Higher Concentrations Of IL-1β Research Articles

Correlation of Serum IL-1β Level in Rheumatoid Arthritis Patients with Disease Severity Parameters

Rheumatoid arthritis (RA) is a systemic inflammatory, chronic disorder, characterized by prolonged inflammation of the synovial joints, with ultimate destruction of joints, high concentrations of IL-1β in the synovial fluid and serum RA patients correlated with RA incidence. This study was conducted to compare IL-1β concentration in serum from patients with RA and healthy controls with the correlation parameter being related to markers indicating disease severity. A case-control study enrolled 71 patients with RA and 46 healthy controls from an Iraqi Arab population. In the present study, the level of serum IL-1β was detected using a quantitative sandwich enzyme immunoassay method of Enzyme-Linked Immunosorbent Assay (ELISA). This study found a correlation between the serum level of IL-1β and DAS28-CRP severity among RA patients (p=0.065). Furthermore, the serum level of IL-1β was significantly increased in RA patients compared to the level noted in the healthy group (p=0.039). Moreover, the results demonstrated a very weak correlation between the IL-1β level with CRP, ESR, and ACCP (r=0.079, r=0.059, r=0.080), respectively. In conclusion, the current study showed a correlation between the serum level of IL-1β and RA disease severity (DAS28) among the Iraqi Arab population, additionally, the study noted a very weak correlation between the IL-1β level with CRP, ESR, and ACCP.

The Impact of Cytokines on Health-Related Quality of Life in Adolescents with Allergic Rhinitis.

Frequent episodes of nasal symptoms are the usual clinical manifestations (CM) of allergic rhinitis (AR) and have a significant negative impact on health-related quality of life (HRQoL) in adolescents. The purpose of this cross-sectional study was to test the hypothesis that cytokines in nasal mucus may be associated with HRQoL in adolescents with AR. European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L), "The Adolescent Rhinoconjunctivitis Quality of Life Questionnaire" (AdolRQLQ) and the Total 4 Symptom Score (T4SS) scoring system were administered to 113 adolescents with AR, nonallergic rhinitis (NAR) and to healthy control subjects. Nasal secretions were sampled and tested for 13 cytokines using a multiplex flow cytometric bead assay. The AR group had significantly lower EQ-5D-3L (0.661 ± 0.267 vs. 0.943 ± 0.088; p < 0.001) and higher AdolRQLQ total scores (2.76 ± 1.01 vs. 1.02 ± 0.10; p < 0.001) compared to the control group. The AR group had higher concentrations of IL-1β (p = 0.002), IL-6 (p = 0.031), IL-8 (p < 0.001), IL17-A (p = 0.013) and IL-18 (p = 0.014) compared to the control group, and IL-1β, IL-6, IL17-A and IL-18 were significantly (p < 0.050) increased with disease progression. Cytokines IL-1β, IL-6, as well as severe CM, were identified as significant predictors of lower HRQoL in adolescents with AR. This study identified IL-1β, IL-6, as well as severe CM, as predictors of lower HRQoL in adolescents with AR. However, these results should only serve as a starting point for additional confirmation research.

IL-1β and iNOS can drive the asthmatic comorbidities and decrease of lung function in perennial allergic rhinitis children.

Allergic asthma and rhinitis (AR) are closely linked, with a significant proportion of AR patients developing asthma. Identification of the early signs of comorbidity of AR and asthma can enable prompt treatment and prevent asthma progression. This study investigated the role of interleukin-1β (IL-1β), a pro-inflammatory cytokine, and inducible nitric oxide synthase (iNOS) in the comorbidity of AR and asthma and lung function in Korean children with perennial AR (PAR). A cohort of 240 subjects (6 to 10 years old) with PAR (PAR alone: 113 children, PAR and asthma: 127 children) was analyzed for various biomarkers, including IL-1β, iNOS, and epithelial-mesenchymal transition (EMT) markers in serum. The blood levels of eosinophils and immunoglobulin E (IgE) were examined. IL-1β, CCL-24, E-cadherin, and vimentin were measured by enzyme-linked immunosorbent assay (ELISA). Epithelial iNOS was measured by the NOS kit. Elevated levels of IL-1β, iNOS, and vimentin in the serum were identified as significant indicators of the likelihood of comorbidity of PAR and asthma in children. Furthermore, higher concentrations of IL-1β, iNOS, and vimentin have been linked to reduced lung function in PAR children. Notably, IL-1β expression shows a relationship with the levels of E-cadherin, vimentin, and CCL-24. However, no correlation was found between IL-1β and iNOS expressions. This study suggests that IL-1β and iNOS can be biomarkers in the progression of PAR and asthma and decreased lung function, suggesting potential targets for early intervention and treatment.

IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion.

The IL-1 Family member IL-38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38-deficient mice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, and Olfm4) expression compared with wild-type organoids. The IL-38 binding to IL-1R6 and IL-1R9 is still a matter of debate. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9-deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild-type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL-1β have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an antiinflammatory molecule in the SI, maintaining homeostasis.

Comparative analysis of tear cytokines in patients with glaucoma, ocular hypertension, and healthy controls

PurposeTo investigate the ocular surface inflammation in patients with primary open angle glaucoma and ocular hypertension by analyzing tears and to compare findings with healthy controls.MethodsObservational case–control study. Tear samples were collected by 5 µl microcapillary tube from 24 patients with glaucoma treated by antiglaucoma drops, 9 non-treated patients with ocular hypertension and 45 healthy controls. Tears were analyzed from right eye by multiplex Bio-Plex system for the presence of 6 cytokines: IL1β, IL10, IL4, IFNγ, MIF and VEGF.ResultsSignificantly higher concentrations of IL1β and IL10 (glaucoma or ocular hypertension vs. healthy controls, p < 0.0001), VEGF (glaucoma vs. ocular hypertension, p < 0.05; ocular hypertension vs. healthy controls, p < 0.02) and MIF (glaucoma vs. healthy controls, p < 0.03) were detected in patients’ tears. Both patient groups have activated to a significantly lower extent the Th1 pathway represented by IFNγ than Th2 pathway represented by IL10 (p < 0.001) and, at the same time, the IFNγ/IL4 ratio was significantly increased in healthy controls (p < 0.001) and patients with ocular hypertension (p < 0.02) compared to glaucoma individuals.ConclusionThis study shows that secretion of inflammation-related cytokines by conjunctival cells is increased in both, glaucoma and ocular hypertension patients and can be detected in their tears. Nevertheless, data indicates stronger ocular surface inflammation in non-treated follow-up patients diagnosed with ocular hypertension than in glaucoma subjects treated by antiglaucoma drops.

Acacetin alleviates neuroinflammation and oxidative stress injury via the Nrf2/HO-1 pathway in a mouse model of spinal cord injury.

Spinal cord injury (SCI) is a severe central nervous system disease, which may cause serious locomotor deficit. Acacetin is a flavone that possesses antioxidant and anti-inflammatory effects in different human diseases. The main purpose of this study was to explore whether acacetin ameliorates SCI in mice. A model of SCI was established in C57BL/6 mice. The Basso Mouse Scale (BMS) score, BMS subscore, mechanical hypersensitivity, and thermal hypersensitivity of mice were tested for determining the motor function. Immunofluorescence staining was utilized to detect NeuN, GFAP, and Iba-1 levels in spinal cord tissues. ELISA was utilized to assess the contents of proinflammatory factors such as interleukin (IL)-1β, IL-18, and tumor necrosis factor-alpha (TNF-α) in spinal cord tissues. The levels of oxidative stress markers, reactive oxygen species, thiobarbituric acid-reactive substances, superoxide dismutase, catalase, glutathione peroxidase, and glutathione were detected using their corresponding kits. Western blot was employed for estimating the levels of heme oxygenase 1 (HO-1), nuclear factor E2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap-1). In this study, acacetin treatment recovered the motor function in SCI mice. Acacetin improved neuron integrity and repressed glial cell activation in the spinal cord tissues of SCI mice. Furthermore, acacetin administration reduced the SCI-induced high concentrations of IL-1β, IL-18, and TNF-α, as well as inhibited oxidative stress in SCI mice. Moreover, acacetin activated HO-1/Nrf2 pathway in SCI mice. The neuroprotective effects of acacetin against SCI were reversed by Nrf2 inhibitor. Overall, acacetin alleviated neuroinflammation and oxidative stress injury by activating the Nrf2/HO-1 signaling pathway in the mouse models of SCI.

Fractional anisotropy and peripheral cytokine concentrations in outpatients with depressive episode: a diffusion tensor imaging observational study

Over the past few years, evidence of a positive relationship between inflammation and depression has grown steadily. The aim of the current study was to investigate whether such depression-related inflammation could also be associated with altered microstructural changes in the white matter. FA and serum cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) were measured in 25 patients with depression (DE) and 24 healthy controls (HC). Diffusion tensor imaging was performed. Fractional anisotropy (FA) was calculated using the FSL pipeline for Tract-Based Spatial Statistics (TBSS). Both voxelwise and mean whole-brain FA were analyzed using general linear models (GLM). Higher concentrations of IL-1β were associated with lower whole-brain fractional anisotropy, particularly in people with depression (ρ = − 0.67; p < 0.001). TNF-α shared some variance with IL-1β and also showed a negative relationship between TNF-α concentrations and FA in depression (F1,46 = 11.13, p = 0.002, η2p = 0.21). In detail, the voxelwise analysis showed that the regression slopes of IL-1β on FA were more negative in the DE group than in the HC group, mainly in the corpus callosum (cluster statistics: genu corpus callosum, p = 0.022; splenium of corpus callosum, p = 0.047). Similar effects were not found for the other remaining cytokines. This study clearly demonstrated an association between peripherally measured IL-1β and white matter integrity in depression as assessed by DTI. The results suggest that microstructural changes in the corpus callosum are associated with increased peripheral IL-1β concentrations in depression.

Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis through IL-1β Inhibition.

Neuropeptide Y (NPY), a 36 amino acid residue polypeptide distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1β concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1β concentrations in the lungs. Moreover, IL-1β neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1β release, and Y1 receptor antagonists inhibited IL-1β release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1β concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays aprotective role against pulmonary fibrosis by suppressing IL-1β release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.

Neuroendocrine, inflammatory, and extracellular vesicle responses during the Navy Special Warfare Screener Selection Course.

Military operational stress is known to increase adrenal hormones and inflammatory cytokines, while decreasing hormones associated with the anabolic milieu and neuroendocrine system. Less is known about the role of extracellular vesicles (EVs), a form of cell-to-cell communication, in military operational stress and their relationship to circulating hormones. The purpose of this study was to characterize the neuroendocrine, cytokine, and EV response to an intense. 24-h selection course known as the Naval Special Warfare (NSW) Screener and identify associations between EVs and cytokines. Blood samples were collected the morning of and following the NSW Screener in 29 men (18-26 yr). Samples were analyzed for concentrations of cortisol, insulin-like growth factor I (IGF-I), neuropeptide-Y (NPY), brain-derived neurotrophic factor (BDNF), α-klotho, tumor necrosis factor-α (TNFα), and interleukins (IL) -1β, -6, and -10. EVs stained with markers associated with exosomes (CD63), microvesicles (VAMP3), and apoptotic bodies (THSD1) were characterized using imaging flow cytometry and vesicle flow cytometry. The selection event induced significant changes in circulating BDNF (-43.2%), IGF-I (-24.6%), TNFα (+17.7%), and IL-6 (+13.6%) accompanied by increases in intensities of THSD1+ and VAMP3+ EVs (all P < 0.05). Higher concentrations of IL-1β and IL-10 were positively associated with THSD1+ EVs (P < 0.05). Military operational stress altered the EV profile. Surface markers associated with apoptotic bodies were positively correlated with an inflammatory response. Future studies should consider a multiomics assessment of EV cargo to discern canonical pathways that may be mediated by EVs during military stress.

Generation and functional characterization of recombinant Porphyromonas gingivalis W83 FimA

Porphyromonas gingivalis (P. gingivalis) is regarded as a keystone pathogen in destructive periodontal diseases. It expresses a variety of virulence factors, amongst them fimbriae that are involved in colonization, invasion, establishment and persistence of the bacteria inside the host cells. The fimbriae also were demonstrated to affect the host immune-response mechanisms. The major fimbriae are able to bind specifically to different host cells, amongst them peripheral blood monocytes. The interaction of these cells with fimbriae induces release of cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α). The aim of this study was to generate recombinant major FimA protein from P. gingivalis W83 fimbriae and to prove its biological activity. FimA of P. gingivalis W83 was amplified from chromosomal DNA, cloned in a vector and transferred into Listeria innocua. (L. innocua).The expressed protein was harvested and purified using FPLC via a His trap HP column. The identity and purity was demonstrated by gel-electrophoresis and mass-spectrometry. The biological activity was assessed by stimulation of human oral epithelial cells and peripheral blood monocytes with the protein and afterwards cytokines in the supernatants were quantified by enzyme linked immunosorbent assay (ELISA) and cytometric bead array. Recombinant FimA could successfully be generated and purified. Gel-electrophoresis and mass-spectrometry confirmed that the detected sequences are identical with FimA. Stimulation of human monocytes induced the release of high concentrations of IL-1β, IL-6, IL-10 and TNF-α by these cells. In conclusion, a recombinant FimA protein was established and its biological activity was proven. This protein may serve as a promising agent for further investigation of its role in periodontitis and possible new therapeutic approaches.

Exosomes from high glucose-treated macrophages activate macrophages and induce inflammatory responses via NF-κB signaling pathway in vitro and in vivo

There is increasing evidence that macrophages play an important role in the development and pathogenesis of diabetic nephropathy (DN) by secreting inflammatory cytokines. Exosomes are a family of extracellular vesicles that are secreted from almost all types of cells and associated with cell-to-cell communications. In this article, we try to investigate whether high glucose (HG)-treated macrophages-derived exosomes could activate macrophages and induce inflammatory responses in vivo and in vitro. We incubated the exosomes from high glucose-treated Raw264.7 cells (HG-Exo) and Raw264.7 cells for 24 h. The expression levels of related inflammatory molecules and NF-κB p65 signaling pathway were identified, as well as the intracellular localization of NF-κB p65 was detected. In vivo, HG-Exo was injected into mice via tail vein and the related parameters of kidneys were detected. Compared with the exosomes from normal glucose-treated Raw264.7 cells (NG-Exo), HG-Exo contained higher concentrations of IL-1β and iNOS. HG-Exo-treated Raw264.7 cells secreted higher level of related inflammatory molecules and promoted NF-κB p65 signaling pathway expression. HG-Exo induced the production of intracellular iNOS and α-SMA. In the HG-Exo group, NF-κB p65 positive signals were mainly distributed in the nucleus area. HG-Exo treated mice kidneys displayed a significantly mesangial expansion and proliferation. NF-κB p65 protein expression levels in mice renal tissue treated with HG-Exo was significantly up-regulated. These findings suggest that high glucose treated macrophages-derived exosomes may activate macrophages and accelerate kidney injury via NF-κB p65 signaling pathway.

The effects of long-term opioid treatment on the immune system in chronic non-cancer pain patients: A systematic review.

Opioids have been increasingly prescribed for chronic non-cancer pain (CNCP). An association between long-term opioid treatment (L-TOT) of CNCP patients and suppression of both the innate and the adaptive immune system has been proposed. This systematic review aims at investigating the effects of L-TOT on the immune system in CNCP patients. A systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and the CINAHL for relevant articles was performed. Studies examining measures of both the innate and the adaptive immune system in adult CNCP patients in L-TOT (≥4weeks of intake) were included. Outcomes and the level of evidence were analysed. A total of 382 studies were identified; however, 376 were excluded (352 inappropriate methodology, 21 duplicates, three full-text could not be obtained) and one randomized controlled trial (RCT) and five cross-sectional studies were included and analysed. L-TOT compared with no treatment was associated with a lower percentage of natural killer (NK) cells, a lower absolute number of CD56bright NK cells, a higher absolute number of IL-2-activated NK cells and a higher concentration of IL-1β as a response to toll-like receptor (TLR) agonists stimulation (Pam3CSK4, LPS, Imiquimod). No other significant differences were reported. Generalizability of the results was limited due to inconsistency of outcomes and an overall low quality of the studies. L-TOT may alter the immune system in CNCP patients, but the level of evidence is still weak. More studies are needed to clarify the impact of L-TOT on immune system function. This systematic review found indication that long-term opioid treatment alters the immune system in chronic non-cancer pain patients. These alterations involved the NK cells and IL-1β production. However, the level of evidence is weak.

5220Maternal high-fat diet exaggerates the development of diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented gasdermin D-mediated pore formation

Abstract Background Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear. Approach and results Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating, and received during pregnancy and lactation. Eight-week-old male offspring of both groups were fed a HFD for 8 weeks. Offspring of HFD-fed dams (O-HFD) showed significantly enhanced IR compared with offspring of ND-fed dams (O-ND). There was no difference in body weight, epidydimal white adipose tissue (eWAT) weight, and cumulative caloric intake between the 2 groups. However, eWAT adipocyte size was significantly increased in O-HFD, accompanied by the abundant crown-like structures. Flow cytometric analysis revealed an increased percentage of M1, but not M2, macrophages. Serum and eWAT concentrations of IL-1β, but not TNF-α, were significantly higher in O-HFD than O-ND (3.7-fold and 2.0-fold, respectively, P&lt;0.05). Treatment with NLRP3 inflammasome inhibitor MCC950 completely abrogated the enhanced IR in O-HFD to a similar extent of that in O-ND, although IR was modestly, but not significantly, ameliorated in O-ND even after MCC950 treatment. Consistent with in vivo findings, in vitro polarization of bone marrow-derived macrophages (BMDMs) did not show any difference in TNF-α mRNA expression after conventional stimulation. In contrast, palmitate acid (PA)-mediated metabolic activation of BMDMs following LPS priming showed a significantly higher concentration of IL-1β in culture supernatants from O-HFD (45%, P&lt;0.05). However, protein expression levels of NLRP-3, ASC, and procaspase-1 after LPS priming were equivalent between the 2 groups. Consistently, intracellular flow cytometric analysis of caspase-1 activity after PA activation did not show any difference, which was compatible with the finding that ex vivo caspase-1 activity of eWAT assessed by fluorescent image of IVIS revealed no difference between the 2 groups. To further examine the mechanism of augmented IL-1β release in BMDM of O-HFD, we examined the cleavage of caspase substrate gasdermin D (GSDMD) and subsequent pore formation. Protein and gene expression levels of GSDM-D after LPS priming were significantly higher in O-HFD (50% and 381%, respectively, P&lt;0.05). At 2 hrs after PA stimulation following LPS priming, cleaved GSDM-D was significantly increased in O-HFD (80%, P&lt;0.01). Consistently, percentage of pore formation assessed by ethidium bromide staining was significantly higher in O-HFD (60%, P&lt;0.05), while LDH release could not be observed. Conclusions Our findings demonstrate that maternal HFD exaggerates diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented GSDM-D-mediated pore formation.

Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response.

It is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5–90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (P = 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (P = 0.002 and 0.0005, respectively), but higher concentration of IL-1β (P = 5.1 × 10−5) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage [P = 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68–11.13]. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent Mtb. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage.

Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants.

Club cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. To evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. A study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24 h from birth. CC16 in gastric fluid increased with gestational age (P = 0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1β (P = 0.028), TNF-α (P = 0.034), and MMP-9 (P = 0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72 h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P = 0.011 and P = 0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO2 at 6 h (P = 0.009), higher PaCO2 at 24 h (P = 0.03), more ventilator days (P = 0.012) and more days with supplemental oxygen (P = 0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P = 0.049). A low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24 h of life and with more need for respiratory support in the neonatal period.

Neuroprotective effects and underlying mechanism of preconditioning with MK-801 in cerebral ischemia/reperfusion injury in rats induced by cardiac arrest-cardiopulmonary resuscitation

Objective To explore effects of dizocilpine (MK-801) preconditioning on excitatory amino acids and inflammatory response in rats induced by cardiac arrest-cardiopulmonary resuscitation (CA-CPR). Methods 18 male Sprague Dawley (SD) rats were randomly divided into three groups: control group, CA group and CA+ MK-801 group. To establish rat models of CA-CPR and keep samples of serum and specimens of brain tissues for following detection. The injury of neurons was observed by HE staining and expression of N-methyl-D-aspartic acid receptor (NMDAR) in brain tissues was detected by Western blot. The concentrations of interleukin 1 beta (IL-1β) and tumor necrosis factor (TNF)-α in serum were detected by enzyme linked immunosorbent assay (ELISA). Results Neurons in CA group were disorganized, cells shrank, nuclei pyknosis, and cytoplasmic eosinophilia, accompanied by inflammatory cell infiltration. Preconditioning with MK-801 reduced the pathological damage of neuron and degree of macrophage infiltration. The relative expression of NMDAR protein in CA group were significantly higher than that in control group (907.9±24.9 vs 321.6±18.4, P<0.001). Preconditioning with MK-801 significantly decreased the expression of NMDAR in CA+ MK-801 group compared with that in CA group (512.4±21.1 vs 907.9±24.9). The CA group showed significantly increased concentrations of IL-1β and TNF-α than that in control group (P<0.001), and this effect was abolished by preconditioning with MK-801. CA rats treated with MK-801 showed higher concentrations of IL-1β and TNF-α than the control group. Conclusions Cardiac arrest causes pathological injury of neurons, up-regulates expression of NMDAR and aggravates inflammatory response. These results induce the apoptosis of nerve cells. Blocking glutamate receptor with MK-801 can inhibit expression of NMDAR, decrease level of cytokines, down-regulate inflammatory reaction degree therefore to protect the brain. Key words: Dizocilpine maleate/AD; Ischemic preconditioning; Brain ischemia; Reperfusion injury/DT; Receptors, glutamate/ME; Interleukin-1beta/ME; Tumor necrosis factor-alpha/ME; Rats

Cytokine Response, Tract-Specific Fractional Anisotropy, and Brain Morphometry in Post-Stroke Cognitive Impairment

Post-stroke cognitive impairment is a clinically heterogeneous condition and its types have a different course and prognosis. The aim of the present study is to address the roles of inflammation, white matter pathology, and brain atrophy in different neuropsychological types of cognitive impairment in the acute period of ischemic stroke. In 92 patients, we performed an assessment of the cognitive status and measured concentrations of cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha, IL-10) in liquor and serum, as well as a number of magnetic resonance imaging (MRI) morphometric parameters and fractional anisotropy. The control group consisted of 14 individuals without cerebrovascular disease. All patients had a higher level of IL-10 in serum than the control group. Patients with dysexecutive cognitive impairment had a higher concentration of IL-1β and IL-10 in liquor, IL-6 level in serum, and a lower fractional anisotropy of the ipsilateral thalamus than patients with normal cognition. Patients with mixed cognitive impairment were characterized by a lower fractional anisotropy of contralateral fronto-occipital fasciculus, compared with patients with dysexecutive cognitive impairment. Patients with both dysexecutive and mixed cognitive deficit had a wide area of leukoaraiosis and a reduced fractional anisotropy of the contralateral cingulum, compared with patients without cognitive impairment. Also, we found numerous correlations between cognitive status and levels of cytokines, MRI morphometric parameters, and fractional anisotropy of certain regions of the brain. The concentrations of cytokines in serum and cerebrospinal fluid studied in combination with MRI morphometric parameters and fractional anisotropy appear to be informative biomarkers of clinical types of post-stroke cognitive impairment.

Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1β.

Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1β signature, the contribution of the IL-1β pathway to host defence is not clear.This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway.Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1β, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells.Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.

Inflammatory responses to acute elevations of carbon dioxide in mice.

Health risks are described from elevated indoor air carbon dioxide (CO2), which often ranges from 1,000 to 4,000 ppm, but the mechanisms are unknown. Here, we demonstrate that mice exposed for 2 h to 2,000 or 4,000 ppm CO2 exhibit, respectively, 3.4 ± 0.9-fold (SE, n = 6) and 4.1 ± 0.7-fold (n = 10) elevations in circulating microparticles (MPs); neutrophil and platelet activation, and vascular leak in brain, muscle, and distal colon. Interleukin (IL)-1β content of MPs also increases after 2,000 ppm by 3.8 ± 0.6-fold (n = 6) and after 4,000 ppm CO2 by 9.3 ± 1.1-fold (n = 10) greater than control. CO2-induced vascular damage is abrogated by treating mice with an antibody to IL-1β or an IL-1β receptor inhibitor. Injecting naïve mice with CO2-induced MPs expressing a protein found on mature neutrophils recapitulates vascular damage as seen with elevated CO2, and destruction of MPs in CO2-exposed mice abrogates vascular injuries without altering neutrophil or platelet activation. We conclude that environmentally relevant elevations of CO2 trigger neutrophils to generate MPs containing high concentrations of IL-1β that cause diffuse inflammatory vascular injury.NEW & NOTEWORTHY Elevated levels of CO2 are often found in indoor air and cause adverse health effects, but the mechanisms have not been identified. In a murine model, environmentally relevant levels of CO2 were found to cause diffuse vascular damage because neutrophils are stimulated to produce microparticles that contain high concentrations of interleukin-1β.

Peroxynitrite Activates the NLRP3 Inflammasome Cascade in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.

Neuroinflammation, characterized by the appearance of reactive microglial and astroglial cells, is one of the several pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a fast-progressing and fatal neurodegenerative disease. Cerebrospinal fluid and spinal cord of ALS patients and SOD1 mutant mice show high concentrations of IL-1β. This interleukin, expressed as an inactive precursor, undergoes a proteolytic maturation by caspase1, whose activation, in turn, depends on inflammasomes. Whether and how inflammasome is activated in ALS models is still to be clarified. The mechanism of inflammasome activation was studied in murine microglial cells overexpressing hSOD1(G93A) and verified in the spinal cord of hSOD1(G93A) mice. Murine microglial hSOD1(G93A) cells express all the inflammasome components and LPS activates caspase1 leading to an increase in the secretion of IL-1β. By activating NF-κB, LPS increases ROS and NO levels that spontaneously react to form peroxynitrite, thus leading to protein nitration. Reduction in peroxynitrite levels results in a decrease in caspase1 activity. Protein nitration and caspase1 activity are concomitantly increased in the spinal cord of pre-symptomatic SOD1(G93A) mice. Oxidative/nitrosative stress induces peroxynitrite formation that may be a key trigger of caspase1/inflammasome activation. Peroxynitrite formation may play a critical role in inflammasome activation and might be exploited as potential therapeutic target for ALS.