-inhibitor induced apoptosis. Distinct requirement for hematopoiesis (versus disease) offers a therapeutic index to evaluate cold-shock proteins as target structures for inflammatory diseases in the future. DisclosuresHeidel:Novartis: Consultancy.

Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease.

Alzheimer’s disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid β (Aβ) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome

BackgroundToxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS.MethodsEffects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 μg of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 μg) in HLA-DR4 transgenic mice.ResultsDespite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNγ, failed to improve survival in experimental TSS.ConclusionsOur results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.

The Inflammatory Cytokines in the Pathogenesis of Parkinson’s Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta. Research and clinical data suggest that the etiology of PD is multifactorial. However, recent studies indicate that neuroinflammation and associated infiltration of inflammatory cells, chemokines and cytokines may play a critical role in the pathogenesis of PD. Cumulative evidences suggest that cytokines activation and neuroinflammation may have deleterious effects on the dopaminergic system and are key factors contributing to disease progression. The levels of proinflammatory cytokines in peripheral blood tend to be higher in PD patients. Studies of brains from PD patients and animal models have provided evidence for neuroinflammation, including activation of microglia, release of IFN-γ and TNF-α and infiltration of the midbrain by CD4 and CD8 lymphocytes. However, the influence of proinflammatory factors on the risk of PD remains unclear. In this review, we attempt to discuss the most recent publications on the role of inflammatory factors in PD. One hypothesis concerning the cause of degeneration of the nigrostriatal dopaminergic neurons is that PD is triggered by programmed cell death (apoptosis) due to increased levels of cytokines, apoptosis-related proteins and/or to decreased levels of neurotrophins such as brain-derived neurotrophic factor. Astrocytes stimulated by neuro-derived α-synuclein synthesize and release a number of proinflammatory cytokines and chemokines that in turn recruit and activate microglia. Thus, the effects of small amounts of neuronal α-synuclein protein can be amplified and sustained, thereby establishing an inflammatory microenvironment and further damaging neurons. This neuroprotection was shown to be associated with the anti-inflammatory properties of drugs that act as PPAR-γ agonists. In addition, these studies suggest that molecules that prevent inflammation and apoptosis may be useful in preventing or treating PD. In conclusion, protection of neurons against inflammation may help in slowing the neuronal degeneration in PD.

Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis

BackgroundNumerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce.MethodsWe studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND).ResultsRRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression.ConclusionsUsing a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

Influence of pain-free and traditional treadmill training on circulating endothelial progenitor cells, pro-angiogenic and pro-inflammatory cytokines in peripheral blood of intermittent claudication patients

Influence of pain-free and traditional treadmill training on circulating endothelial progenitor cells, pro-angiogenic and pro-inflammatory cytokines in peripheral blood of intermittent claudication patients

INHALED NITRIC OXIDE: CLINICAL EFFECTS AND INFLUENCE ON THE PROFILE OF INFLAMMATORY MARKERS IN PATIENTS WITH IDIOPATHIC PULMONARY HYPERTENSION

Aim. To study the effect of treatment with inhaled nitric oxide (iNO) on the clinical status of patients with idiopathic pulmonary hypertension (IPH), and the profile of proinflammatory cytokines in peripheral blood. Material and methods. Patients with IPH (n=48) were included into the study. Evaluation of the IPH functional class (FC), the 6-minute walk test (6MWT) with the assessment of the Borg index, echocardiography , laboratory tests [blood count, evaluation of high-sensitivity C-reactive protein (hsCRP), interleukins (IL), interferon-γ (INFγ), tumor necrosis factor a (TNFa), macrophage inflammatory protein a (MIP1 a), soluble adhesion molecules (sICAM-1, sVCAM-1) in peripheral blood] were performed at baseline and on day 21 of iNO therapy course. The iNO course 40 ppm during 5 hours a day for 21 days was carried out additionally to the standard IPH therapy under the toxicity control by the PrinterNOx (England). Results. Increase in exercise tolerance, improvement of IPH FC (from 3.35±0.52 to 2.71±0.56; p=0.008), reduction in systolic pulmonary artery pressure (SPAP) by Doppler echocardiography (from 96.23±23.65 to 82.36±20.92 mmHg; p&lt;0.05) were found in IPH patients as a result of iNo therapy. The significance of inflammation in IPH pathogenesis was confirmed due to assessment of the initial levels of proinflammatory cytokines. iNO therapy resulted in significant decrease in proinflammatory cytokines-IL-1β, IL-6, IL-8, TNFa levels. iNO induced significant dynamics of IL-1β and sVCAM in patients with IPH FC II. It reduced IL-8 and TNFa and increase INFγ (p&lt;0.05) in patients with IPH FC III-IV. Changes in IL-1β and sVCAM levels (ΔIL-1β and ΔsVCAM) by the 21 day of iNO therapy in comparison with these at baseline correlated with ΔSPAP , and ΔIL-6 correlated with ΔFC and Δ6MWT distance (30.5 [21.0; 53.0] m; p&lt;0.001). This allows considering these indicators as markers of iNO treatment efficacy. Conclusions. 21-day iNO therapy in IPH patients resulted in significant improvement of functional status, reduce SPAP and caused the positive dynamics of proinflammatory cytokines blood levels.

Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancy

Interferon-alpha (IFN-α) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated with impaired response to IFN-α in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets, and IFN-α-induced signal transduction in 40 patients with GI malignancies. Plasma IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33(+)HLADR(-)CD11b(+)CD15(+) and CD33(+)HLADR(-/low)CD14(+) MDSC subsets were also elevated in patients versus normal donors (P < 0.0001). Plasma IL-6 was correlated with CD33(+)HLADR(-)CD15(+) MDSC (P = 0.008) and IL-10 with CD33(+)HLADR(-)CD15(-) MDSC (P = 0.002). The percentage of CD15(+) and CD15(-) but not CD14(+) MDSC subsets were inversely correlated with IFN-α-induced STAT1 phosphorylation in CD4(+) T cells, while co-culture with in vitro generated MDSC led to reduced IFN-α responsiveness in both PBMC and the CD4(+) subset of T cells from normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased percentage of the CD33(+)HLADR(-)CD15(-) MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33(+)HLADR(-/low)CD14(+) subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-α responsiveness in patients with GI malignancies.

Effect of bone marrow mesenchymal stem cells engraftment on secretion of inflammatory cytokine in the early stages of smoke inhalation injury in rabbits

To explore the effect of bone marrow mesenchymal stem cells (MSCs) engraftment on secretion of tumor necrosis factor-α (TNF-α), interleukins (IL-1β, IL-6, IL-10) in peripheral blood and lung homogenates in the early stages of smoke inhalation injury. MSCs were proliferated by the method of whole marrow culture and identified by flow cytometry. Fifty-six healthy New Zealand rabbits were randomly divided into control group (C group, n=8), smoke inhalation injury group (S group, n=24) and smoke inhalation injury+MSCs engraftment group (M group, n=24). The latter two groups were subdivided into 2, 4, 6 hours after injury subgroups, with 8 rabbits in each group. The levels of TNF-α, IL-1β, IL-6 and IL-10 in peripheral blood and lung homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Compared with C group, concent of pro-inflammatory and anti-inflammatory cytokines in peripheral blood at each time point in S group were increased significantly. The concent of pro-inflammatory cytokines in lung homogenate at each time point in S group was significantly higher than those in C group, and that of anti-inflammatory cytokines showed no significant changes. Compared with the S group, concent of pro-inflammatory cytokines in peripheral blood in M group was decreased significantly, and that of anti-inflammatory cytokines was increased significantly [6 hours TNF-α (μg/L): 1.7±1.7 vs. 4.1±1.6, IL-1β (ng/L): 9.9±1.7 vs. 21.2±2.6, IL-6 (μg/L): 1.0±0.3 vs. 1.3±0.2, IL-10 (ng/L): 15.2±4.4 vs. 7.9±3.5, all P<0.05]. Concent of pro-inflammatory cytokines at each time point in M group was decreased significantly when compared with S group in lung homogenate, while only anti-inflammatory cytokine at 4 hours and 6 hours was increased significantly [6 hours TNF-α (ng/L): 503.0±156.4 vs. 587.7±171.2, IL-1β (ng/L): 0.4±0.2 vs. 0.6±0.2, IL-6 (ng/L): 155.2±13.7 vs. 350.2±20.3, IL-10 (ng/L): 23.3±5.4 vs. 11.0±5.6, all P<0.05]. MSCs engraftment could decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines in the early stages of smoke inhalation injury, thus ameliorates inflammatory response, which confers protective effect on smoke inhalation injury.