Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers

OBJECTIVE: The burnout syndrome has been associated with an increased risk of cardiovascular disease. The physiological mechanisms potentially involved in this link are underexplored. Knowing that a chronic low-grade systemic inflammatory state contributes to atherosclerosis, we investigated circulating cytokine levels in relation to burnout symptoms. METHODS: We studied 167 schoolteachers (median, 48 years; range, 23-63 years; 67% women) who completed the Maslach Burnout Inventory with its three subscales emotional exhaustion (EE), lack of accomplishment (LA), and depersonalization (DP). Levels of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 were determined in fasting morning plasma samples. The TNF-alpha/IL-4 ratio and the TNF-alpha/IL-10 ratio were computed as two indices of increased inflammatory activity. Analyses were adjusted for demographic factors, medication, lifestyle factors (including sleep quality), metabolic factors, and symptoms of depression and anxiety. RESULTS: Higher levels of total burnout symptoms aggregating the EE, LA, and DP subscales independently predicted higher TNF-alpha levels (DeltaR(2)=.024, P=.046), lower IL-4 levels (DeltaR(2)=.021, P=.061), and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.040, P=.008). Higher levels of LA predicted decreased IL-4 levels (DeltaR(2)=.041, P=.008) and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.041, P=.007). The categorical dimensions of the various burnout scales (e.g., burnout yes vs. no) showed no independent relationship with any cytokine measure. CONCLUSION: Burnout was associated with increased systemic inflammation along a continuum of symptom severity rather than categorically. Given that low-grade systemic inflammation promotes atherosclerosis, our findings may provide one explanation for the increased cardiovascular risk previously observed in burned-out individuals.

Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms

Activation of prosurvival kinases and subsequent nitric oxide (NO) production by certain G protein-coupled receptors (GPCRs) protects myocardium in ischemia/reperfusion injury (I/R) models. GPCR signaling pathways are regulated by GPCR kinases (GRKs), and GRK2 has been shown to be a critical molecule in normal and pathological cardiac function.

A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3.

Mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in nonhematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and nonhematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild-type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES.

Effects and uptake of gold nanoparticles deposited at the air–liquid interface of a human epithelial airway model

The impact of nanoparticles (NPs) in medicine and biology has increased rapidly in recent years. Gold NPs have advantageous properties such as chemical stability, high electron density and affinity to biomolecules, making them very promising candidates as drug carriers and diagnostic tools. However, diverse studies on the toxicity of gold NPs have reported contradictory results. To address this issue, a triple cell co-culture model simulating the alveolar lung epithelium was used and exposed at the air-liquid interface. The cell cultures were exposed to characterized aerosols with 15 nm gold particles (61 ng Au/cm2 and 561 ng Au/cm2 deposition) and incubated for 4 h and 24 h. Experiments were repeated six times. The mRNA induction of pro-inflammatory (TNFalpha, IL-8, iNOS) and oxidative stress markers (HO-1, SOD2) was measured, as well as protein induction of pro- and anti-inflammatory cytokines (IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, TNFalpha, INFgamma). A pre-stimulation with lipopolysaccharide (LPS) was performed to further study the effects of particles under inflammatory conditions. Particle deposition and particle uptake by cells were analyzed by transmission electron microscopy and design-based stereology. A homogeneous deposition was revealed, and particles were found to enter all cell types. No mRNA induction due to particles was observed for all markers. The cell culture system was sensitive to LPS but gold particles did not cause any synergistic or suppressive effects. With this experimental setup, reflecting the physiological conditions more precisely, no adverse effects from gold NPs were observed. However, chronic studies under in vivo conditions are needed to entirely exclude adverse effects.

Cyclooxygenase-2 and 5-lipoxygenase in dogs with chronic enteropathies.

BACKGROUND Cyclooxygenase-2 (COX-2) is a key enzyme in the synthesis of pro-inflammatory prostaglandins and 5-lipoxygenase (5-LO) is the major source of leukotrienes. Their role in IBD has been demonstrated in humans and animal models, but not in dogs with chronic enteropathies (CCE). HYPOTHESIS COX-2 and 5-LO are upregulated in dogs with CCE. ANIMALS Fifteen healthy control dogs (HCD), 10 dogs with inflammatory bowel disease (IBD), and 15 dogs with food-responsive diarrhea (FRD). METHODS Prospective study. mRNA expression of COX-2, 5-LO, IL-1b, IL-4, IL-6, TNF, IL-10 and TFG-β was evaluated by quantitative real-time RT-PCR in duodenal and colonic biopsies before and after treatment. RESULTS COX-2 expression in the colon was significantly higher in IBD and FRD before and after treatment (all P < .01). IL-1b was higher in FRD in the duodenum after treatment (P = .021). TGF-β expression was significantly higher in the duodenum of HCD compared to FRD/IBD before treatment (both P < .001) and IBD after treatment (P = .012). There were no significant differences among groups and within groups before and after treatment for IL-4, IL-6, TNF, and IL-10. There was a significant correlation between COX-2 and IL-1b in duodenum and colon before treatment in FRD and IBD, whereas 5-LO correlated better with IL-6 and TNF. IL-10 and TGF-β usually were correlated. CONCLUSIONS AND CLINICAL IMPORTANCE COX-2 is upregulated in IBD and FRD, whereas IL-1b and TGF-β seem to be important pro- and anti-inflammatory cytokines, respectively. The use of dual COX/5-LO inhibitors could be an interesting alternative in the treatment of CCE.

Cytokine and anti-cytokine therapy for asthma

Cytokines play a critical role in the pathogenesis of asthma. Asthma resolution may depend on the correction of dysregulated cytokine expression, which is a characteristic feature of this chronic inflammatory disease. It is, therefore, not surprising that attempts have been made to either block cytokines present at elevated levels or to substitute cytokines that are insufficiently expressed in asthma. In this article, the results of these studies are discussed, and the obtained insights regarding asthma pathogenesis and new treatment options are summarized.

The causative pathogen determines the inflammatory profile in cerebrospinal fluid and outcome in patients with bacterial meningitis

BACKGROUND The brain's inflammatory response to the infecting pathogen determines the outcome of bacterial meningitis (BM), for example, the associated mortality and the extent of brain injury. The inflammatory cascade is initiated by the presence of bacteria in the cerebrospinal fluid (CSF) activating resident immune cells and leading to the influx of blood derived leukocytes. To elucidate the pathomechanisms behind the observed difference in outcome between different pathogens, we compared the inflammatory profile in the CSF of patients with BM caused by Streptococcus pneumonia (n = 14), Neisseria meningitidis (n = 22), and Haemophilus influenza (n = 9). METHODS CSF inflammatory parameters, including cytokines and chemokines, MMP-9, and nitric oxide synthase activity, were assessed in a cohort of patients with BM from Burkina Faso. RESULTS Pneumococcal meningitis was associated with significantly higher CSF concentrations of IFN-γ , MCP-1, and the matrix-metalloproteinase (MMP-) 9. In patients with a fatal outcome, levels of TNF-α, IL-1 β, IL-1RA, IL-6, and TGF-α were significantly higher. CONCLUSION The signature of pro- and anti-inflammatory mediators and the intensity of inflammatory processes in CSF are determined by the bacterial pathogen causing bacterial meningitis with pneumococcal meningitis being associated with a higher case fatality rate than meningitis caused by N. meningitidis or H. influenzae.

Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men

Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-κB-BA and delayed increases in plasma IL-6 and mRNA of IL-1ß, IL-6, and IκBα (p's<.045). In the stress group, significant increases over time were also observed for NF-κB mRNA and plasma IL-1ß and IL-10 (p's<.055). NF-κB-BA correlated significantly with mRNA of IL-1β (r=.52, p=.002), NF-κB (r=.48, p=.004), and IκBα (r=.42, p=.013), and marginally with IL-6 mRNA (r=.31, p=.11). Plasma cytokines did not relate to NF-κB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF-κB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress-induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells.

A differential concentration-dependent effect of IVIg on neutrophil functions: relevance for anti-microbial and anti-inflammatory mechanisms

Background Polymorphonuclear neutrophils (PMN) play a key role in host defences against invading microorganisms but can also potentiate detrimental inflammatory reactions in case of excessive or misdirected responses. Intravenous immunoglobulins (IVIg) are used to treat patients with immune deficiencies and, at higher doses, in autoimmune, allergic and systemic inflammatory disorders. Methodology/Principal Findings We used flow cytometry to examine the effects of IVIg on PMN functions and survival, using whole-blood conditions in order to avoid artifacts due to isolation procedures. IVIg at low concentrations induced PMN activation, as reflected by decreased L-selectin and increased CD11b expression at the PMN surface, oxidative burst enhancement, and prolonged cell survival. In contrast, IVIg at higher concentrations inhibited LPS-induced CD11b degranulation and oxidative burst priming, and counteracted LPS-induced PMN lifespan prolongation. Conclusions/Significance IVIg appears to have differential, concentration-dependent effects on PMN, possibly supporting the use of IVIg as either an anti-microbial or an anti-inflammatory agent.

Atopic dermatitis: from new pathogenic insights toward a barrier-restoring and anti-inflammatory therapy

Recent published work on atopic dermatitis focusing on the pathogenesis and epidemiology, which have a direct effect on treatment, is presented.

Conventional and anti-erosion fluoride toothpastes: effect on enamel erosion and erosion-abrasion

New toothpastes with anti-erosion claims are marketed, but little is known about their effectiveness. This study investigates these products in comparison with various conventional NaF toothpastes and tin-containing products with respect to their erosion protection/abrasion prevention properties. In experiment 1, samples were demineralised (10 days, 6 × 2 min/day; citric acid, pH 2.4), exposed to toothpaste slurries (2 × 2 min/day) and intermittently stored in a mineral salt solution. In experiment 2, samples were additionally brushed for 15 s during the slurry immersion time. Study products were 8 conventional NaF toothpastes (1,400-1,490 ppm F), 4 formulations with anti-erosion claims (2 F toothpastes: NaF + KNO(3) and NaF + hydroxyapatite; and 2 F-free toothpastes: zinc-carbonate-hydroxyapatite, and chitosan) and 2 Sn-containing products (toothpaste: 3,436 ppm Sn, 1,450 ppm F as SnF(2)/NaF; gel: 970 ppm F, 3,030 ppm Sn as SnF(2)). A mouth rinse (500 ppm F as AmF/NaF, 800 ppm Sn as SnCl(2)) was the positive control. Tissue loss was quantified profilometrically. In experiment 1, most NaF toothpastes and 1 F-free formulation reduced tissue loss significantly (between 19 and 42%); the Sn-containing formulations were the most effective (toothpaste and gel 55 and 78% reduction, respectively). In experiment 2, only 4 NaF toothpastes revealed significant effects compared to the F-free control (reduction between 29 and 37%); the F-free special preparations and the Sn toothpaste had no significant effect. The Sn gel (reduction 75%) revealed the best result. Conventional NaF toothpastes reduced the erosive tissue loss, but had limited efficacy regarding the prevention of brushing abrasion. The special formulations were not superior, or were even less effective.

Analgesic and anti-inflammatory actions of robenacoxib in acute joint inflammation in dog

The objectives of this study were to establish dose-response and blood concentration-response relationships for robenacoxib, a novel nonsteroidal anti-inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)-2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra-articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX-1 and COX-2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose-related improvement in weight-bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED(50) was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti-inflammatory effects of robenacoxib were significantly superior to placebo (0.25-4 mg/kg robenacoxib) and were non-inferior to meloxicam (0.5-4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose-related inhibition of COX-2 (estimated ED(50) was 0.52 mg/kg) but no inhibition of COX-1. At a dosage of 1-2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.

Echinococcus multilocularis and its intermediate host: a model of parasite-host interplay

Host-parasite interactions in the E. multilocularis-intermediate host model depend on a subtle balance between cellular immunity, which is responsible for host's resistance towards the metacestode, the larval stage of the parasite, and tolerance induction and maintenance. The pathological features of alveolar echinococcosis. the disease caused by E. multilocularis, are related both to parasitic growth and to host's immune response, leading to fibrosis and necrosis, The disease spectrum is clearly dependent on the genetic background of the host as well as on acquired disturbances of Th1-related immunity. The laminated layer of the metacestode, and especially its carbohydrate components, plays a major role in tolerance induction. Th2-type and anti-inflammatory cytokines, IL-10 and TGF-beta, as well as nitric oxide, are involved in the maintenance of tolerance and partial inhibition of cytotoxic mechanisms. Results of studies in the experimental mouse model and in patients suggest that immune modulation with cytokines, such as interferon-alpha, or with specific antigens could be used in the future to treat patients with alveolar echinococcosis and/or to prevent this very severe parasitic disease.

Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" effect--a Chinese concept for a worldwide pandemic

Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.

Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis

ABSTRACT: INTRODUCTION: In transgenic animal models of sepsis, members of the Bcl-2-family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro- and anti-apoptotic members of the Bcl-2-family of proteins in patients with early stage severe sepsis. METHODS: In this prospective case-control study patients were recruited from three intensive care units in a university hospital. Sixteen patients were enrolled as soon as they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and eleven healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine (PS) externalization in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed by flow cytometry. Specific mRNA's of Bcl-2 family members were quantified from whole blood by real-time polymerase chain reaction. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc testing was performed. RESULTS: In all lymphocyte populations caspase-3 (p<0.05) was activated, which was reflected in an increased PS externalization (p<0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p<005) and in B-cells (p<0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared to critically ill patients (p<0.001) and 51.6 fold as compared to healthy controls (p<0.05). Bid was increased 12.9 fold compared to critically ill (p<0.001). In the group of the mitochondrial apoptosis-inducers, Bak was upregulated 5.6 fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p<0.001, p<0.05). CONCLUSIONS: In early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis.