interleukin-8 and Central-Nervous-System-Diseases

Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.

Topics: Animals; Blood-Brain Barrier; Central Nervous System; Central Nervous System Diseases; Chemokine CCL2; Chemokines; Humans; Interleukin-8; Macrophages; Mice; Neuroprotective Agents; Receptors, CCR2; Receptors, Interleukin-8B; Signal Transduction; Synaptic Transmission

The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses.. C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis.. Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed.. The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

Topics: Adolescent; Biomarkers; Blood Cell Count; Central Nervous System Diseases; Chemokine CCL2; Chemokine CXCL10; Chemokine CXCL13; Chemokines; Child; Child, Preschool; Female; Humans; Interleukin-6; Interleukin-8; Male; ROC Curve

To investigate the cytokine profile in serum and cerebrospinal fluid (CSF) from patients with systemic lupus erythematosus (SLE) and central nervous system infection, we measured interferon-g (IFN-g), interleukin-1b (IL-1b), IL-4, IL-6, IL-8, IL-10, and IL-17 levels in serum and CSF from 50 SLE patients and 38 matched controls. In patients with active compared to quiescent disease, serum levels were higher for IL-1b (P = 0.042) and IL-17 (P = 0.041) but we found no significant correlation between IL-1b and IL-17 and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (r = 0.055, r = 0.219, respectively). IL-10 level in active patients was lower compared to that in quiescent controls (P = 0.032). When comparing specific disease manifestations, IL-1b levels in patients with fever (P = 0.035) and IL-6 (P = 0.048) and IL-8 (P = 0.048) levels in those showing nervous system involvement were higher than in controls. Based on MRI results, we found that only increased cerebral ischemia was associated with increased IFN-g levels (P = 0.009). In neuropsychiatric lupus erythematous patients, CSF levels of IL-6 (P = 0.002), IL-8 (P = 0.009), and IL-17 (P = 0.034) were significantly higher when compared with control patients. IL-10:IL-1b ratio in patients with moderate and quiescent disease was higher than in patients with disease activity (P = 0.000). Pro-inflammatory adaptive cytokines were elevated during disease flare, while regulatory mediators were elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may be targets for novel immunotherapeutic agents for managing autoimmune diseases.

Topics: Aged; Central Nervous System Diseases; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged

Aspiration lung disease (ALD) is a common cause of respiratory morbidity in children and adults with severe neurodisability (sND). Recent studies suggest that chronic microaspiration of gastric contents is associated with mild rather than low, airway acidification. We investigated inflammatory responses to infection by airway epithelial cells (AECs) exposed to weakly acidic media.. Using pH measurements from children with sND at high risk of ALD as a guide, we incubated AECs in weakly acidic (pH5.5-7.4) media alone; in combination with lipopolysaccharide (LPS); or prior to LPS stimulation at normal pH. Interleukin (IL) -6 and IL-8 expression were measured.. IL-6/8 expression in AECs simultaneously exposed to weakly acidic media and LPS for 4 h was reduced with no effect on cell viability. Pre-incubation of AECs at weakly acidic pH also reduced subsequent LPS-induced cytokine expression. Suppression of inflammation was greatest at lower pHs (pH 5.5-6.0) for prolonged periods (16/24 h), but this also adversely affected cell viability.. AEC inflammatory responses to bacterial stimuli is markedly reduced in a mildly acidic environment.

Topics: Cell Line; Cell Survival; Central Nervous System Diseases; Down-Regulation; Epithelial Cells; Humans; Hydrogen-Ion Concentration; Inflammation Mediators; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Respiratory Aspiration of Gastric Contents; Time Factors

Neurological manifestations of Behçet's disease (neuro-Behçet's disease) present in 5-30% of patients. Although cytokines play a pivotal role in pathogenesis of Behçet's disease, published studies about the cerebrospinal fluid (CSF) levels of cytokines in neuro-Behçet's disease are scanty.. Nine patients with active parenchymal, one patient with non-parenchymal neuro-Behçet's disease, six patients with headache attributed to Behçet's disease, 13 patients with viral meningitis, and 19 healthy controls were recruited. Interleukin 6, 8, 10, tumor necrotic factor-alpha, and interferon-gamma were measured in the CSF using enzyme-linked immunosorbent assay method.. Patients with viral meningitis had significantly higher levels of all investigated cytokines except for interferon-gamma in comparison with the patients with parenchymal neuro-Behçet's disease, headache attributed to Behçet's disease and controls (P values <0.05). CSF interleukin 6 was significantly higher in patients with parenchymal neuro-Behçet's disease in comparison with the controls (P=0.025). CSF levels of investigated cytokines had no significant difference between patients with headache attributed to Behçet's disease and controls (P values >0.05). Patients with headache attributed to BD and patients with parenchymal NBD had no significant difference in measured cytokines (P values >0.05).. In contrast to some previous studies, our investigation showed loss of analogy between CSF cytokine profiles of patients with parenchymal neuro-Behçet's disease and viral meningitis. Also we postulated a crucial role for interleukin 6 in immunopathogenesis of neuro-Behçet's disease.

Topics: Adult; Behcet Syndrome; Case-Control Studies; Central Nervous System Diseases; Cytokines; Female; Headache; Humans; Interferon-gamma; Interleukin-10; Interleukin-6; Interleukin-8; Male; Meningitis, Viral; Reference Values; Statistics, Nonparametric; Tumor Necrosis Factor-alpha; Young Adult

We investigated cerebrospinal fluid (CSF) samples from patients with Creutzfeldt-Jakob disease (CJD) and other neurological diseases. Concentrations of pro- and anti-inflammatory cytokines IL-1beta, IL-6, IL-8, IL-12, TNF-alpha and TGF-beta 2 were determined in CSF using ELISA. Significant changes were found for IL-8 and TGF-beta 2. IL-8 levels were elevated in the CSF of CJD patients. Of interest, the increase was significant to other dementia and to controls. In contrast, TGF-beta 2 was significantly decreased in CSF of CJD compared to all groups. IL-1beta, IL-12 and TNF-alpha could not be detected in CSF or in case of IL-6 in only low concentrations without significant difference.

Topics: Adolescent; Adult; Aged; Central Nervous System Diseases; Creutzfeldt-Jakob Syndrome; Dementia; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Sensitivity and Specificity; Statistics, Nonparametric; Transforming Growth Factor beta

Topics: Case-Control Studies; Central Nervous System Diseases; Chemokine CCL17; Chemokine CXCL10; Chemokines, CC; Chemokines, CXC; Humans; Interferon-alpha; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Osmolar Concentration

Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain; Central Nervous System Diseases; Cerebrospinal Fluid Proteins; Enzyme Induction; Female; Glial Fibrillary Acidic Protein; Humans; Interleukin-6; Interleukin-8; Leukocytosis; Lupus Erythematosus, Systemic; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Meningitis, Aseptic; Middle Aged; Myelitis, Transverse; Nerve Tissue Proteins; Psychotic Disorders; Seizures; tau Proteins

The serum levels of several cytokines were determined in 94 patients with Adamantiades-Behçet's disease (ABD), aged 36.1+/-11.0 years, during the active stage (n = 75) and the inactive stage (n = 19) of the disease. A group of 75 healthy individuals matched for age and sex served as controls. Cytokine levels were determined using commercially available ELISA kits. Of the 75 patients with active disease and 19 with inactive disease, 38 (51%) and 4 (21%), respectively, and 23 healthy controls (31%) were found to have detectable levels of interleukin 8 (IL-8) in their serum (P < 0.05). Also, increased IL-8 serum levels were found in patients with active disease (median 12 pg/ml, P = 0.010) compared to patients with inactive disease (< or = 10 pg/ml) and to healthy controls (< or = 10 pg/ml). In particular, patients with oral aphthous ulcers (n = 51, 34 pg/ml) and neurological features (n = 4, 71 pg/ml) exhibited increased IL-8 levels. In contrast, there was no correlation between disease activity and the serum levels of IL-1alpha, IL-1beta, tumor necrosis factor alpha (TNF-alpha), soluble intercellular adhesion molecule-1 or basic fibroblast growth factor (bFGF). In a second set of experiments, the involvement of dermal microvascular endothelial cells in IL-8 secretion was investigated. Immortalized human dermal microvascular endothelial cells (HMEC-1 cells) were maintained for 4 h in vitro with serum from 18 ABD patients or with IL-1beta, a known stimulator of IL-8 synthesis, TNF-alpha or their combination at five- to tenfold higher concentrations than those found in the serum of ABD patients. Increased IL-8 secretion was found after incubation with ABD patients' serum (median 20 pg/ml), but IL-1beta, TNF-alpha and IL-1beta + TNF-alpha failed to induce IL-8 secretion by HMEC-1 cells (< or = 1-1.2 pg/ml) in biologically relevant concentrations. Our study showed increased IL-8 serum levels in ABD patients with active oral and neurological manifestations. Human microvascular endothelial cells may, at least partially, be responsible for the enhanced IL-8 secretion in the active stage of the disease.

Topics: Acute Disease; Adult; Behcet Syndrome; Blood; Cell Line; Central Nervous System Diseases; Cytokines; Endothelium, Vascular; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Male; Middle Aged; Oral Ulcer

The initial demyelinating lesions in canine distemper virus (CDV) infection develop during a period of severe immunosuppression in the absence of inflammation. In vitro and in vivo studies suggest that early demyelination is due to directly virus-induced oligodendroglial changes. In the present spatiotemporal study in experimentally CDV-infected dogs we observed diffuse up-regulation of T cells throughout the central nervous system (CNS) and T cell invasion in early demyelinating lesions. Invasion of T cells in the CNS occurred despite severe immunosuppression and without any perivascular cuffing. However, the major fraction of invading T cells correlated with sites of viral replication and coincided with the demonstration of an early immune response against the nucleocapsid protein of CDV. Activation of microglial cells was thought to have elicited the migration of T cells to the CNS by secretion of chemokines: marked IL-8 activity was found in the CSF of dogs with acute lesions. In areas of early demyelination, large numbers of CD3+ cells accumulated in the tissue in the absence of any morphological sign of inflammation. Whether the T cells at lesion sites contribute to the development of acute demyelination remains uncertain at this stage. Antiviral cytotoxicity was not apparent since viral clearance in demyelinating lesions is only effective when B cells and concurring antiviral antibody production appeared in the subacute and chronic inflammatory stage of the disease. CD3+ cells appear to persist for several weeks after infection since they were also found in recovered dogs that did not develop demyelination. Accumulation of immune cells, including a significant proportion of resting T cells (CD45RA+) in the CNS in the early stages of the disease may facilitate the later development of the intrathecal immune response and associated immunopathological complications.

Topics: Animals; Antigens, CD; Central Nervous System Diseases; Demyelinating Diseases; Distemper; Dogs; Immunophenotyping; Inflammation; Interleukin-8; Ki-67 Antigen; RNA, Viral; Specific Pathogen-Free Organisms; T-Lymphocytes; Time Factors; Virus Replication