interleukin-8 and Arthritis--Juvenile

Familial Mediterranean fever (FMF) is a disease of unknown etiology characterized by recurrent attacks of polyserositis (peritonitis, pleuritis, and arthritis) and fever. We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 8 (IL-8), which are important mediators in leukocyte-endothelial adhesion and leukocyte accumulation in tissues.. sICAM-1 and IL-8 levels were studied in 30 patients with FMF during attacks and remission, along with 23 healthy and 26 disease controls. sICAM-1 and IL-8 levels were measured with commercial ELISA systems.. Median levels of sICAM-1 were significantly elevated in patients with FMF during attacks (FMF-a) and remission periods (FMF-r) compared to healthy controls (HC) (FMF-a: 600 ng/ml, FMF-r: 520 ng/ml, HC: 353 ng/ml; FMF-a vs. HC: p<0.0001, FMF-r vs. HC: p = 0.002). IL-8 levels were also significantly elevated in FMF-a compared to HC (37 vs. 25 pg/ml; p = 0.009), but not during remission (26 pg/ml; p = 0.7). A significant correlation was observed between sICAM-1 and IL-8 levels (r = 0.33, p = 0.01). sICAM-1 levels also correlated significantly with erythrocyte sedimentation rate, C-reactive protein, and fibrinogen levels of patients with FMF.. Increased levels of sICAM-1 and IL-8 in FMF suggest that neutrophils are active with increased adhesion in FMF. Since increased levels of sICAM-1 are also observed during remission, subclinical disease activity and inflammation seem to be present in some patients.

Topics: Acute Disease; Adolescent; Adult; Arthritis, Juvenile; Child; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Familial Mediterranean Fever; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Prognosis; Sensitivity and Specificity; Severity of Illness Index

Familial Mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (sJIA) are chronic inflammatory diseases and anti-inflammatory agents are used in their treatment. This study evaluates the periodontal status and cytokine response in pediatric patients with FMF or sJIA.. Forty-eight FMF/sJIA patients were under treatment/control and in attack-free period; 20 systemically healthy children participated in the study. FMF/sJIA patients were divided into two subgroups based on the treatment they received: receiving anti-IL-1 therapy (anti-IL-1 ( +)) and not receiving anti-IL-1 therapy (anti-IL-1 ( -)). The clinical periodontal indices were recorded. Gingival crevicular fluid (GCF) and serum samples were collected. Cytokine levels (IL-1β, IL-1α, TNF-α, IL-6, IL-8, IL-10, IL-17, IL-33) in GCF and serum were measured using ELISA kits.. There was no significant difference between the groups in terms of GCF IL-1β and IL-1α levels although, BoP and GI were significantly lower in the anti-IL-1 ( +) group compared to the control group. GCF IL-10 level was higher in the anti-IL-1 ( -) group than in the control group; GCF IL-8 levels were lower in both FMF/sJIA subgroups versus controls. There was no significant difference between serum cytokine levels of FMF/sJIA subgroups.. Considering the significant decrease in GI, BoP, and GCF IL-8 levels in the anti-IL-1 ( +) group, it can be concluded that anti-IL-1 medications may suppress periodontal inflammation clinically and immunologically.. Anti-IL agents are not currently used in periodontal therapy. However, this study demonstrated the positive effect of anti-IL-1 medications on periodontal inflammation in pediatric patients with FMF or sJIA.

Topics: Arthritis, Juvenile; Child; Familial Mediterranean Fever; Gingival Crevicular Fluid; Humans; Inflammation; Interleukin-10; Interleukin-8

Biomarkers for juvenile idiopathic arthritis-associated uveitis (JIA-U) are needed. We aimed to measure inflammatory biomarkers in tears as a non-invasive method to identify biomarkers of uveitis activity.. Tears were collected from children with JIA-U (n=20) and pediatric controls (n=20) using Schirmer strips. S100A8, A9, A12, IL-18, IL-8, IP-10, MCP-1, RANTES, and sICAM-1 were measured by ELISA and Luminex assays. Levels of biomarkers were compared between children with JIA-U and controls, and active and inactive JIA-U.. IL-8, sICAM-1, and S100A12 levels were similar between JIA-U and controls, but differed by activity. Active JIA-U had significantly increased S100A12 compared to inactive JIA-U (mean 27,722.5 pg/ML (SE 1.3) vs. 5,937.2 (1.3), p=0.002), IL-8 (73.5 [1.2] vs. 36.2 [1.2], p=0.009), and sICAM-1 (15,822.7 [1.2) vs. 8,778.0 [1.6], p=0.024).. We detected inflammatory biomarkers non-invasively in tears of children with JIA-U. IL-8, sICAM-1, and S100A12 are potential biomarkers for uveitis activity.

Topics: Adolescent; Arthritis, Juvenile; Biomarkers; Child; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Eye Proteins; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; S100A12 Protein; Tears; Uveitis

JIA is an autoimmune, inflammatory disease with involvement of innate and adaptive immune responses. However, the role of neutrophils in JIA pathogenesis remains unclear. This study aimed to identify and validate neutrophil gene expression signatures in JIA using public microarray datasets and new clinical samples.. Three suitable datasets were analysed by significance analysis of microarray and Ingenuity. Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from a new cohort of JIA patients and healthy paediatric controls (HCs). Gene expression was validated using quantitative PCR. Serum concentrations of proteins were measured using ELISA. Low-density granulocytes (LDGs) in JIA and HC PBMCs were quantified by flow cytometry using forward/side-scatter properties.. Ingenuity identified transcriptional regulation (false discovery rate < 0.05) by G-CSF, GM-CSF and IL-8 along with expression of neutrophil granule protein genes including ELANE, MPO, MMP8 and MMP9 in datasets from JIA PBMCs. LDG counts were elevated in JIA compared with HCs (2.5% vs 1.4%; P = 0.007). Transcripts for MMP8 (P = 0.005), MPO (P = 0.0124) and Fcγ Receptor 1B (FCγR1B) (P = 0.0417) were significantly higher in JIA compared with HC neutrophils. MMP9 protein levels were lower in systemic JIA patient sera [355.95 ng/ml (s.d. 250.03)] compared with HCs [675.41 ng/ml (s.d. 181.17); P = 0.007], but levels of elastase, MPO and MMP8 were not significantly different.. LDGs are elevated in JIA and contribute to the transcriptomic profile of JIA PBMCs. JIA neutrophils express higher levels of MMP8 and FCGR1B, which may be implicated in disease pathology through the release of proteases and reactive oxygen metabolites, causing systemic inflammation and damage to joints.

Topics: Adolescent; Arthritis, Juvenile; Child; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Histocompatibility Antigens Class I; Humans; Interleukin-8; Leukocyte Count; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 8; Neutrophil Activation; Neutrophils; Real-Time Polymerase Chain Reaction; Receptors, Fc; Transcription, Genetic; Transcriptome

The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)-α inhibitors. TNF-α inhibitor-naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time-points after initiation of TNF-α inhibition for anti-TNF-α-treated (anti-TNF) JIA subjects, and at two subsequent time-points for other JIA (non-TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti-TNF, 31 non-TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti-TNFs) had higher baseline TNF-α, IL-6 and IL-8 than those with lower disease activity (non-TNFs) (P < 0·05). TNF-α and IL-10 increased, and IL-6 and IL-8 no longer remained significantly higher after TNF-α inhibitor initiation in anti-TNF subjects. Subgroup analysis of etanercept versus adalimumab-treated subjects showed that TNF-α and IL-17 increased significantly in etanercept but not adalimumab-treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF-α inhibition resulted in suppression of IL-6 and IL-8 in parallel with clinical improvement in all anti-TNF-treated subjects, but was also associated with elevated TNF-α and IL-17 in etanercept-treated subjects.

Topics: Adalimumab; Adolescent; Antirheumatic Agents; Arthritis, Juvenile; Case-Control Studies; Child; Etanercept; Female; Gene Expression Regulation; Humans; Interleukin-10; Interleukin-17; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Prospective Studies; Severity of Illness Index; Surveys and Questionnaires; Tumor Necrosis Factor-alpha; Young Adult

The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/β-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the d

Topics: Apoptosis; Arthritis, Juvenile; Autoimmune Diseases; B-Cell Lymphoma 3 Protein; Cell Proliferation; Chemokine CXCL1; Chemokine CXCL5; Chemokine CXCL6; Chemokines, CXC; Colitis, Ulcerative; Crohn Disease; Diabetes Mellitus, Type 1; Gene Expression; Humans; Inflammation; Interferon-gamma; Interleukin-8; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Multiple Sclerosis; Protein Interaction Maps; Proto-Oncogene Proteins; Receptors, Calcitriol; Receptors, IgE; Signal Transduction; Transcription Factors; Transcriptome

We examined expression and function of TLRs in enthesitis-related arthritis (ERA) patients. RNA levels of TLR1, TLR3, and TLRs 5–8 were measured in 24 ERA peripheral blood mononuclear cells (PBMC), 18 synovial fluid mononuclear cells (SFMC), and IRAK1, IRAK4, TRIF, TRAF3, and TRAF6 in 18 PBMC and 10 SFMC. IL-6 and IL-8 were measured in supernatants from ERA PBMC (n=7), SFMC (n=3), and healthy PBMC (n=5) cultured with ligands for TLR1/2 (Pam 3-cys), TLR3 (polyI:C), TLR5 (flagellin), and TLR2/6 (zymosan). TLRs 1, 3, 5, and 6 were measured in whole blood (n=20 ERA, seven healthy) and SFMC (n=2) by flow cytometry. ERA PBMC compared to healthy PBMC and SFMC compared to ERA PBMC had higher RNA expression of TLR1, TLR3, TLR5, TLR6, IRAK1, IRAK4, TRIF, TRAF3, and TRAF6. TLR7 and TLR8 RNA expression was similar in all study groups. IL-6 and IL-8 levels were higher in stimulated ERA SFMC compared to ERA PBMC and in ERA PBMC compared to control PBMC. TLRs 1, 3, and 6 were also overexpressed at the protein level.

Topics: Adaptor Proteins, Vesicular Transport; Adolescent; Adult; Arthritis, Juvenile; Child; Female; Humans; Inflammation Mediators; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Male; RNA; Synovial Fluid; TNF Receptor-Associated Factor 3; TNF Receptor-Associated Factor 6; Toll-Like Receptors; Young Adult

Cytokines are the major mediators of joint damage in chronic arthritis. Data on synovial fluid (SF) concentration of Th17 cell-derived cytokine interleukin 17 (IL-17) in patients with juvenile idiopathic arthritis (JIA) are sparse. We measured levels of IL-17 in SF specimens from children with enthesitis-related arthritis (ERA) and polyarticular JIA (poly-JIA), and studied the ability of IL-17 to produce matrix metalloproteinases (MMP) and cytokines by fibroblast-like synoviocytes (FLS) from patients with ERA.. IL-17 levels were measured in SF of patients with ERA (n = 43), poly-JIA (n = 17), rheumatoid arthritis (RA; n = 35), and osteoarthritis (OA; n = 10) by ELISA. In patients with JIA, 10 paired serum samples were also assayed. FLS were cultured from SF of patients with ERA and subsequently stimulated for 48 h by IL-17 or tumor necrosis factor-alpha. Later the production of IL-6, IL-8, MMP-1, MMP-3, and tissue inhibitor of metalloproteinase (TIMP)-1 was measured in the culture supernatants by ELISA.. Median IL-17 levels in SF were higher in patients with JIA [28 pg/ml (range 0-200)] compared to OA [0 pg/ml (range 0-84); p < 0.001] and RA (p < 0.05). The levels were comparable between poly-JIA patients and the ERA group. The median SF IL-17 levels were significantly higher compared to serum levels in children with JIA (p < 0.005). In ERA, SF IL-17 correlated with number of swollen joints (r = 0.35; p < 0.05), number of joints with limited mobility (r = 0.55; p < 0.001), and number of tender joints (r = 0.46; p < 0.01); however, no correlation was seen with erythrocyte sedimentation rate. IL-17 induced FLS to produce IL-6, IL-8, MMP-3, and MMP-1. However, there was no effect on the production of TIMP.. Increased IL-17 levels in ERA SF correlate with disease activity and this may be due to increased production of MMP and cytokines by IL-17.

Topics: Adolescent; Adult; Arthritis, Juvenile; Arthritis, Rheumatoid; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; Cytokines; Female; Fibroblasts; Humans; Interleukin-17; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Matrix Metalloproteinases; Osteoarthritis; Synovial Fluid

Although strong epidemiologic evidence suggests an important role for adaptive immunity in the pathogenesis of polyarticular juvenile rheumatoid arthritis (JRA), there remain many aspects of the disease that suggest equally important contributions of the innate immune system. We used gene expression arrays and computer modeling to examine the function in neutrophils of 25 children with polyarticular JRA. Computer analysis identified 712 genes that were differentially expressed between patients and healthy controls. Computer-assisted analysis of the differentially expressed genes demonstrated functional connections linked to both interleukin (IL)-8- and interferon-gamma (IFN-gamma)-regulated processes. Of special note is that the gene expression fingerprint of children with active JRA remained essentially unchanged even after they had responded to therapy. This result differed markedly from our previously reported work, in which gene expression profiles in buffy coats of children with polyarticular JRA reverted to normal after disease control was achieved pharmacologically. These findings suggest that JRA neutrophils remain in an activated state even during disease quiescence. Computer modeling of array data further demonstrated disruption of gene regulatory networks in clusters of genes modulated by IFN-gamma and IL-8. These cytokines have previously been shown to independently regulate the frequency (IFN-gamma) and amplitude (IL-8) of the oscillations of key metabolites in neutrophils, including nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and superoxide ion. Using real-time, high-speed, single-cell photoimaging, we observed that 6/6 JRA patients displayed a characteristic defect in 12% to 23% of the neutrophils tested. Reagents known to induce only frequency fluctuations of NAD(P)H and superoxide ion induced both frequency and amplitude fluctuations in JRA neutrophils. This is a novel finding that was observed in children with both active (n = 4) and inactive (n = 2) JRA. A subpopulation of polyarticular JRA neutrophils are in a chronic, activated state, a state that persists when the disease is well controlled pharmacologically. Furthermore, polyarticular JRA neutrophils exhibit an intrinsic defect in the regulation of metabolic oscillations and superoxide ion production. Our data are consistent with the hypothesis that neutrophils play an essential role in the pathogenesis of polyarticular JRA.

Topics: Adolescent; Adult; Arthritis, Juvenile; Biomarkers; Child; Child, Preschool; Cluster Analysis; Humans; Interferon-gamma; Interleukin-8; NADP; Neutrophils; Oligonucleotide Array Sequence Analysis; Superoxides; Synovial Fluid

Cytokines are the major mediators of joint damage in chronic arthritis. Data on synovial fluid (SF) cytokine concentrations in patients with juvenile idiopathic arthritis (JIA), especially enthesitis related arthritis (ERA), are limited. We measured levels of different monocyte derived cytokines, T cell derived cytokines, and a proinflammatory chemokine in SF specimens from children with ERA or polyarticular (Poly) rheumatoid factor (RF)-negative JIA.. Macrophage products [tumor necrosis factor-a (TNF-a), interleukin 1ss (IL-1ss), IL-6, IL-12p40)], T lymphocyte products [IL-2, IL-4, interferon-g (IFN-g)], and a proinflammatory chemokine (IL-8) were assayed using ELISA in SF specimens from 53 patients with JIA [ERA 34, polyarticular RF-negative 19] and 40 patients with rheumatoid arthritis (RA).. In the ERA group, median SF cytokine levels were higher compared to RA (all values are pg/ml): IL-1ss [< 15.6 (< 15.6-213) vs < 15.6 (< 15.6-41); p < 0.01], IL-12p40 [236 (< 15.6-1714) vs 21 (< 15.6-520); p < 0.0001], and IL-6 [1139 (< 4.6-2187) vs 835 (< 4.6-875); p < 0.0001]. TNF-a and IFN-g levels were similar to RA. IL-8 levels were significantly less than RA (p < 0.0001). The median levels of IL-1ss [39.4 (< 15.6-558) vs < 15.6 (< 15.6-41); p < 0.0001] and IL-12p40 [209 (< 15.6-849) vs 21 (< 15.6-520); p < 0.0001] were higher in patients with Poly-JIA compared to RA. TNF-a, IL-6, and IL-8 levels in Poly-JIA were comparable to RA. IL-2 and IL-4 were not detectable in any patient with JIA. Cytokine profile comparison between the 2 subsets revealed that the median IL-6 [1139 (< 4.6-2187) vs 790 (17.4-2119); p < 0.01] and IFN-g levels [235 (< 4.6-600) vs < 4.6 (< 4.6-412); p < 0.0001] were higher in ERA than in Poly-JIA. In contrast, median IL-8 levels were higher in Poly-JIA [200 (3.8-200)] compared to ERA [74.6 (4-200); p < 0.001]. However, there was no difference in levels of TNF-a, IL-1ss, and IL-12p40 between patients with these 2 subtypes of JIA.. SF levels of IL-1ss and IL-12p40 are increased in both Poly-JIA and ERA as compared to RA. IL-6 levels were higher in ERA compared to RA. Levels of TNF-a were comparable to RA in both Poly-JIA and ERA. This suggests that joint inflammation in JIA is mediated predominantly by monocytes. In ERA the levels of IL-6 and IFN-g are higher than in Poly-JIA. The increase in IFN-g in children with ERA with undetectable IL-4 suggests a Th1-dominant immune response in this disease subset.

Topics: Adolescent; Adult; Arthritis, Juvenile; Child; Child, Preschool; Cytokines; Female; Humans; Interferon-gamma; Interleukin-1; Interleukin-12; Interleukin-12 Subunit p40; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Male; Monocytes; Protein Subunits; Synovial Fluid; T-Lymphocytes; Tumor Necrosis Factor-alpha

Examination of expression of the chemokine macrophage inflammatory protein-3a (CCL20/Mip-3alpha) in blood polymorphonuclear neutrophils (PMN) and synovial fluid (SF) PMN of patients with rheumatoid arthritis (RA).. Paired samples of blood PMN and SF PMN were obtained from 11 patients with RA. In addition, SF was prepared from 9 patients with osteoarthritis (OA) and 10 patients with juvenile idiopathic arthritis (JIA). PMN were isolated via density centrifugation to a purity of 98%. Total RNA was isolated and the expression of CCL20 was determined by reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time PCR. In some experiments blood PMN obtained from healthy donors were stimulated with individual SF of patients with RA. For quantitative considerations, CXCL8, CCL20, interleukin 1, and tumor necrosis factor-alpha (TNF-alpha) levels were determined in SF by ELISA.. In SF of RA patients CCL20 and CXCL8 levels were elevated, up to 7.5 ng/ml and 23.6 ng/ml, respectively. No significant level of either chemokine was found in SF of patients with JIA and OA. CCL20 mRNA was undetectable in blood PMN of all patients with RA. In SF PMN, CCL20 mRNA was found in 6/11 RA patients. Expression of CCL20 mRNA in 5/6 SF PMN samples was observed in the absence of detectable TNF-alpha levels in SF. Cell culture experiments, however, confirmed the ability of TNF-alpha in SF to induce CCL20 mRNA expression in blood PMN. Notably, expression of CCL20 was also found in PMN after stimulation with SF lacking TNF-alpha.. Recruitment of PMN to the synovial microenvironment induces expression of CCL20 mRNA independent of the concentrations of TNF-alpha accumulating in SF of patients with RA.

Topics: Adult; Aged; Arthritis, Juvenile; Arthritis, Rheumatoid; Case-Control Studies; Cells, Cultured; Chemokine CCL20; Chemokines, CC; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Macrophage Inflammatory Proteins; Male; Middle Aged; Neutrophils; Osteoarthritis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synovial Fluid; Synovial Membrane; Tumor Necrosis Factor-alpha

IL-8 is a strong inductor of inflammation. Accordingly, it plays a pivotal role in acute inflammatory responses during respiratory syncytial virus (RSV) infections and in chronic inflammatory diseases such as bronchial asthma and juvenile idiopathic arthritis. Recently, 2 studies have found association of the polymorphism -251A of IL8 with RSV bronchiolitis. Furthermore, epidemiologic studies have demonstrated an increased risk for the development of asthma after RSV bronchiolitis, and a common genetic background for the 2 diseases is currently being discussed.. This study investigated whether IL-8 is in association with asthma and/or arthritis and whether the results can confirm a common genetic background of RSV bronchiolitis and asthma.. The polymorphisms -A251T, C781T, C1633T, and A2767T within IL8 were genotyped in the following 4 populations: children with asthma, atopic children, children with juvenile idiopathic arthritis, and control subjects. Statistical analysis made use of the Armitage trend test and the software program Arlequine.. Association of all polymorphisms was found with asthma ( P =.008 to P =.03). Surprisingly -251T was associated with asthma, which is the opposite allele as described in association with RSV bronchiolitis. Furthermore, all polymorphisms were significantly more common in children with arthritis than in asthmatic children ( P =.006 to P =.02). No association was seen with the diagnosis of arthritis per se or with atopy.. This is the first study to describe association of IL-8 with asthma and a significant inverse distribution of the polymorphisms in juvenile idiopathic arthritis. In addition, the results of this study might suggest that RSV bronchiolitis and bronchial asthma have at least some different genetic factors.

Topics: Adolescent; Adult; Arthritis, Juvenile; Asthma; Bronchiolitis, Viral; Child; Child, Preschool; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Interleukin-8; Polymorphism, Genetic; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human

We investigated serum levels of interleukin (IL)-1beta, IL-6, IL-8, IL-12 and tumour necrosis factor (TNF)-alpha in JRA patients during both active and inactive phases of the disease. The systemic JRA patients had the highest IL-1beta and IL-6 levels during both active and inactive periods. In the systemic group IL-1beta, IL-6 and IL-12 levels during the active period were elevated compared to the inactive period (p = 0.0173, p = 0.0359 and p = 0.0117, respectively). Levels of these cytokines during the inactive stage were still greater than those of controls. IL-8 and TNF-alpha levels during both active and inactive periods were comparable to controls. IL-1beta correlated strongly with CRP and ESR (p = 0.008 and p = 0.031, respectively). IL-6 correlated significantly with CRP (p = 0.002). IL-12 levels were found to be correlated with ESR and CRP (p = 0.03 and p = 0.04, respectively). In active polyarticular JRA patients, IL-6 levels were elevated compared to the inactive phase, and the control (p = 0.001) IL-12 levels decreased significantly with clinical remission (p = 0.018). There was a strong correlation between 11-12 levels and number of joint with limited motion (p = 0). In oligoarticular JRA patients, IL-12 levels during active period were greater than in the controls and there was a marked decrease in IL-12 levels when the patients entered the inactive phase (p = 0.001) In conclusion, IL-1beta, IL-6 and IL-12 may play an important role in JRA and may be used as a marker of disease activity.

Topics: Adolescent; Arthritis, Juvenile; Child; Child, Preschool; Cytokines; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Interleukin-1; Interleukin-12; Interleukin-6; Interleukin-8; Male; Statistics as Topic; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Juvenile rheumatoid arthritis (JRA) is characterized by chronic inflammation of the joints. In the present study we demonstrate that exposure of JRA patients to a noradrenergic stressor (cold pressor test) results in enhanced LPS-induced IL-6 production by peripheral blood cells of these patients. Healthy, age-matched controls had the same rise in norepinephrine, but do not respond with changes in IL-6 production after exposure to the cold pressor test. Moreover, PBMC of patients with JRA express mRNA encoding alpha(1)-adrenergic receptors (AR), predominantly of the alpha(1d)-AR subtype. In contrast, we could not detect mRNA encoding for alpha(1)-AR in PBMC of healthy controls. The results of this study suggest that expression of alpha(1)-AR mRNA in PBMC during chronic inflammation is associated with altered responses of the immune system to stress.

Topics: Acute Disease; Adolescent; Arthritis, Juvenile; Child; Child, Preschool; Chronic Disease; Cold Temperature; DNA Primers; Female; Gene Expression; Humans; Interleukin-6; Interleukin-8; Male; Monocytes; Norepinephrine; Receptors, Adrenergic, alpha-1; RNA, Messenger; Stress, Physiological

To measure serum and synovial fluid (SF) levels of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in patients with juvenile rheumatoid arthritis (JRA) and to compare them with adult rheumatoid factor-positive rheumatoid arthritis (RA).. IL-8 and MCP-1 were measured by immunoassay (1) in sera obtained from 55 children with JRA and from 16 adults with RA, and (2) in SF obtained from 30 children with JRA and 11 adults with RA.. Patients with active systemic JRA had serum levels of IL-8 and MCP-1 higher than in controls (p<0.01) and in patients with active polyarticular or pauciarticular JRA (p<0.05). In patients with RA serum MCP-1 levels were higher than in patients with the 3 JRA onset types, while no difference was found for IL-8 levels. Patients with systemic JRA and with current systemic features had serum levels of IL-8 and MCP-1 higher (p = 0.03 and p = 0.04, respectively) than patients in which systemic features had subsided. No significant differences in SF IL-8 or MCP-1 levels were found among the 3 JRA onset types or adults with RA. In patients with JRA SF leukocyte counts were correlated with SF IL-8 levels (p = 0.002), but not with MCP-1 levels. Moreover, SF levels of both IL-8 and MCP-1 were correlated with those of IL-1beta (p<0.001) and IL-6 (p<0.01), but not with those of TNF-alpha.. Elevated serum levels of IL-8 and MCP-1 in patients with systemic JRA with current systemic features at sampling suggest systemic production of the 2 chemokines during systemic phases of the disease. Similar SF levels of IL-8 and MCP-1 among the 3 JRA onset-types and RA suggest comparable local production of the 2 chemokines.

Topics: Adolescent; Adult; Age of Onset; Aged; Arthritis, Juvenile; Arthritis, Rheumatoid; Blood Sedimentation; Chemokine CCL2; Child; Child, Preschool; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Count; Middle Aged; Receptors, Tumor Necrosis Factor; Synovial Fluid; Tumor Necrosis Factor-alpha

Immune complexes that vary in size and composition are present in the sera and synovial fluid of juvenile rheumatoid arthritis (JRA) patients. They are believed to be potent inducers of the ongoing inflammatory process in JRA. However, the precise composition and role of these complexes in the pathophysiology of JRA remain unclear. We hypothesized that circulating ICs have the potential to interact with resident joint synovial fibroblasts (synoviocytes) and induce the expression of inflammatory cytokines. To test this hypothesis, cultures of synoviocytes from healthy individuals were treated with ICs isolated from the sera of JRA patients. Studies reported in this work demonstrate that IgM affinity-purified ICs from the sera of JRA patients contain IgM, C1q, IgG, and C3 to a variable extent. These ICs induce IL-8 mRNA and protein production in normal synoviocytes. Our data indicate that C1q in these ICs mediates, in part, IL-8 induction in synoviocytes. This is based on our findings of C1q-binding proteins for collagen stalks (cC1qR) and globular heads (gC1q-binding protein) of C1q in synoviocytes. In addition, collagen stalk and to some extent globular head fragments of C1q inhibit IC-mediated IL-8 induction in synoviocytes. Together, these findings provide evidence for a novel mechanism of IL-8 production by synoviocytes, which could play a key role in inflammation by recruiting leukocytes to synovial tissue and fluid-and subsequently contributing to joint disease.

Topics: Adolescent; Adult; Antigen-Antibody Complex; Arthritis, Juvenile; Carrier Proteins; Cell Communication; Cells, Cultured; Child; Child, Preschool; Complement C1q; Female; Flow Cytometry; Humans; Hyaluronan Receptors; Immunohistochemistry; Interleukin-8; Male; Membrane Glycoproteins; Mitochondrial Proteins; Peptide Fragments; Protein Binding; Receptors, Complement; Receptors, IgG; Synovial Membrane

The immunoinflammatory pathogenesis of juvenile chronic arthritis (JCA) involves the activation of many pathways including various cytokines. We have evaluated the levels of interleukin(IL)-1, IL-6 and IL-8 in 29 JCA patients. The age range was 1-16 with a mean of 10.1. A disease activity score was developed on the basis of: 1. constitutional symptoms and/or morning stiffness, 2. presence of joint swelling, 3.warmth, 4.limited range of motion, and 5.joint pain. This score correlated very significantly with laboratory disease activity markers such as erythrocyte sedimentation rate (ESR) and CRP (both p = 0.006) and also correlated with IL-1 and IL-6 levels. The levels of IL-1 decreased in four of the five patients with improved disease activity. IL-6 but not IL-1 correlated significantly with the number of inflamed joints (p = 0.013); IL-6 also strongly correlated with rheumatoid factor supporting this cytokine's role in B cell induction (p = 0). Haemoglobin values correlated negatively with the activity index, ESR, CRP, IL-1 and IL-6. IL-8 did not correlate with disease activity markers. In the systemic patients all cytokines tended to be higher. Our data suggest that interleukins 1 and 6 are effective in the pathogenesis of JCA. Whether cytokines may be used for monitoring therapy may be clarified with further studies.

Topics: Adolescent; Arthritis, Juvenile; Blood Sedimentation; C-Reactive Protein; Child; Child, Preschool; Female; Hemoglobins; Humans; Infant; Interleukin-1; Interleukin-6; Interleukin-8; Male

To characterize juvenile rheumatoid arthritis synovial fluid (SF) immune complexes and to examine their interaction with leukocytes.. SF immunoglobulin-containing fractions were prepared by sequential chromatography on protein A and Sephacryl 300. Fractions were subdivided according to molecular weight, characterized for immunoglobulin and complement content, and incubated with either promonocytic U937 cells or normal human peripheral blood mononuclear cells (PBMC).. High molecular weight SF immunoglobulin-containing fractions stimulated the release of interleukin-1beta (IL-1beta) from U937 cells. These same complexes stimulated tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) from PBMC. Lower molecular weight material was less efficient in inducing any of the cytokines. TNFalpha and IL-1beta were the earliest of the messenger RNAs examined to be induced by the high molecular weight complexes. However, the secretion of IL-6, IL-8, and GM-CSF stimulated by the complexes was not completely dependent upon the secretion of IL-1beta. Addition of IL-1 receptor antagonist to the cell cultures reduced GM-CSF and IL-6 production by 40% and IL-8 production by 25% in PBMC.. SF immunoglobulin fractions contain immune complexes that vary in size, composition, and phlogistic potential. High molecular weight complexes are capable of inducing a spectrum of proinflammatory cytokines, all of which have been implicated in the pathogenesis of rheumatic disease.

Topics: Adolescent; Antigen-Antibody Complex; Arthritis, Juvenile; Child; Child, Preschool; Complement Activation; Cytokines; Enzyme-Linked Immunosorbent Assay; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Interleukin-1; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Synovial Fluid; Time Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

To determine the levels of the inflammatory cytokines IL1 alpha, IL1 beta, TNF alpha, IL6, IL8 and of their inhibitors TNF-sR55, TNF-s R75 and IL1-Ra during temperature elevation in systemic juvenile chronic arthritis.. Fifty-six serum samples were collected at regular intervals from seven children during 8 fever cycles. Cytokine levels were determined using enzyme-linked immunoassays.. Levels of IL1 alpha, IL1 beta, TNF alpha and IL8 showed no variations. In contrast, IL6 and IL1-Ra levels paralleled the fever spikes. TNF-sR75 levels were also correlated with the fever.. Fever dynamics in systemic juvenile chronic arthritis may be partly related to cytokine variations.

Topics: Arthritis, Juvenile; Child; Child, Preschool; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fever; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Prognosis; Tumor Necrosis Factor-alpha