Higher Serum Cytokine Levels Research Articles

Serum cytokine variations among inpatients with major depression, bipolar disorder, and schizophrenia versus healthy controls: a prospective ‘true-to-life’ study

There is increasing evidence of the association between chronic low-grade inflammation and severe mental illness (SMI). The objective of our study was to assess serum cytokine levels (SCLs) at admission and discharge in a true-to-life-setting population of inpatients with major depression (MD), bipolar disorder (BD), and schizophrenia (Sz), as well as of healthy controls. We considered MD, BD, and Sz to be SMIs. We evaluated 206 inpatients [MD, N = 92; BD, N = 26; mania (Ma), N = 44; Sz, N = 44). Generalized estimating equations were used to analyze variations in SCL [interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17] at hospital admission and discharge. Results of 100 healthy controls were compared with those of SMI patients at both time points. We evaluated patients' improvement during in-hospital treatment in terms of general psychiatric symptoms, global clinical impression, functionality, and manic and depressive symptoms with validated scales. In all, 68.9% of patients completed the study. Overall, SMI inpatients had higher SCL when compared with controls regardless of diagnosis. There was a significant decrease in Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity Scale (CGI-S) scores, and an increase in Global Assessment of Functioning (GAF) scores for all disorders evaluated (p < 0.001), as well as a significant decrease in HDRS-17 scores among MD inpatients (p < 0.001) and in YMRS scores among Ma inpatients (p < 0.001). IL-2 and IL-6 levels decreased significantly between admission and discharge only among MD inpatients (p = 0.002 and p = 0.03, respectively). We found no further statistically significant changes in SCL among the remaining disorders (BD, Ma, and Sz). There was no significant decrease in IFN-γ (p = 0.64), TNF-α (p = 0.87), IL-4 (p = 0.21), IL-10 (p = 0.88), and IL-17 (p = 0.71) levels in any of the evaluated diagnoses. MD inpatients had a decrease in IL-2 and IL-6 levels during hospitalization, which was accompanied by clinical improvement. No associations were found for the remaining SMIs (BD, Ma, and Sz).

Early Life Polychlorinated Biphenyl 126 Exposure Disrupts Gut Microbiota and Metabolic Homeostasis in Mice Fed with High-Fat Diet in Adulthood.

Evidence supports the potential influence of persistent organic pollutants (POPs) on the pathogenesis and progression of obesity and diabetes. Diet-toxicant interactions appear to be important in diet-induced obesity/diabetes; however, the factors influencing this interaction, especially the early life environmental exposure, are unclear. Herein, we investigated the metabolic effects following early life five-day exposure (24 μg/kg body weight per day) to 3,3′,4,4′,5-pentacholorobiphenyl (PCB 126) at four months after exposure in mice fed with control (CTRL) or high-fat diet (HFD). Activation of aryl hydrocarbon receptor (AHR) signaling as well as higher levels of liver nucleotides were observed at 4 months after PCB 126 exposure in mice, independent of diet status. Inflammatory responses including higher levels of serum cytokines and adipose inflammatory gene expression caused by early life PCB 126 were observed only in HFD-fed mice in adulthood. Notably, early life PCB 126 exposure worsened HFD-induced impaired glucose homeostasis characterized by glucose intolerance and elevated gluconeogenesis and tricarboxylic acid (TCA) cycle flux without worsening the effects of HFD related to adiposity in adulthood. Furthermore, early life PCB 126 exposure resulted in diet-dependent changes in bacterial community structure and function later in life, as indicated by metagenomic and metabolomic analyses. These data contribute to a more comprehensive understanding of the interactions between diet and early life environmental chemical exposure.

Host inflammatory response is the major factor in the progression of Chlamydia psittaci pneumonia.

Purpose Chlamydia psittaci (C. psittaci) has caused sporadic, but recurring, fatal community-acquired pneumonia outbreaks worldwide, posing a serious threat to public health. Our understanding of host inflammatory responses to C. psittaci is limited, and many bronchitis cases of psittaci have rapidly progressed to pneumonia with deterioration.MethodsTo clarify the host inflammatory response in psittacosis, we analyzed clinical parameters, and compared transcriptomic data, concentrations of plasma cytokines/chemokines, and changes of immune cell populations in 17 laboratory-confirmed psittacosis cases, namely, 8 pneumonia and 9 bronchitis individuals, in order to assess transcriptomic profiles and pro-inflammatory responses.ResultsPsittacosis cases with pneumonia were found to have abnormal routine blood indices, liver damage, and unilateral pulmonary high-attenuation consolidation. Transcriptome sequencing revealed markedly elevated expression of several pro-inflammatory genes, especially interleukins and chemokines. A multiplex-biometric immunoassay showed that pneumonia cases had higher levels of serum cytokines (G-CSF, IL-2, IL-6, IL-10, IL-18, IP-10, MCP-3, and TNF-α) than bronchitis cases. Increases in activated neutrophils and decreases in the number of lymphocytes were also observed in pneumonia cases.ConclusionWe identified a number of plasma biomarkers distinct to C. psittaci pneumonia and a variety of cytokines elevated with immunopathogenic potential likely inducing an inflammatory milieu and acceleration of the disease progression of psittaci pneumonia. This enhances our understanding of inflammatory responses and changes in vascular endothelial markers in psittacosis with heterogeneous symptoms and should prove helpful for developing both preventative and therapeutic strategies.

Performance of the modified Systemic Manifestation Score for systemic juvenile idiopathic arthritis in Adult-onset Still's disease.

To compare the ability of the modified Systemic Manifestation Score (mSMS) and the mPouchot score to distinguish adult-onset Still's disease (AOSD) with high disease severity in a large cohort. We scored the disease severity of 174 patients and categorized them into high and low disease severity states. The correlation of mSMS and mPouchot score with ESR, CRP, ferritin, liver function tests, and serum cytokines was investigated. Receiver operator characteristic (ROC) curve and logistic regression analysis were performed to compare the ability of mSMS and mPouchot to distinguish patients with severe AOSD. Both mSMS and mPouchot score were positively correlated with ESR (both P < 0.001), CRP (both P < 0.0001), and serum ferritin (both P < 0.0001). Moreover, both mSMS and mPouchot score are significantly associated with liver dysfunction and high IL-18 (both P < 0.0001) and IL-6 (both P < 0.01) levels in AOSD patients. Furthermore, the area under curve (AUC) value of mSMS was significantly less than of mPouchot score (0.71 for mSMS, 0.81 for mPouchot score, P < 0.0001). Compared with mPouchot score, mSMS had higher sensitivity (75.64% vs 74.36%) and lower specificity (55.06% vs 76.40%). And mSMS had a worse performance in assessing high disease severity than mPouchot score in logistic analysis. Both scores are proven as effective to assess disease severity of AOSD. By contrast, mSMS perform worse in assessing high disease severity of AOSD patients than mPouchot score. Key Points • Both modified Systemic Manifestation Score (mSMS) and modified Pouchot score (mPouchot score) positively correlated with ESR, CRP, and serum ferritin of AOSD patients. • Both scores are significantly associated with impaired liver function and high serum cytokine levels. • mSMS had lower discriminative ability than mPouchot score to distinguish high disease severity of AOSD patients.

Aged IRF3-KO Mice are Protected from Sepsis.

PurposeSepsis is a leading cause of hospital admissions and deaths. Older adults (>65 years) are particularly susceptible to sepsis and experience higher morbidity and mortality rates than younger people. We previously showed that interferon regulatory factor 3 (IRF3) contributes to sepsis pathogenesis in young mice subject to cecal ligation and puncture (CLP). In this study, we investigated if IRF3 contributes to sepsis in the context of aging.MethodsSepsis was induced in aged wild-type (WT) and IRF3-knock-out (KO) mice, using a clinically-relevant CLP-sepsis model including fluids and antibiotics. Animal survival, disease score and hypothermia were evaluated as indicators of sepsis pathogenesis. Serum cytokines and serum enzymes indicative of organ damage were also measured.ResultsAged WT mice were highly susceptible to sepsis (90% mortality). In comparison, aged IRF3-KO mice were significantly protected (20% mortality). Aged IRF3-KO mice showed a lower disease score and reduced hypothermia following CLP, compared to WT mice. Serum cytokines interleukin (IL)-6, IL-12/23p40 and macrophage chemoattractant protein (MCP)-1, and creatinine kinase (CK) were lower in aged IRF3-KO septic mice compared to WT counterparts. Aged male mice were found to be more susceptible to sepsis compared to females. Female mice, however, produced higher levels of serum cytokines and CK.ConclusionThese results demonstrate that IRF3 plays a detrimental role in sepsis in aged mice and highlight the impact of biological sex.

Peroxiredoxin AhpC1 protects Pseudomonas aeruginosa against the inflammatory oxidative burst and confers virulence

Pseudomonas aeruginosa is an opportunistic bacterium in patients with cystic fibrosis and hospital acquired infections. It presents a plethora of virulence factors and antioxidant enzymes that help to subvert the immune system. In this study, we identified the 2-Cys peroxiredoxin, alkyl-hydroperoxide reductase C1 (AhpC1), as a relevant scavenger of oxidants generated during inflammatory oxidative burst and a mechanism of P. aeruginosa (PA14) escaping from killing. Deletion of AhpC1 led to a higher sensitivity to hypochlorous acid (HOCl, IC50 3.2 ± 0.3 versus 19.1 ± 0.2 μM), hydrogen peroxide (IC50 91.2 ± 0.3 versus 496.5 ± 6.4 μM) and the organic peroxide urate hydroperoxide. ΔahpC1 strain was more sensitive to the killing by isolated neutrophils and less virulent in a mice model of infection. All mice intranasally instilled with ΔahpC1 survived as long as they were monitored (15 days), whereas 100% wild-type and ΔahpC1 complemented with ahpC1 gene (ΔahpC1 attB:ahpC1) died within 3 days. A significantly lower number of colonies was detected in the lung and spleen of ΔahpC1-infected mice. Total leucocytes, neutrophils, myeloperoxidase activity, pro-inflammatory cytokines, nitrite production and lipid peroxidation were much lower in lungs or bronchoalveolar liquid of mice infected with ΔahpC1. Purified AhpC neutralized the inflammatory organic peroxide, urate hydroperoxide, at a rate constant of 2.3 ± 0.1 × 106 M−1s−1, and only the ΔahpC1 strain was sensitive to this oxidant. Incubation of neutrophils with uric acid, the urate hydroperoxide precursor, impaired neutrophil killing of wild-type but improved the killing of ΔahpC1. Hyperuricemic mice presented higher levels of serum cytokines and succumbed much faster to PA14 infection when compared to normouricemic mice. In summary, ΔahpC1 PA14 presented a lower virulence, which was attributed to a poorer ability to neutralize the oxidants generated by inflammatory oxidative burst, leading to a more efficient killing by the host. The enzyme is particularly relevant in detoxifying the newly reported inflammatory organic peroxide, urate hydroperoxide.

High serum cytokine levels may predict the responsiveness of patients with severe asthma to benralizumab

Objective: Benralizumab, a humanized monoclonal antibody against human IL-5 receptor alpha, is effective in treating eosinophilic severe asthma. However, patients’ response to benralizumab varies widely. In this study, we aimed to identify a new serum biomarker to accurately predict benralizumab response. Methods: Seventeen benralizumab-treated patients with severe eosinophilic asthma were enrolled. Blood samples were collected; pulmonary function tests were performed and questionnaires were disseminated at baseline and after 1, 2, 4, and 6 months of treatment. Blood cytokine levels were measured. Response was defined as an elevation in forced expiratory volume in 1 s of at least 10.4% from baseline after 4 months of treatment. Results: There were nine respondents and eight non-respondents. The non-responders showed significantly higher baseline serum interferon-γ; interleukin (IL)-4, -5, -6, -7, and -12p70; IL-17/IL-17A; IL-17E/IL-25; IL-18/IL-1F4; chemokine (C-C motif) ligand (CCL)3/macrophage inflammatory protein (MIP)-1α; CCL4/MIP-1β; CCL11/eotaxin; matrix metalloproteinase-12; tumor necrosis factor-α, and thymic stromal lymphopoietin levels. After benralizumab administration, the serum CCL3/MIP-1α and CCL11/eotaxin levels significantly and persistently increased in the responders (CCL3/MIP-1α, responders: 144.5 ± 37.9 pg/ml (baseline) vs. 210.3 ± 59.4 pg/ml (4 months), p = 0.009; non-responders: 270.8 ± 139.8 pg/ml (baseline) vs. 299.5 ± 159.9 pg/ml (4 months), p = 0.33; CCL11/eotaxin, responders: 167.9 ± 62.6 pg/ml (baseline) vs. 326.7 ± 134.4 pg/ml (4 months), p = 0.038; non-responders: 420.9 ± 323.1 pg/ml (baseline) vs. 502.1 ± 406.0 pg/ml (4 months), p = 0.30). Conclusion: Low baseline serum inflammatory cytokine levels may be useful in predicting a good benralizumab response. Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Autonomic balance determines the severity of COVID-19 courses

COVID-19 has left mankind desperately seeking how to manage dramatically rising infection rates associated with severe disease progressions. COVID-19 courses range from mild symptoms up to multiple organ failure and death, triggered by excessively high serum cytokine levels (IL 1β, IL 6, TNF α, IL 8). The vagally driven cholinergic anti-inflammatory pathway (CAP) stops the action of nuclear factor κB (NF-κB), the transcriptional factor of pro-inflammatory cytokines. Thus, well-balanced cytokine release depends on adequate vagal signaling. Coronaviruses replicate using NF-κB transcriptional factor as well. By degrading the cytoplasmatic inhibitor of NF-κB subunits (IκB), coronaviruses induce unrestricted NF-κB expression accelerating both, virus replication and cytokine transcription.We hypothesize that CAP detriment due to depressed vagal tone critically determines the severity of COVID-19.

An observational study of innate immune responses in patients with acute appendicitis

Acute appendicitis is a common surgical emergency worldwide. Exaggerated immune responses could be associated with appendicitis. This study aimed at characterizing immune responses towards a large variety of gut commensals and pathogens, and pattern recognition receptor (PRR) ligands, and investigating the course of systemic inflammation in a prospective cohort of acute appendicitis patients. PBMC responses of 23 patients of the cohort and 23 healthy controls were characterized more than 8 months post-surgery. Serum cytokine levels were measured in 23 patients at the time of appendicitis and after one month. CRP, WBC and percentage of neutrophils were analyzed in the total cohort of 325 patients. No differences in PBMC responses were found between patients and controls. Stronger IL-10 responses were found following complicated appendicitis. A trend towards lower IL-8 responses was shown following gangrenous appendicitis. Serum IL-10 and IL-6 were significantly elevated at presentation, and IL-6, IL-8 and TNF-α levels were higher in complicated appendicitis. Routine biomarkers could predict severity of appendicitis with high specificities, but low sensitivities. Cytokine responses in patients following acute appendicitis did not differ from healthy controls. Higher serum cytokine levels were found in acute complicated and gangrenous cases. Further research into discriminative biomarkers is warranted.

Effect of High Carbohydrate Diet on Complete Freund’s Adjuvant Induced Inflammation in Rats

Chronic low grade inflammation is an essential pathological feature of a variety of non-communicable diseases (NCDs). These diseases have now superseded infectious diseases where the burden of disease is concerned. One of the important modifiable factors contributing to chronic disease is food high in carbohydrate. This study was planned to study the role of high carbohydrate diet on a model of inflammation induced by Complete Freund’s adjuvant (CFA) in male Wistar rats. Animals were divided into 3 groups of 10 rats each. Group I fed with standard diet serving as control; Group II fed with high carbohydrate diet (HCD) and Group III fed with standard diet serving as disease free normal group. CFA was injected subcutaneously into the hind paw 4weeks after starting the diet into groups I and II only. Diet was continued for up to 21days after CFA injection. Digital plethysmometer measured the paw volume. Blood obtained before euthanasia served for estimating cytokines and oxidative stress parameters. A rise in paw edema was seen in control and high carbohydrate diet groups up to day 21. In the high carbohydrate group there were high serum cytokine levels and significant depletion of antioxidant enzymes. The authors conclude that, a high carbohydrate diet contributes significantly to the process of inflammation which has now been established as a significant factor in the causation of NCDs. Therefore it would be prudent to restrict carbohydrates in our diet.

Profiles of serum cytokines and their clinical implications in patients with peripheral T-cell lymphoma

To better predict the outcomes of patients with peripheral T-cell lymphoma (PTCL), we measured the levels of various cytokines in serum samples from patients with PTCL and analyzed their clinical outcomes. We measured 34 cytokines in samples from 121 PTCL patients (55 PTCL-not otherwise specified (NOS), 44 angioimmunoblastic T-cell lymphoma (AITL), and 22 ALK− anaplastic large cell lymphoma) at diagnosis. Their impact on clinical outcomes, including overall survival and complete response rate, were analyzed with other clinical variables. The median age of patients was 58 years (range, 20–85 years) and 81 patients (66.9%) were male. The median overall survival among all patients was 56.1 months (95% CI 21.4–90.8) and median progression-free survival was 19.3 months (95% CI 12.3–26.3). Patients with AITL were more likely to express higher levels of serum cytokines, and 7 cytokines showed mean levels that were significantly higher than those in other subtypes. In this subgroup, IL-10 higher than 3.8 pg/mL was associated with adverse outcomes. In patients with ALK− anaplastic large cell lymphoma, 9 cytokines showed a prognostic impact, with higher levels of interferon γ, interleukin (IL)-8, IL-10, IL-17, IL-23, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and RANTES negatively affecting clinical outcomes. In PTCL-NOS, patients with elevated levels of interferon γ, IL-7, and IL-23 showed poor outcomes. The current analysis demonstrated different cytokine profiles according to histologic subtype, which revealed the heterogeneity of PTCL. In addition, cytokine levels can be used as prognostic markers and may be useful for therapeutic applications in PTCL patients.

Corticosteroid therapy in IgA nephropathy with minimal proteinuria and high renal pathological score: A single‑center cohort study.

Currently, there is no clear evidence that advocates the widespread use of corticosteroids for the treatment of immunoglobulin A nephropathy (IgAN) with minimal proteinuria (<1g/day). The recent Kidney Disease: Improving Global Outcomes Clinical Practice Guideline recommends supportive corticosteroid treatment. In the present study, 45IgAN patients with high renal pathological scores and minimal proteinuria were enrolled. The patients were randomly divided into two groups. The treatment group received methylprednisolone tablets in addition to angiotensin‑converting‑enzyme inhibitor (ACE‑I) and/or angiotensin‑receptor blocker (ARB) treatment. The control group only received ACE‑I and/or ARB treatment. In the treatment group, a single dose of 1mg/kg (maximum 60mg/day) methylprednisolone tablets was given daily followed by gradually decreasing dosage. The follow‑up time of the patients was 3years. In addition, the underlying mechanisms were investigated. The results indicated that there was a significant reduction in the amount of urinary proteins in the treatment group compared with the control group. At the end of the follow‑up, the endpoint event rate of moderate or severe proteinuria and decrease in estimated glomerular filtration rate (eGFR) in the treatment group was significantly lower than the control group. Furthermore, higher levels of serum cytokines, interleukin (IL)‑4, IL‑17, transforming growth factor‑β1 and IL‑21, were detected in patients with IgAN compared with a group of healthy controls. There was no significant difference in IFN‑γ expression between the IgAN and healthy control groups. Furthermore, the expression of Janus kinase (Jak)1, Jak3, signal transducer and activator of transcription (STAT)3 and STAT6 was significantly upregulated in patients with IgAN compared with healthy controls. However, the expression levels of STAT5 and chaperone protein, C1GALT1 specific chaperone1, in IgAN patients were significantly reduced compared with healthy controls. In addition, there was no significant difference in the expression of Jak2, tyrosine kinase 2, STAT1 and STAT4 between the two groups. In conclusion, for IgAN patients with minimal proteinuria and high renal pathological score corticosteroid therapy is likely to be effective. The dysregulation of serum cytokine levels in these patients with IgAN may have a role in the pathogenesis and progression of disease, which is associated with the activation of the JAK/STAT signaling pathway.

Effect of melatonin on cytokine levels in a hyperthermia-induced febrile seizure model.

Higher serum cytokine levels have been reported in children admitted with febrile seizures and in some experimental models. However, other studies have shown that cytokine levels are influenced by melatonin. In this study, we investigated serum cytokine levels in a hyperthermia-induced febrile rat seizure model and the effect of melatonin. A total of 28 male Sprague-Dawley rats were divided into four groups: the control (C) group, healthy melatonin (MT) group, and hyperthermia-induced febrile seizure groups with (HIFS-MT) and without (HIFS) administration of melatonin. Melatonin (80 mg/kg) was given intraperitoneally 15 min before the seizure. HIFS was induced by placing the rats in 45°C water. The rats were sacrificed under anesthesia after the seizure. Blood samples were drawn by transcardiac puncture to measure serum cytokine and melatonin levels. Serum interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α levels were lower in the HIFS group than those in the C group (p = 0.005, p = 0.200, p = 0.011, and p = 0.016, respectively). All serum cytokine levels of rats in the MT and HIFS-MT groups were similar to those in the C group. This experimental rat model demonstrated that serum cytokine levels decrease with HIFS and that administering melatonin maintains serum cytokine levels. These results suggest that cytokines may play role in the anticonvulsive activity of melatonin in rats with febrile seizures.

Neurodevelopment of Preterm Infants at 24 Months After Neonatal Supplementation of a Prebiotic Mix: A Randomized Trial.

Fetal brain maturation is disrupted by preterm birth. Inflammation during the neonatal period may further harm neurodevelopmental outcomes. The present study aimed to determine the effect of short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides/pectin-derived acidic oligosaccharides (scGOS/lcFOS/pAOS) on neurodevelopmental outcomes measured by Bayley Scales of Infant and Toddler Development in preterm infants at 24 months. In this randomized controlled trial, scGOS/lcFOS/pAOS or placebo was supplemented between days 3 and 30 of life. Serum samples at day 1, 7, and 14 were analyzed for cytokine levels. Stool samples at day 1, 7, 14, and 30 were measured for bacterial count and bifidobacteria percentage. At 24 months corrected age infants were followed up by a blinded pediatric psychologist for the Bayley Scales of Infant and Toddler Development II or III. Seventy-seven of one hundred one (76%) eligible infants participated in the follow-up study. Neurodevelopmental outcomes were not different in the scGOS/lcFOS/pAOS and placebo group. Infections during the neonatal period, lower percentages of bifidobacteria at day 7 (F = 3.8, P = 0.05) and day 14 (F = 5.0, P = 0.02) and higher levels of Interleukine (IL)-1β (F = 4.0, P = 0.04) and IL-8 (F = 8.0, P = 0.01) at day 7 are associated with lower mental developmental index. Lower psychomotor outcomes are associated with IL-2 (F = 4.0, P = 0.05), IL-4 (F = 6.0, P = 0.02) at birth, and interferon gamma at day 7 (F = 4.4, P = 0.04). scGOS/lcFOS/pAOS showed no significant improvement of neurodevelopmental outcomes at 24 months in preterm infants. Infections, lower bifidobacteria counts, and higher serum cytokine levels during the neonatal period were associated with lower neurodevelopmental outcomes at 24 months of age indicating the relevance of microbiome and immune responses in neurodevelopmental processes.

Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases

BackgroundMany intervertebral disc diseases cause low back pain (LBP). Proinflammatory cytokines and matrix metalloproteinases (MMPs) participate in disc pathology. In this study, we examined levels of serum cytokines and MMPs in human subjects with diagnoses of disc herniation (DH), spinal stenosis (SS), or degenerative disc disease (DDD) relative to levels in control subjects. Comparison between subjects with DH and those with other diagnoses (Other Dx, grouped from SS and DDD) was performed to elaborate a pathological mechanism based on circulating cytokine levels.MethodsStudy participants were recruited from a spine neurosurgery practice (n = 80), a back pain management practice (n = 27), or a control cohort (n = 26). Serum samples were collected before treatment and were assayed by multiplex assays for levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ, tumor necrosis factor-α, MMP-1, MMP-3, and MMP-9. Inflammatory and degradative mediator levels were compared for subjects with LBP and control subjects, by diagnosis and by treatment groups, controlling for effects of sex, age, and reported history of osteoarthritis. Spearman’s correlation coefficient was used to examine relationships with age, body mass index (BMI), symptom duration, and smoking history.ResultsSerum levels of IL-6 were significantly higher in subjects with LBP compared with control subjects. Participants with LBP due to Other Dx had significantly higher levels of IL-6 than DH and controls. Serum levels of MMP-1 were significantly lower in LBP subjects, specifically those with DH, than in control subjects. Positive correlations were found between IL-6 levels and BMI, symptom duration, and age. MMP-1 levels were positively correlated with age.ConclusionsThe findings of the present clinical study are the results of the first examination of circulating cytokine levels in DDD and SS and provide evidence for a more extensive role of IL-6 in disc diseases, where patients with DDD or SS have higher serum cytokine levels than those with DH or control subjects. These findings suggest that LBP subjects have low-grade systemic inflammation, and biochemical profiling of circulating cytokines may assist in refining personalized diagnoses of disc diseases.

IBS-like Symptoms in Patients with Ulcerative Colitis in Deep Remission Are Associated with Increased Levels of Serum Cytokines and Poor Psychological Well-being.

Gastrointestinal symptoms (GI) compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in remission. The causes of these symptoms remain to be clarified. Our aim was to investigate prevalence and factors associated with IBS-like symptoms in patients with UC in deep remission. We included 298 patients with UC and used Mayo score, sigmoidoscopy, and fecal calprotectin to define deep remission versus active disease. Presence of IBS-like symptoms according to the Rome III criteria, severity of GI, extraintestinal and psychological symptoms, stress levels, and quality of life were measured with validated questionnaires. Serum cytokines and high-sensitive C-reactive peptide were determined. The criteria for deep remission was fulfilled by 132 patients (44%) and 24 of these fulfilled the Rome III criteria for IBS (18%). Patients with UC in deep remission with IBS-like symptoms had comparable levels of GI symptoms, non-GI somatic symptoms, and quality of life as patients with active UC. The patients with UC in deep remission with IBS-like symptoms had similar levels of fecal calprotectin as patients in deep remission without IBS-like symptoms (18 versus 31 μg/g, P = 0.11), but higher levels of serum cytokines (interleukin [IL]-1β, IL-6, IL-13, IL-10 and IL-8, P < 0.05) and higher levels of anxiety (P < 0.001), depression (P = 0.02) and perceived stress (P = 0.03). IBS-like symptoms in patients with UC in deep remission are common, but not as prevalent as previously reported. Poor psychological well-being and increased serum cytokine levels, but not colonic low-grade inflammation, were associated with IBS-like symptoms.

S86 The Inflammatory Response To Streptococcus Pneumoniae Is Exaggerated By The Polysaccharide Capsule

Streptococcus pneumoniae infections characteristically cause a high degree of inflammation. The S. pneumoniae polysaccharide capsule prevents opsonophagocytosis and is essential for virulence. The capsule might also be expected to reduce the host’s inflammatory response by inhibiting bacterial interactions with pro-inflammatory signalling proteins eg toll-like receptors (TLR), but this has not previously been investigated. Using isogenic unencapsulated strains and in vitro and in vivo models of infection we have characterised capsule effects on the inflammatory response to S. pneumoniae. Surprisingly, although the unencapsulated (Δ cps ) S. pneumoniae strain was much more sensitive to phagocytosis by macrophages and induced a stronger NFκB response by human monocyte derived macrophages (MDMs) it caused similar levels of stimulation of a TLR2 reporter cell line as the encapsulated strain TIGR4. In addition, microarrays demonstrated increased transcription of pro-inflammatory cytokines by MDMs in response to TIGR4 compared to the Δ cps strain, and quantitative PCR and ELISAs confirmed stronger TNF, IL1β, and IL6 responses by MDMs to TIGR4. Furthermore, compared to the Δ cps strain the TIGR4 strain caused greater neutrophil recruitment and higher cytokine levels in the lungs in a mouse model of pneumonia, as well as higher serum cytokine levels with worse hypotension in a rat model of sepsis. Additional in vitro experiments excluded antibody, complement, pneumolysin, the inflammasome, and lectin-mediated signalling as mechanisms driving differences in inflammatory responses between TIGR4 and Δ cps . Expression of the TIGR4 capsule in Streptococcus mitis did not increase MDM or murine inflammatory responses. Notably, preventing phagocytosis with cytochalasin D did not alter differences in the inflammatory response between TIGR4 and the Δ cps strains, and in silico analysis suggested the Δ cps strain activated a wider range of transcription factors. Overall, the data indicate that unencapsulated S. pneumoniae stimulate a wider range of host cell signalling pathways than encapsulated bacteria, some of which are likely to be anti-inflammatory. Hence the capsule, rather than reducing inflammation, causes increased pro-inflammatory responses and subsequent disturbances to host physiology during S. pneumoniae infection. Targeting the mechanisms responsible for capsule-dependent inflammation could offer novel treatment options for reducing the morbidity and mortality associated with S. pneumoniae infections.

Altered L-type Ca2+ channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice.

We determined the contribution of vascular large conductance Ca2+-activated K+ (BK) and L-type Ca2+ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-KO mice that were either untreated, given volume resuscitation (saline), or saline + calcium channel blocker nicardipine. Some mice were euthanized 24 h post-CLP to measure tissue injury and vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK β1-KO mice, but BK β1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK β1-KO mice. Saline + nicardipine-treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK β1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 h post-CLP, BK and L-type Ca2+ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK β1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.

Metabolic and Inflammatory Responses after ERCP

Background: We aim to evaluate the metabolic and inflammatory responses after ERCP procedure in patients who have common bile duct stones. Methods: Between September 2009 and October 2010, we studied prospectively 50 patients who diagnosed with common bile duct stones. Our study was included patients who had previously been suspected with common biliary duct stone via radiological and biochemical examinations. We investigated parameters of pro-inflammatory cytokines (IL-1β, IL-6, Il-8, IL-12, IFN-γ, TNF-α), anti inflammatory cytokines (IL-4, IL-10, IL-13), stress hormones (ACTH, cortisol, growth hormone, aldosterone) and acute phase reactant (CRP). All venous blood samples were taken firstly 1hr before endoscopic intervention as a control. After ERCP procedure, venous blood samples were taken two more times, the first in 1hr, the second in 24 hours. Results: We performed ERCP successfully to 50 patients due to common bile duct stones. All of them had higher serum cytokine levels (p&lt;0.01) after an hour and 24 hours later ERCP than before endoscopic intervention except IL-13 level. A significant increase (p&lt;0,01) was found in ACTH, cortisol, GH and aldosterone levels 1 hour and 24 hours after ERCP, except GH level (p&gt;0.05). CRP level was significiantly increased 1 hour and 24 hours after ERCP. Conclusion: ERCP procedure is a kind of invasive attempt as known, also causes, with its effects, systemically inflammatory response in the body. This response, mostly not staying at the local stage, becomes systemic inflammatory response. Therefore, before ERCP is performed, the applications of other non-invasive methods of diagnosis are strongly advised

A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results.

5016 Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ≤12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P&lt;.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.