interleukin-8 and Lupus-Erythematosus--Systemic

We performed this meta-analysis in order to evaluate circulating interleukin-8 (IL-8) levels in systemic lupus erythematosus (SLE) patients more accurately and explore its related influencing factors.. The related literature was systematically searched in PubMed, Embase and The Cochrane Library database (up to 28 March 2018). All data analysis was performed by Stata 12.0 software.. The results showed SLE patients had a higher circulating IL-8 levels than normal controls (pooled standardized mean difference = 0.963; 95% CI: 0.416-1.511). Subgroup analyses indicated SLE patients with age <40 years, Asia group and disease duration <10 years had higher IL-8 levels.. Compared with normal controls, circulating IL-8 levels in SLE patients are elevated and affected by age, region and disease duration.

Topics: Adult; Age Factors; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Time Factors

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10⁻⁵), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.

Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Humans; I-kappa B Kinase; Interferon Type I; Interleukin-8; Linkage Disequilibrium; Lupus Erythematosus, Systemic; Signal Transduction; STAT1 Transcription Factor; Sweden; White People

Topics: Arthritis, Rheumatoid; Behcet Syndrome; Biomarkers; Bronchitis; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-10; Interleukin-7; Interleukin-8; Interleukin-9; Lupus Erythematosus, Systemic; Psoriasis; Reagent Kits, Diagnostic; Sjogren's Syndrome

Systemic lupus erythematosus (SLE) susceptibility was found to be correlated with genetic polymorphisms. Therefore, the current study aimed to investigate the association of the IL-8-251 T/A polymorphism with the risk of SLE.. A total of 135 SLE patients and 75 controls were enrolled in our study. The IL-8-251 T/A polymorphism was analysed by PCR-RFLP. Also, the serum concentration of IL-8 was measured using ELISA. Finally, investigate possible IL-8 pathways in SLE pathogenesis by using the STRING database.. Our results revealed that the risk of having SLE in AA genotype carriers was significantly increased (OR = 1.92, 95 % CI = 1.23-3.10, p = 0.006) when compared with TT genotype carriers. Patients with SLE had a significantly higher frequency of the A allele (OR = 1.37, 95 % CI = 1.09-1.7; P = 0.01) than controls. Serum IL-8 levels were significantly increased in SLE patients (77.81 ± 21.27; p < 0.001) when compared to healthy controls (48.85 ± 7.89). Also, it was found that the serum IL-8 level had significant positive correlations with proteinuria, ESR, ANA, urea and SELADI, and significant negative correlations with RBCs count, C3 and hemoglobin. According to ROC curve analysis, serum IL-8 levels are a good biomarker for the detection of SLE disease, with 87.5 % sensitivity and 85 % specificity. STRING analysis revealed that IL-8 interacts with key SLE signaling pathway members such as TNF-α, IL-1β, IL-6, and IL-10.. There was a correlation between the IL-8-251 T/A polymorphism and the risk of SLE. Our findings also suggest that the IL8-251 A allele may be an important risk factor for the development of SLE.

Topics: Case-Control Studies; Egypt; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Polymorphism, Single Nucleotide

Systemic lupus erythematosus (SLE) is a chronic recurrent autoimmune disease affecting almost all organs. This study was conducted to investigate cognitive impairment of SLE mice (MRL/lpr mice), and explore associated pathological mechanism. Behavior tests (open-field test, elevated plus-maze test, forced swimming test, sucrose preference test, and Morris water maze test) were conducted in MRL/MPJ and MRL/lpr mice. ELISA test was performed to determine levels of antibodies (anti-dsDNA, anti-RPA, anti-ACA, and anti-NR2a/b) and inflammatory factors [tumour necrosis factor a (TNF-a), interleukin (IL)-6, IL-8, and IL-10]. Micro-vascular endothelial cells (MVECs) were isolated, identified, and divided into MVECs (NC), anti-NR2a/2b, memantine, glycine, dexamethasone, and IL-1b groups. Cell proliferation was measured using cell counting kit-8 (CCK-8) assay, and Western blotting was applied to evaluate ELAM-1, VCAM-1, ICAM-1, IKBa, p-IKBa expression. MRL/lpr mice demonstrated lower locomotion/exploration ability, higher anxiety, obvious depression symptoms, lower learning/memory capability compared with MRL/MPJ mice. MRL/lpr mice demonstrated high levels of anti-NR2a/b antibody and auto-antibodies. NMDA receptor antagonist (memantine) significantly increased, and NMDA receptor agonist (glycine) significantly decreased MVECs proliferation compared with NC group ( p < 0.05). Memantine significantly reduced and glycine predominantly enhanced TNF-a, IL-6, IL-8, and IL-10 levels compared with NC group ( p < 0.05). NMDA receptor antagonist and agonist modulated adhesion molecules expression in MVECs. ELAM-1, VCAM-1, and ICAM-1 expressions were significantly down-modulated in memantine group, and remarkably up-modulated in glycine group compared with NC group ( p < 0.05). NMDA receptor antagonist and agonist regulated phosphorylation of p-IKBa. The above effects of memantine evenly equaled to dexamethasone, and glycine evenly equaled to IL-1b. In conclusion, cognitive impairment of MRL mice might be associated with NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived MVECs.

Topics: Animals; Cognitive Dysfunction; Dexamethasone; E-Selectin; Endothelial Cells; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-8; Lupus Erythematosus, Systemic; Memantine; Mice; Mice, Inbred MRL lpr; Receptors, N-Methyl-D-Aspartate; Vascular Cell Adhesion Molecule-1

We investigated the effect of hydroxychloroquine (HCQ) as an add-on treatment to immunosuppressants on the expression of proinflammatory cytokines in patients with systemic lupus erythematosus. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and interleukin 1 receptor antagonist (IL-1ra) were measured immediately before and 3 months after treatment with oral HCQ. Among the 51 patients enrolled in the study, HCQ treatment led to significantly reduced serum levels of TNF-α, IL-6, IL-8, VEGF-A, IL-1ra, and IL-2 (p < 0.0001; p = 0.0006; p = 0.0460, p = 0.0177; p < 0.0001; p = 0.0282, respectively) and to decreased (but not significantly) levels of MIP-1α (p = 0.0746). No significant changes were observed in the serum MCP-1 levels before and after HCQ administration (p = 0.1402). Our results suggest that an add-on HCQ treatment modulates the expression of proinflammatory cytokines even in systemic lupus erythematosus patients with low disease activity.

Topics: Chemokine CCL3; Cytokines; Humans; Hydroxychloroquine; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

In patients with systemic lupus erythematosus (SLE), a higher frequency of atherosclerotic lesions is associated with poor prognosis. Hydroxychloroquine (HCQ) has been reported to improve the lifespan and the prognosis of dyslipidaemia in patients with SLE, but the mechanism is unclear. We investigated the effect of supplemental HCQ treatment on the levels of serum cytokines associated with atherosclerosis in patients with stable SLE.. Patients with SLE who received supplemental HCQ and maintained low disease activity between January 2016 and September 2020 were included in this study. Disease activity was assessed using Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index, Cutaneous Lupus Erythematous Disease Area and Severity Index, and Lupus Low Disease Activity State. Serum complement titres, anti-dsDNA antibodies, and serum cytokines (adiponectin, resistin, and leptin) were analyzed before and after HCQ treatment.. Forty-one patients (4 males and 37 females, mean age 41.3 ± 13.2 years) were included. Serum adiponectin levels were significantly increased after 3 months of HCQ treatment compared to baseline, and serum resistin levels were significantly reduced. The change in serum resistin level after HCQ administration was correlated with a significant reduction in serum TNF-α, interleukin (IL)-6, IL-8, and IL-1RA levels.. Supplemental HCQ treatment in patients with SLE improved adipokine levels. HCQ may improve prognosis by controlling disease activity in SLE and reducing risk factors for atherosclerosis. Key Points • Hydroxychloroquine has been reported to improve the prognosis of dyslipidaemia in patients with SLE, but the underlying mechanism is unclear. • In this study, hydroxychloroquine improved adipokine levels in patients with SLE, implicating adipokines as a potential mechanism underlying the benefit of hydroxychloroquine on dyslipidaemia. • Supplemental hydroxychloroquine should be considered in patients with SLE harboring lipid abnormalities and risk factors for atherosclerosis.

Topics: Adipokines; Adiponectin; Adult; Antibodies, Antinuclear; Antirheumatic Agents; Atherosclerosis; Cytokines; Estrogens; Female; Humans; Hydroxychloroquine; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Leptin; Lipids; Lupus Erythematosus, Systemic; Male; Middle Aged; Resistin; Tumor Necrosis Factor-alpha

Emerging studies reveal unique bacterial communities in the human bladder, with alteration of composition associated to disease states. Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is characterized by frequent impairment of the kidney. Here, we explored the bladder microbiome, metabolome, and cytokine profiles in SLE patients, as well as correlations between microbiome and metabolome, cytokines, and disease profiles. We recruited a group of 50 SLE patients and 50 individually matched asymptomatic controls. We used transurethral catheterization to collect urine samples, 16S rRNA gene sequencing to profile bladder microbiomes, and liquid chromatography-tandem mass spectrometry to perform untargeted metabolomic profiling. Compared to controls, SLE patients possessed unique bladder microbial communities and increased alpha diversity. These differences were accompanied by differences in urinary metabolomes, cytokines, and patients' disease profiles. The SLE-enriched genera, including

Topics: Bacteria; Biomarkers; Complement C3; Cytokines; Humans; Immunoglobulin G; Interleukin-8; Lupus Erythematosus, Systemic; Metabolome; Microbiota; Olopatadine Hydrochloride; Phenotype; RNA, Ribosomal, 16S; Urinary Bladder

Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer.. Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH.. In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression.. Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery.

Topics: Animals; Apoptosis; Extracellular Traps; Hemorrhage; HMGB1 Protein; Humans; Interleukin-8; Lung Diseases; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; MicroRNAs; Neutrophils; TNF Receptor-Associated Factor 6

To explore cooperation between activated naïve (aNAV) B cells and CD4. Peripheral blood mononuclear cell samples were obtained from 31 patients with SLE and used to characterise phenotype of aNAV B cells (n=14) and measured the phosphorylation of B-cell receptor (BCR) signalling molecules (n=5). Upregulation of T-cell costimulatory molecules after BCR and toll-like receptor (TLR)-7/TLR-8 stimulation was detected in cells from four subjects. To explore the role of these cells in SLE pathogenesis via T cell-dependent mechanisms, four subjects were analysed to detect the promotion of CD4. The aNAV B cells of patients with SLE had increased expression of surface CD40, HLA-DR and interleukin-21 receptor (IL-21R) and FCRL5 molecules. With BCR stimulation, these cells greatly increased PLCγ2 phosphorylation. Integrated BCR and TLR-7/TLR-8 signals induced overexpression of CD40, CD86, IL-21R and HLA-DR on lupus aNAV B cells. In T-cell-B-cell cocultures, lupus aNAV B cells (with upregulated costimulatory molecules) promoted CD4. Cooperation between aNAV B cells and CD4

Topics: Antibodies, Antinuclear; CD4-Positive T-Lymphocytes; Cytokines; HLA-DR Antigens; Humans; Interleukin-23; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Phospholipase C gamma; Receptors, Antigen, B-Cell; T-Lymphocytes; Toll-Like Receptor 7; Toll-Like Receptor 8

Topics: Animals; Cell Line; Female; Humans; Hydrolyzable Tannins; Intercellular Adhesion Molecule-1; Interleukin-8; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred NZB; NIH 3T3 Cells; Podocytes; Proteinuria; Receptor, PAR-2; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3

Topics: Adult; Animals; Cardiovascular Diseases; Endothelial Cells; Female; Human Umbilical Vein Endothelial Cells; Humans; Immunophenotyping; Immunosenescence; Interleukin-8; Lupus Erythematosus, Systemic; Male; Risk; T-Lymphocyte Subsets; T-Lymphocytes

Identification of universal biomarkers to predict systemic lupus erythematosus (SLE) flares is challenging due to the heterogeneity of the disease. Several biomarkers have been reported. However, the data of validated biomarkers to use as a predictor for lupus flares show variation. This study aimed to identify the biomarkers that are sensitive and specific to predict lupus flares.. One hundred and twenty-four SLE patients enrolled in this study and were prospectively followed up. The evaluation of disease activity achieved by the SLE disease activity index (SLEDAI-2K) and clinical SLEDAI (modified SLEDAI). Patients with active SLE were categorized into renal or non-renal flares. Serum cytokines were measured by multiplex bead-based flow cytometry. The correlation and logistic regression analysis were performed.. Levels of IFN-α, MCP-1, IL-6, IL-8, and IL-18 significantly increased in active SLE and correlated with clinical SLEDAI. Complement C3 showed a weakly negative relationship with IFN-α and IL-18. IL-18 showed the highest positive likelihood ratios for active SLE. Multiple logistic regression analysis showed that IL-6, IL-8, and IL-18 significantly increased odds ratio (OR) for active SLE at baseline while complement C3 and IL-18 increased OR for active SLE at 12 weeks. IL-18 and IL-6 yielded higher sensitivity and specificity than anti-dsDNA and C3 to predict active renal and active non-renal, respectively.. The heterogeneity of SLE pathogenesis leads to different signaling mechanisms and mediates through several cytokines. The monitoring of cytokines increases the sensitivity and specificity to determine SLE disease activity. IL-18 predicts the risk of active renal SLE while IL-6 and IL-8 predict the risk of active non-renal. The sensitivity and specificity of these cytokines are higher than the anti-dsDNA or C3. We propose to use the serum level of IL-18, IL-6, and IL-8 to monitor SLE disease activity in clinical practice.

Topics: Adult; Biomarkers; Cytokines; Female; Humans; Inflammation Mediators; Interleukin-18; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Young Adult

BACKGROUND Patients with systemic lupus erythematosus (SLE), especially with lupus nephritis (LN), undergo vascular damage and repair during the course of the disease. Since the recently identified angiogenic T cells (Tang) are involved in endothelial repair coupled with endothelial progenitor cells (EPCs), this study investigated the circulating Tang cells in LN patients and their potential correlations with disease features. MATERIAL AND METHODS Circulating Tang cells and EPCs were assessed by flow cytometry in peripheral blood samples from 67 SLE patients; of these, 32 had LN and 30 were matched healthy controls (HCs). The plasma levels of interleukin IL-17, IL-8, and vascular endothelial growth factor (VEGF) were quantified by immunoassays. RESULTS The percentage of circulating Tang cells in LN patients was significantly increased as compared to the non-LN patients and HCs, and they were positively correlated with the level of EPC and VEGF. Additionally, circulating Tang cell percentages were positively correlated with the extent of proteinuria in LN patients. CONCLUSIONS The increased levels of circulating Tang cells in LN patients might play a role in the balance of endothelium dysfunction in these patients.

Topics: Adult; Angiogenesis Inducing Agents; Endothelial Cells; Female; Flow Cytometry; Humans; Interleukin-17; Interleukin-8; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; T-Lymphocytes; Vascular Endothelial Growth Factor A

Anti-DNA autoantibodies are a hallmark of systemic lupus erythematosus (SLE). A subset of anti-DNA IgG autoantibodies is cell-internalizable; thus they can enter living cells in the form of free IgG. However, the contribution made by the Fc region of internalized free-form IgG to the cytokine response has not been studied, despite the recent discovery of tripartite motif-containing 21 (TRIM21), a cytosolic Fc receptor involved in immune signaling. This study used an internalizable IgG anti-DNA antibody (3D8) to examine the cytokine responses of human monocytes to the Fc region of cytosolic free IgG. Internalization of 3D8 IgG and a 3D8 single-chain variable fragment-Fc (scFv-Fc) induced production of IL-8 and TNF-α via activation of NF-κB. By contrast, a 3D8 scFv (comprising variable domains alone) did not. This suggests Fc-dependent cytokine signaling. A 3D8 IgG-N434D mutant that is not recognized by TRIM21 induced greater production of cytokines than 3D8 IgG. Moreover the amounts of cytokines induced by 3D8 IgG in TRIM21-knockdown THP-1 cells were higher than those in control cells, indicating that cytokine signaling is not mediated by TRIM21. The results suggest the existence of a novel Fc-dependent signaling pathway that is activated upon internalization of IgG antibodies by human monocytes.

Topics: Antibodies, Antinuclear; Cytosol; Endocytosis; Humans; Immunoglobulin G; Inflammation Mediators; Interleukin-8; Lupus Erythematosus, Systemic; Monocytes; Mutation; NF-kappa B; Receptors, Fc; Ribonucleoproteins; RNA, Small Interfering; Signal Transduction; Single-Chain Antibodies; THP-1 Cells; Tumor Necrosis Factor-alpha

The Fc portion of immunoglobulin (Ig)G harbours a single glycosylation site. Glycan sialylation is critical for structure and for certain effector functions of IgG. Anti-histone IgG of patients with systemic lupus erythematosus is reportedly responsible for the recruitment of polymorphonuclear cells (PMN) to the clearance of apoptotic cells. Autoantibodies decorating secondary necrotic cells (SNEC) induce proinflammatory responses after activation of blood-borne phagocytes. Analysing the sialylation status of affinity-purified anti-histone IgG in patients with systemic lupus erythematosus (SLE), we demonstrated that the anti-histone IgG was contained preferentially in the non-sialylated fraction. In functional ex-vivo phagocytosis studies, non-sialylated anti-SNEC IgG directed SNEC preferentially into PMN but did not change their cytokine secretion profiles. In contrast, sialylated IgG reduced the phagocytosis by monocytes of SNEC. Moreover, the sialylated anti-SNEC IgG was not simply anti-inflammatory, but switched the cytokine secretion profiles from interleukin (IL)-6/IL-8 to tumour necrosis factor (TNF)-α/IL-1β. Here we describe how different sialylation statuses of IgG autoantibodies contribute to the complex inflammatory network that regulates chronic inflammation.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Autoantibodies; Case-Control Studies; Gene Expression Regulation; Glycosylation; Histones; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Interleukin-1beta; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Middle Aged; Neutrophils; Phagocytosis; Primary Cell Culture; Sialic Acids; Tumor Necrosis Factor-alpha

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

We investigated the expression and proinflammatory activity of interleukin (IL)-36 in patients with systemic lupus erythematosus (SLE). The expression level of IL-36, its putative receptors and the frequency of CD19⁺CD24(high)CD27⁺ regulatory B (Breg) lymphocytes of peripheral blood from 43 SLE patients and 16 normal control (NC) subjects were studied using ELISA and flow cytometry. Plasma cytokines/chemokines and ex vivo productions of cytokine/chemokine from peripheral blood mononuclear cells (PBMC) stimulated with recombinant IL-36 were determined by Luminex multiplex assay. Plasma concentrations of IL-36α, IL-36γ and the proportions of circulating IL-36R-positive CD19⁺ B lymphocytes in total B lymphocytes and PBMC were significantly increased in active SLE patients compared with NC (all p < 0.05). Plasma IL-36α and IL-36γ correlated positively with SLE disease activity and elevated plasma IL-10 concentration (all p < 0.05). The frequencies of circulating Breg lymphocytes in total B lymphocytes and PBMC were significantly decreased in both inactive and active SLE patients compared with NC (all p < 0.01). The frequency of Breg lymphocytes in total B lymphocytes correlated negatively with the proportion of IL-36R-positive B lymphocytes (p < 0.05). IL-36α exerted substantial proinflammatory effect in PBMC from SLE patients by inducing the production of IL-6 and CXCL8. Upon stimulation with IL-36α and IL-36γ, ex vivo productions of IL-6 and CXCL8 were significantly increased in SLE patients compared with NC (all p < 0.05). This cross-sectional study demonstrated that over expression of circulating IL-36α may exert a proinflammatory effect as observed in human SLE.

Topics: Adult; B-Lymphocytes, Regulatory; Cross-Sectional Studies; Female; Gene Expression Regulation; Humans; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Receptors, Interleukin; Up-Regulation; Young Adult

The purpose of this study is to evaluate the relationship between the concentration of interleukin-8 (IL-8) in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) with the disease activity score and pulmonary function of systemic lupus erythematosus (SLE) patients with and without pulmonary fibrosis. Thirty-four SLE patients and 31 healthy controls were enrolled and evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, systemic lupus activity measure (SLAM), assessing BALF and EBC. IL-8 levels in BALF and EBC samples were measured with an enzyme-immunosorbent assay kit. The mean (±SEM) IL-8 concentrations in BALF and EBC were higher in SLE patients compared to healthy controls (34.84 ± 95.0 vs. 7.65 ± 21.22 pg/ml, p < 0.001; 3.82 ± 0.52 pg/m vs. 1.7 ± 1.7 pg/ml, p < 0.001, respectively). SLE patients had increased percentage of neutrophils in BALF when compared with control group (1.00 ± 5.99 vs. 0.00 ± 0.56 %, p = 0.0003). Pulmonary fibrosis in HRCT was found in 50 % of SLE patients. The disease activity scored by SLAM was significantly higher and total lung capacity was significantly lower in SLE patients with pulmonary fibrosis (8.00 ± 3.17 vs. 6.00 ± 2.31, p = 0.01; 88.00 ± 28.29 vs. 112.00 ± 21.08 % predicted, p = 0.01, respectively). In SLE patients with pulmonary fibrosis, correlations were found between SLAM and IL-8 concentration in BALF, forced expiratory volume in 1 s and forced vital capacity (r = 0.65, p = 0.006; r = -0.53, p = 0.035; r = -0.67, p = 0.006, respectively). Our results indicate that IL-8 plays an important role in the pathogenesis of SLE. An increased concentration of IL-8 according to BALF could be considered as a useful biomarker of SLE activity and pulmonary fibrosis in SLE.

Topics: Adult; Biomarkers; Breath Tests; Bronchoalveolar Lavage Fluid; Disease Progression; Exhalation; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Pulmonary Fibrosis; Spirometry; Young Adult

Systemic lupus erythematosus (SLE) is an autoimmune systemic disease caused as a result of an imbalance of Th1-/Th2-type cytokines. The soluble form of CD30 (CD30s) released from peripheral blood cells has been described as a marker of active disease in Th2-type immune response as in SLE. However, the expression of CD30 on CD3 T lymphocytes from patients with SLE has not been studied yet. Therefore, we have addressed our study to attempt this issue, studying CD30 expression by flow cytometry on CD3 T lymphocytes and CD4/CD8 subsets in samples from SLE patients mainly with lupus nephritis. In parallel, we have determined the production of the cytokines IL-4 (Th2), IFNγ (Th1), IL-10 and TGFβ by intracellular staining. Differences between positive CD30 T cells in healthy controls and patients with SLE were found, with a higher percentage of CD30-expressing T cells in patients with SLE (P = 0.001). In contrast to healthy controls, CD30 was mainly expressed on CD8 T cells from patients with SLE. The intracellular cytokine staining showed that TGFβ is the main cytokine expressed in CD3 T cells from patients with SLE. In addition to this, we have found a positive correlation between CD30-expressing T cells and IL-4, IFNγ, and immunosuppressive cytokines (IL-10 and TGFβ) (P < 0.05). These results suggest that CD30 could play a role in the pathogenesis of SLE and its expression on CD3 T lymphocytes is not restricted only to Th2-type response.

Topics: Adult; Biomarkers; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-8; Ki-1 Antigen; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; T-Lymphocyte Subsets; Transforming Growth Factor beta

Chemokines promote leukocyte traffic into the site of inflammation. Serum levels of monocyte chemotactic protein 1 (MCP-1), stromal cell-derived factor-1 (SDF-1), interferon-gamma-inducible protein 10 (IP-10), and interleukin-8 (IL-8) were evaluated in 48 treated women with systemic lupus erythematosus (SLE) and mild-to-moderate disease severity. The results were compared between the whole SLE group and the control (29 women). The relationships between chemokines, their concentrations, and peripheral blood leukocyte count and between the chemokines and individual leukocyte populations (polymorphonuclear leukocytes-PMNs, lymphocytes-Ls, monocytes-Ms, eosinophils) counts were determined. The relationships between the analyzed chemokines were also determined in the control. SLE subjects had significantly higher MCP-1, SDF-1, IP-10, and lower IL-8 concentrations compared to the control. Moderate, positive correlations between MCP-1/SDF-1, SDF-1/IP-10 and a negative correlation between MCP-1/IL8 were observed in the patient group. Moderate, negative correlations were found between SDF-1/total leukocyte count, SDF-1/absolute number of PMNs as well as between IP-10/total leukocyte count, IP-10/absolute PMNs, Ls, and Ms counts in peripheral blood of SLE group. We suggest that the obtained results and correlations observed between the examined parameters might be used to monitor SLE course and progression. However, further randomized clinical studies should be carried out on in untreated and treated patients with SLE.

Topics: Adult; Aged; Chemokine CCL2; Chemokine CXCL10; Chemokine CXCL12; Chemokines; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Middle Aged; Retrospective Studies

The clearance of apoptotic cells occurs in a non-inflammatory context. Defects in this clearance process have been linked to the emergence of human autoimmune diseases like systemic lupus erythematosus (SLE). A characteristic of apoptotic cell death is the shedding of membrane coated vesicles from the cellular surfaces. Those vesicles have recently been recognized as mediators of intercellular communication or as adjuvant in the pathogenesis of autoimmune diseases. We analyzed the interactions between these apoptotic cell-derived membrane vesicles and professional antigen presenting cells. These vesicles were engulfed by monocyte-derived dendritic cells (mDC) and stimulated their maturation towards a phenotype comprising an upregulation of CD80, CD83, CD86, and a remarkable downregulation of MHC class II molecules. We observed only a minor release of proinflammatory cytokines from these mDC when compared to LPS stimulation. mDC stimulated by apoptotic vesicles did not cause significant T-cell expansion. Interestingly, when compared to normal healthy donors SLE patients-derived dendritic cells showed a significantly different phenotype lacking the downregulation of MHC class II, which correlated to disease activity.

Topics: Adult; Aged; Antigens, CD; Apoptosis; B7-1 Antigen; B7-2 Antigen; CD4-Positive T-Lymphocytes; CD83 Antigen; Cell Communication; Cell Proliferation; Cells, Cultured; Cytoplasmic Vesicles; Dendritic Cells; Female; Histocompatibility Antigens Class II; Humans; Immunoglobulins; Interleukin-12; Interleukin-8; Lupus Erythematosus, Systemic; Male; Membrane Glycoproteins; Middle Aged; Phagocytosis; 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 sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA).. Plasma/serum samples from SLE patients (n = 35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1β, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls.. Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p = 0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p = 0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p = 0.0087).. Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE.

Topics: Adolescent; Adult; Antirheumatic Agents; Biomarkers; CD40 Ligand; Chemokine CCL2; Chemokine CXCL10; Cohort Studies; Cytokines; Female; Humans; Hydroxychloroquine; Interferon-alpha; Interleukin-1beta; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Severity of Illness Index; Statistics, Nonparametric; Tumor Necrosis Factor-alpha; United States; Young Adult

The underlying mechanisms for the subsets of self-limiting, intermittent or chronic and deforming arthritis in systemic lupus erythematosus (SLE) are not well understood. We performed a cross-sectional analysis of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8 and TNF-α) and joint status in 47 SLE patients (79% females, age 42 years, disease duration 8.6 years). All cytokines levels were significantly elevated in SLE patients compared with controls, but only IL-2 and IL-8 levels were higher than in patients with rheumatoid arthritis. SLE patients with ongoing synovitis (19%) and joint deformities (11%) had increased erythrocyte sedimentation rate (ESR), IL-6 and anti-dsDNA Ab levels. IL-6 levels correlated with ESR, anti-dsDNA Ab and haemoglobin, but not with C-reactive protein levels. Arthritis constitutes a considerable burden of disease in SLE over time, and joint deformations are associated with longstanding disease and arthritis flare rates. IL-6 is a potential biomarker and therapeutic target in the prevention of joint damage in SLE arthritis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; Case-Control Studies; Cross-Sectional Studies; Cytokines; Female; Humans; Interleukin-2; Interleukin-6; Interleukin-8; Joint Deformities, Acquired; Lupus Erythematosus, Systemic; Male; Middle Aged; Registries; Synovitis

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organ systems. Previous studies have suggested that interferon-lambda 1 (IFN-λ1), a type III interferon, plays an immunomodulatory role. In this study we investigated its role in SLE, including its correlation with disease activity, organ disorder and production of chemokines.. We determined levels of IFN-λ1 mRNA in peripheral blood mononuclear cells (PBMC) and serum protein levels in patients with SLE using real-time polymerase chain reaction (real-time PCR) and enzyme-linked immunoassay (ELISA). Further, we detected the concentration of IFN-inducible protein-10 (IP-10), monokine induced by IFN-γ (MIG) and interleukin-8 (IL-8) secreted by PBMC under the stimulation of IFN-λ1 using ELISA.. IFN-λ1 mRNA and serum protein levels were higher in patients with SLE compared with healthy controls. Patients with active disease showed higher IFN-λ1 mRNA and serum protein levels compared with those with inactive disease as well. Serum IFN-λ1 levels were positively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), anti-dsDNA antibody, C-reactive protein (CRP) and negatively correlated with complement 3. Serum IFN-λ1 levels were higher in SLE patients with renal involvement and arthritis compared with patients without the above-mentioned manifestations. IFN-λ1 with different concentrations displayed different effects on the secretion of the chemokines IP-10, MIG and IL-8.. These findings indicate that IFN-λ1 is probably involved in the renal disorder and arthritis progression of SLE and associated with disease activity. Moreover, it probably plays an important role in the pathogenesis of SLE by stimulating secretion of the chemokines IP-10, MIG and IL-8. Thus, IFN-λ1 may provide a novel research target for the pathogenesis and therapy of SLE.

Topics: Adolescent; Adult; Cells, Cultured; Chemokine CXCL10; Chemokine CXCL9; Chemokines; Female; Humans; Immunomodulation; Interferon-gamma; Interferons; Interleukin-8; Interleukins; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; RNA, Messenger; Severity of Illness Index; Young Adult

This case-controlled study was designed to correlate urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) levels, with renal involvement in a cohort of systemic lupus erythematosus (SLE) patients to examine their diagnostic performance.. In 73 SLE patients, and in 23 healthy volunteers, urinary levels of TWEAK, OPG, MCP-1, and IL-8 levels were measured. Disease activity was assessed by total SLE disease activity index, and renal activity by renal activity index (rSLEDAI), and both were correlated with urinary biomarkers. Sensitivity, specificity, and predictive values of individual biomarkers to predict lupus nephritis were also calculated.. Significantly higher levels of urinary biomarkers were observed in SLE patients with lupus nephritis (LN) compared with those without LN (TWEAK, p < 0.001; MCP-1, p < 0.001; OPG, p < 0.001; IL-8, p < 0.032). Other significantly higher levels were observed in SLE patients with LN compared with control subjects (TWEAK, MCP-1, OPG, and IL-8 p < 0.001). Positive correlations were observed between rSLEDAI and TWEAK (r = 0.612 and p < 0.001), MCP-1 (r = 0.635 and p < 0.001), and OPG (r = 0.505 and p < 0.001).. Urinary levels of TWEAK, OPG, and MCP-1 positively correlate with renal involvement as assessed by rSLEDAI with reasonable sensitivity, specificity, and predictive values to detect lupus nephritis while IL-8 was not significantly associated with global or rSLEDAI.

Topics: Adult; Biomarkers; Case-Control Studies; Cohort Studies; Cytokine TWEAK; Disease Progression; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Membrane Cofactor Protein; Molecular Targeted Therapy; Osteoprotegerin; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Tumor Necrosis Factors

Sterile inflammation resulting from cell death is due to the release of cell contents normally inactive and sequestered within the cell; fragments of cell membranes from dying cells also contribute to sterile inflammation. Endothelial cells undergoing stress-induced apoptosis release membrane microparticles, which become vehicles for proinflammatory signals. Here, we show that stress-activated endothelial cells release two distinct populations of particles: One population consists of membrane microparticles (<1 μm, annexin V positive without DNA and no histones) and another larger (1-3 μm) apoptotic body-like particles containing nuclear fragments and histones, representing apoptotic bodies. Contrary to present concepts, endothelial microparticles do not contain IL-1α and do not induce neutrophilic chemokines in vitro. In contrast, the large apoptotic bodies contain the full-length IL-1α precursor and the processed mature form. In vitro, these apoptotic bodies induce monocyte chemotactic protein-1 and IL-8 chemokine secretion in an IL-1α-dependent but IL-1β-independent fashion. Injection of these apoptotic bodies into the peritoneal cavity of mice induces elevated serum neutrophil-inducing chemokines, which was prevented by cotreatment with the IL-1 receptor antagonist. Consistently, injection of these large apoptotic bodies into the peritoneal cavity induced a neutrophilic infiltration that was prevented by IL-1 blockade. Although apoptosis is ordinarily considered noninflammatory, these data demonstrate that nonphagocytosed endothelial apoptotic bodies are inflammatory, providing a vehicle for IL-1α and, therefore, constitute a unique mechanism for sterile inflammation.

Topics: Animals; Apoptosis; Autoimmunity; Cell-Derived Microparticles; Chemokine CCL2; Endothelial Cells; Histones; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-8; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury

Deficiencies in the recognition and engulfment of apoptotic cells have been reported in patients with systemic lupus erythematosus (SLE). If dying cells are not promptly cleared, they undergo secondary necrosis and release nuclear autoantigens. Secondarily necrotic cell-derived material (SNEC) can be generated in vitro employing various methods. SNEC generated by either methods shows similar DNA content, light scatter characteristics, and binding pattern of dead and dying cell ligands and is readily recognized by autoantibodies (AAb) of many patients with SLE. In whole blood, AAb opsonize SNEC and foster its uptake by blood-borne non-professional phagocytes. We observed a significant secretion of the inflammatory cytokines IL-8 and TNF-alpha by phagocytes which had engulfed different types of opsonized SNEC. Phagocytosis of SNEC and the subsequent production of inflammatory cytokines were strongly influenced by the presence of DNA in this prey, since DNase I treatment reduced both the uptake of SNEC and the induction of IL-8 and TNF-alpha production. In conclusion, the proinflammatory phagocytosis by circulating phagocytes of IgG-opsonized cellular remnants fosters systemic inflammation in SLE.

Topics: Apoptosis; Autoantibodies; DNA; Humans; Immunoglobulin G; Inflammation; Interleukin-8; Lupus Erythematosus, Systemic; Necrosis; Opsonin Proteins; Phagocytosis; Tumor Necrosis Factor-alpha

Decreased apoptotic cells (ACs) removal has been described as relevant in systemic lupus erythematosus (SLE) pathogenesis. Binding/phagocytosis of ACs was decreased in SLE patients. Blocking experiments suggested a role for CD36 in ACs clearance in healthy controls, not observed in SLE patients. Binding/phagocytosis of ACs induced the production of IL-6, CXCL8 and CCL22 in patients and controls and IL-1β, TNF-α and CCL3 only in healthy controls. ACs clearance induced an increase in CD80 and a decrease in CD86 expression in healthy controls and atherosclerotic patients. However, SLE patients did not up-regulate CD80 expression. The number and expression of CD36 and CD163 in monocytes was not different between the groups. ACs removal induced a down-regulation of CD36 expression in adherent HLA-DR(+) cells in SLE patients but not healthy controls. The decreased binding/phagocytosis of ACs observed in SLE patients, induces a distinct immune response compared with healthy controls.

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Atherosclerosis; B7-1 Antigen; B7-2 Antigen; CD36 Antigens; CD40 Antigens; Chemokine CCL2; Chemokine CCL22; Chemokine CCL3; Culture Media, Conditioned; Female; HLA-DR Antigens; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Male; Middle Aged; Monocytes; Phagocytosis; Receptors, Cell Surface; Tumor Necrosis Factor-alpha; Young Adult

C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFNalpha).. Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFNalpha production was determined by an immunoassay.. C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNalpha production induced by ICs and CpG DNA but increased PDC IFNalpha production induced by HSV. The regulatory role of C1q was not specific for IFNalpha but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins.. Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.

Topics: Antigen-Antibody Complex; Cells, Cultured; Complement C1q; Dendritic Cells; Humans; Integrin alpha2; Interferon-alpha; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Membrane Glycoproteins; Receptors, Complement; Receptors, Complement 3b; Risk Factors; Simplexvirus; Tumor Necrosis Factor-alpha

Systemic lupus erythematosus (SLE) predominantly affects women, especially those in reproductive age. Genetic contributions to disease susceptibility as well as immune dysregulation, particularly persistent inflammatory responses, are considered essential features. Our aim was to determine whether human umbilical vein endothelial cells (HUVEC) isolated from healthy newborns to women with inactive SLE show inflammation-related abnormalities that might lead to an early development of SLE in the offsprings. HUVEC isolated from six women with inactive SLE were stimulated with 2.5 ng/mL of TNF-alpha and/or physiological and pharmacological doses of 17-I(2) estradiol (E2). Then the expression of VCAM-1, ICAM-1, E-selectin, toll-like receptor-9 (TLR-9), heat shock protein 70 (HSP70) and HSP90 were measured. The concentrations of IL-6, IL-8, and IL-10 were also determined in maternal serum and in TNF-alpha stimulated and non-stimulated HUVEC culture supernatant. HUVEC from children with no family history of autoimmune disease served as controls. Our results showed that in HUVEC from SLE+ mothers, a constitutively low expression of adhesion molecules was enhanced by TNF-alpha treatment. The E2 (1 ng/mL) increased the expression of adhesion molecules but had no effect upon TNF-alpha-treated cells. IL-6 was constitutively higher in SLE+ HUVEC, whereas IL-8 was lower; E2 treatment diminished the latter. The E2 had no effect upon IL-6 and IL-8 secretions in TNF-alpha-treated cells. SLE+ HUVEC showed a disordered cytoskeleton and overexpressed HSP70, HSP90, and TLR-9. Our results indicate that endothelial cells of newborns to SLE+ mothers are in a proinflammatory condition which can be upregulated by estrogens.

Topics: Adult; Cells, Cultured; Cytoskeleton; E-Selectin; Endothelial Cells; Estrogens; Female; Fluorescent Antibody Technique; Heat-Shock Proteins; Humans; Infant, Newborn; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Pregnancy; Pregnancy Complications; Toll-Like Receptor 9; Umbilical Veins; Young Adult

To elucidate the molecular basis of hyporesponsiveness of polymorphonuclear neutrophils (PMN) to interleukin-8 (IL-8) stimulation in patients with active SLE.. PMN obtained from active SLE and well-matched healthy individuals were studied. The expression of two IL-8 receptors, CXCR1 and CXCR2, in PMN were detected by flow cytometry and reverse transcriptase-polymerase chain reaction. The binding affinity of PMN with IL-8 was calculated by Scatchard plotting. Soluble CXCR2 level in IL-8-stimulated PMN culture supernatant was measured by sandwich enzyme-linked immunosorbent assay. The resting and IL-8-stimulated membrane potential (MP) changes, and membrane expression of cationic ion transporters including Na+-K+-ATPase, renal epithelial Na+ channel (ENaC) and renal outer medullary epithelial K+ channel 1 (ROMK1) on PMN were detected by flow cytometry.. Compared with normal PMN, decreased CXCR2 gene expression, but normal IL-8-binding affinity of SLE-PMN, was found. For exploring the molecular basis of the defect, the modulation of CXCR2 in SLE-PMN was intensively investigated. We found that increased cytosolic CXCR2 expression in SLE-PMN was due to defective surface translocation, increased spontaneous internalization and/or increased spontaneous synthesis. The IL-8-induced CXCR2 down-regulation in SLE-PMN was also impaired due to decreased proteolytic cleavage of IL-8-IL-8 receptor complexes from the cell surface whereas IL-8-induced internalization of the complexes was normal. In addition, we originally found that increased resting but decreased IL-8-stimulated MP in SLE-PMN was relevant to defective expression of Na+-K+-ATPase, ENaC and ROMK1 on the cell surface.. The abnormal CXCR2 modulation and impaired cationic ion transporter expression cause SLE-PMN hyporesponsiveness to IL-8 stimulation in vitro.

Topics: Female; Flow Cytometry; Gene Expression Regulation; Humans; Interleukin-8; Lipopolysaccharides; Lupus Erythematosus, Systemic; Male; Neutrophils; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The literature on cytokine response in systemic lupus erythematosus (SLE) is confusing. It is possible that different disease phenotypes have different cytokine profiles. Our aim was to examine the levels of selected pro-inflammatory and anti-inflammatory cytokines in SLE patients with and without pulmonary involvement.. Patients with SLE were interviewed and were subjected to the pulmonary function test and high-resolution computed tomography studies. Serum levels of interleukin (IL)-6, IL-8, IL-10, Il-12, interferon (IFN) gamma, and tumor necrosis factor (TNF) alpha were estimated by enzyme-linked immunosorbent assay.. Forty-nine of the 61 SLE patients had pulmonary involvement. Median levels of IL-8, IFNgamma, and TNFalpha were significantly higher in the pulmonary group as compared to the non-pulmonary group (p = 0.027, 0.027 and 0.002, respectively). Ratios of pro-inflammatory cytokines to anti-inflammatory cytokines were higher in the pulmonary group as compared to the non-pulmonary group as well as in the pulmonary restrictive subgroup compared to the obstructive subgroup.. Lupus patients with pulmonary involvement have a stronger pro-inflammatory cytokine bias than those without pulmonary involvement.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Lung Diseases; Lupus Erythematosus, Systemic; Male; Middle Aged; Phenotype; Plethysmography, Whole Body; Spirometry; Tumor Necrosis Factor-alpha

Acute confusional state (ACS) is an uncommon but severe central nervous system (CNS) syndrome in systemic lupus erythematosus (SLE) defined by clinical manifestations. To develop useful and reliable diagnostic tools for ACS, we evaluated the association of cerebral spinal fluid (CSF) tests with ACS and their predictive values for the diagnosis of ACS in SLE.. We performed a prospective study using a cohort of 59 patients with SLE and compared those with and without ACS. Associations between ACS and each CSF test [interleukin 6 (IL-6), IL-8, interferon-alpha, IgG index, and Q-albumin] were statistically evaluated. Each patient underwent all CSF evaluations.. ACS was diagnosed in 10 patients (ACS group), SLE-related CNS syndromes except ACS in 13, and no CNS syndromes in 36 (non-CNS group). CSF IL-6 levels in the ACS group were significantly higher than those in the non-CNS group (p < 0.05). A positive IgG index (p = 0.028) was significantly associated with ACS. No other test showed a significant association with ACS. The positive and negative predictive values for the diagnosis of ACS in SLE were 80% and 85% for elevated CSF IL-6 levels (> or = 31.8 pg/ml), and 75% and 83% for the IgG index, respectively.. No single CSF test had sufficient predictive value to diagnose ACS in SLE, although CSF IL-6 levels and the IgG index showed statistical associations with ACS. Use of CSF tests combined with careful history and clinical examinations is recommended for proper diagnosis of ACS in SLE.

Topics: Adolescent; Adult; Cohort Studies; Delirium; Female; Humans; Interferon-alpha; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Predictive Value of Tests

Chemokines are involved in leucocyte chemotaxis. Infiltrating leucocytes play an important role of tissue injury in systemic lupus erythematosus (SLE).. To investigate the role of inflammatory chemokines and their association with interleukin 18 (IL18) in SLE pathogenesis and disease activity.. Plasma concentrations and ex vivo peripheral blood mononuclear cell production of inflammatory chemokines IP-10, RANTES, MIG, MCP-1, TARC, IL8, and GROalpha, and proinflammatory cytokines IL18, IFNgamma, IL2, IL4, and IL10 were assayed in 80 SLE patients with or without renal disease and 40 healthy controls by immunofluorescence flow cytometry and enzyme linked immunosorbent assay.. Plasma IP10, RANTES, MIG, MCP-1, GROalpha, and IL18 concentrations in all SLE patients were higher than in controls, and correlated significantly with SLEDAI score (all p<0.05). In SLE patients without renal disease, IP10, RANTES, MIG, MCP-1, IL8, and IL18 correlated positively with SLEDAI score, while in those with renal derangement, IP10, IL8, IL10, and IL18 correlated with disease activity (all p<0.05). Plasma IL18 concentration correlated positively with IP10, MIG, GROalpha, and IL8 in all SLE patients (all p<0.005). Mitogen induced increases in ex vivo production of IP10, MCP-1, TARC, IFNgamma, IL4, and IL10 were higher in all SLE patients regardless of their difference in disease activity (all p<0.05). Patients with renal disease had an augmented ex vivo release of RANTES.. The correlation of raised plasma concentration and ex vivo production of inflammatory chemokines with disease activity, and their association with IL18, supports the view that chemotaxis of Th1/Th2 lymphocytes and neutrophils is important in SLE pathogenesis.

Topics: Acute Disease; Adult; Analysis of Variance; Case-Control Studies; Cells, Cultured; Chemokine CCL17; Chemokine CCL2; Chemokine CCL5; Chemokine CXCL9; Chemokines; Chemokines, CC; Chemokines, CXC; Female; Humans; Intercellular Signaling Peptides and Proteins; Interferon-gamma; Interleukin-10; Interleukin-18; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; Lupus Erythematosus, Systemic; Male; Middle Aged; Phytohemagglutinins; T-Lymphocytes

Dendritic cells (DCs) play a key role in regulating immune responses, especially in priming naïve T-cells. Recently, DCs have been suggested to be involved in systemic lupus erythematosus (SLE) development by activating autoreactive T-helper lymphocytes. As a consequence, we compared the activation state of human monocyte-derived DCs (MDDCs) obtained from lupus patients and normal individuals.. The MDDCs were generated in vitro from blood from healthy donors and lupus patients. Immature and mature MDDCs were analysed by flow cytometry for several cell surface molecules. In parallel, cytokine secretion was determined by ELISA before and after MDDC activation. In each experiment, lupus DCs were compared with normal DCs.. Here, we show for the first time that lupus MDDCs spontaneously over-express CD86 in the absence of any DC activation signal as compared with normal MDDCs (P = 0.025). Moreover, activation-induced IL-6 secretion was increased in lupus DCs with high CD86 over-expression as compared with normal DCs (P = 0.010). Interestingly, the percentage of MDDCs in lupus preparations is negatively correlated with disease activity scores (SLEDAI; P = 0.031).. Lupus MDDCs are pre-activated suggesting that they might be more efficient antigen-presenting cells. This result might partly explain how the peripheral tolerance is broken in SLE.

Topics: Adult; Autoimmunity; B7-2 Antigen; Case-Control Studies; Cell Differentiation; Cells, Cultured; Dendritic Cells; Female; Flow Cytometry; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Probability; Tumor Necrosis Factor-alpha

Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1alpha, and MCP-1 for systemic lupus erythematosus.. The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1alpha, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay.. No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1alpha, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found.. These results suggest that the tested functional variation of RANTES, IL-8, IL-1alpha, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population.

Topics: Adult; Chemokine CCL2; Chemokine CCL5; Chemokines; Female; Genetic Predisposition to Disease; Genotype; Humans; Inflammation; Interleukin-1; Interleukin-8; Interleukins; Lupus Erythematosus, Systemic; Male; Polymorphism, Single Nucleotide

Systemic lupus erythematosus (SLE) is characterized by a systemic autoimmune response with profound and diverse T cell changes. Dendritic cells (DCs) are important orchestrators of immune responses and have an important role in the regulation of T cell function. The objective of this study was to determine whether myeloid DCs from individuals with SLE display abnormalities in phenotype and promote abnormal T cell function. Monocyte-derived DCs and freshly isolated peripheral blood myeloid DCs from lupus patients displayed an abnormal phenotype characterized by accelerated differentiation, maturation, and secretion of proinflammatory cytokines. These abnormalities were characterized by higher expression of the DC differentiation marker CD1a, the maturation markers CD86, CD80, and HLA-DR, and the proinflammatory cytokine IL-8. In addition, SLE patients displayed selective down-regulation of the maturation marker CD83 and had abnormal responses to maturation stimuli. These abnormalities have functional relevance, as SLE DCs were able to significantly increase proliferation and activation of allogeneic T cells when compared with control DCs. We conclude that myeloid DCs from SLE patients display significant changes in phenotype which promote aberrant T cell function and could contribute to the pathogenesis of SLE and organ damage.

Topics: Adult; Antigens, CD; Cell Differentiation; Cell Proliferation; Dendritic Cells; Female; HLA-DR Antigens; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Middle Aged; Monocytes; Myeloid Cells; Phenotype; T-Lymphocytes; Up-Regulation

The nucleosome is a major autoantigen in systemic lupus erythematosus (SLE); it can be detected as a circulating complex in the serum, and nucleosomes have been suggested to play a key role in disease development. In the present study, we show for the first time that physiological concentrations of purified nucleosomes trigger innate immunity. The nucleosomes are endocytosed and induce the direct activation of human neutrophils (polymorphonuclear leukocytes (PMN)) as revealed by CD11b/CD66b up-regulation, IL-8 secretion, and increased phagocytic activity. IL-8 is a neutrophil chemoattractant detected in high concentrations in the sera of patients, and IL-8 secretion might thus result in enhanced inflammation, as observed in lupus patients, via an amplification loop. Nucleosomes act as free complexes requiring no immune complex formation and independently of the presence of unmethylated CpG DNA motifs. Both normal and lupus neutrophils are sensitive to nucleosome-induced activation, and activation is not due to endotoxin or high-mobility group box 1 contamination. In mice, i.p. injection of purified nucleosomes induces neutrophil activation and recruitment in a TLR2/TLR4-independent manner. Importantly, neutrophils have been suggested to link innate and adaptive immunity. Thus, nucleosomes trigger a previously unknown pathway of innate immunity, which may partially explain why peripheral tolerance is broken in SLE patients.

Topics: Animals; Autoantigens; CD11b Antigen; Electrophoresis, Gel, Two-Dimensional; Endocytosis; Flow Cytometry; Humans; Immune Tolerance; Immunity, Innate; Interleukin-8; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Neutrophil Activation; Neutrophil Infiltration; Nucleosomes; Toll-Like Receptor 2; Toll-Like Receptor 4

The purpose of this study was to determine whether interleukin (IL)-6 and IL-8 gene polymorphisms were markers of susceptibility to or severity of systemic lupus erythematosus (SLE) in Chinese patients. The study included 150 Chinese patients with SLE. A total of 130 unrelated healthy individuals living in central Taiwan served as control subjects. Polymorphisms of the IL-6 and IL-8 gene were typed from genomic DNA. The genotypes, allelic frequencies, and carriage rates were compared between SLE patients and control subjects. The relationship between allelic frequencies and clinical manifestations of 135 SLE patients was evaluated. There were no statistically significant differences in IL-6 and IL-8 gene polymorphisms between the SLE and control groups (chi-squared test, P=0.53, chi(2)=1.27 and P=0.44, chi(2)=1.62, respectively). In addition, there was no significant association between the two groups in allelic frequency of IL-6 and IL-8 (P=0.89 and P=0.26, respectively). We also did not detect any association between the IL-6 and IL-8 genotype and clinical or laboratory profiles in SLE patients. The results suggest that the IL-6 and IL-8 gene polymorphisms are not related to SLE.

Topics: Adolescent; Adult; Aged; Alleles; Asian People; Case-Control Studies; Chi-Square Distribution; Female; Gene Frequency; Humans; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Polymorphism, Genetic; Taiwan

The purpose of this study was to evaluate urine monocyte chemoattractant protein-1 (MCP-1) and IL-8 as biomarkers of SLE flare. Urine was collected every 2 mo from patients who were followed prospectively in the Ohio SLE Study. Renal and nonrenal flares were identified and MCP-1 and IL-8 were measured by specific ELISA in samples that were collected at flare. When available, MCP-1 and IL-8 were also measured in urine samples before and after flare. For comparison, MCP-1 and IL-8 were measured in the urine of healthy individuals and in renal and nonrenal SLE patients with stable disease activity (disease controls). Most patients were receiving maintenance immunosuppressive therapy before flare. At renal flare, mean urine MCP-1 (uMCP-1) was significantly greater than uMCP-1 at nonrenal flare and from healthy volunteers and renal disease controls. The level of uMCP-1 correlated with the increase in proteinuria at flare and was higher in patients with proliferative glomerulonephritis and in patients with impaired renal function. Urine MCP-1 was increased beginning 2 to 4 mo before flare. Patients who responded to therapy showed a slow decline in uMCP-1 over several months, whereas nonresponders had persistently high uMCP-1. In contrast, uIL-8 did not change with disease activity and was not elevated at renal or nonrenal flare compared with disease controls. In conclusion, uMCP-1 but not uIL-8 is a sensitive and specific biomarker of renal SLE flare and its severity, even in patients who receive significant immunosuppressive therapy. Persistently elevated uMCP-1 after treatment may indicate ongoing kidney injury that may adversely affect renal prognosis.

Topics: Adult; Analysis of Variance; Biomarkers; Case-Control Studies; Chemokine CCL2; Chemokines; Cohort Studies; Disease Progression; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Probability; Prognosis; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Urinalysis

Proteinase 3 (PR3) is a pleiotropic and destructive serine protease and it is also a major target for autoantibodies in systemic small vessel vasculitis. We have shown recently that patients in stable remission have increased circulating levels of PR3, independent of autoantibody titre, inflammation, neutrophil degranulation and renal function. Here we explore the possibility of increased PR3 gene transcription. RNA was purified from peripheral blood monocytes from vasculitis patients and controls. Specific mRNA was measured by TaqMan real-time polymerase chain reaction (PCR). The monocyte-like cell lines THP-1 and U937 and human peripheral blod monocytes from healthy controls were stimulated with cytokines and lipopolysaccharide (LPS) for different time periods. PR3 protein was measured in plasma with enzyme-linked immunosorbent assay (ELISA). The median result for PR3 mRNA was 9.6 (1.8-680) for 22 patients, compared to 1 (0.1-2.8) for the 15 healthy controls. Elastase expression was also significantly increased, whereas myeloperoxidase and interleukin-8 were not. Stimulation of monocytes with tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma or LPS did not result in any increase of PR3 or elastase transcription, whereas interleukin (IL)-8 transcription was increased 10-fold. Circulating monocytes from patients with systemic vasculitis display increased PR3 gene transcription compared to healthy controls and patients with sytemic lupus erythematosus (SLE). This may be important for the development of vasculitis. Our results do not favour a role for cytokines, antineutrophil cytoplasmic antibodies (ANCA) or immunosuppressive medication in the upregulation of PR3 transcription in vasculitis.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Cell Line, Tumor; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Monocytes; Myeloblastin; Peroxidase; Polymerase Chain Reaction; RNA, Messenger; Serine Endopeptidases; Transcription, Genetic; Up-Regulation; Vasculitis

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

Decreased number and impaired functions of polymorphonuclear neutrophils (PMN) due to the presence of anti-PMN autoantibodies in the serum render patients with systemic lupus erythematosus (SLE) susceptible to bacterial infections. However, the cognate antigens and pathological mechanisms of anti-PMN autoantibodies in SLE are rarely reported in the literature. In this study, we found approximately 20% of SLE sera contained anti-PMN autoantibodies detected by human PMN-coated cellular ELISA. A membrane protein with molecular weight of 50 kDa was identified as the cognate antigen of anti-PMN in Western blot after membrane-biotinylation and streptavidin column elution. The 50 kDa molecule was proved to be SSB/La after immunoscreening, molecular cloning and nucleotide sequencing of the gene from the human leucocyte cDNA library. Human anti-SSB/La autoantibodies purified from active SLE sera passing through the recombinant SSB/La conjugated Sepharose 4B affinity column could bind and penetrate into normal human PMN. Functional analysis revealed that the anti-SSB/La autoantibodies exerted a number of potent effects on human PMN, including suppressed phagocytosis, accelerated apoptosis and enhanced IL-8 production. These in vitro results suggest that anti-SSB/La is one of the anti-PMN autoantibodies capable of penetrating into PMN and responsible for neutropenia and functional impairment of PMN in patients with SLE.

Topics: Apoptosis; Autoantibodies; Autoantigens; Base Sequence; Chromatography, Affinity; DNA, Complementary; Gene Expression; Humans; Interleukin-8; Jurkat Cells; Lupus Erythematosus, Systemic; Molecular Sequence Data; Neutropenia; Neutrophils; Phagocytosis; Ribonucleoproteins; SS-B Antigen

To determine whether serum concentrations of 2 CXC chemokines, interleukin 8 (IL-8) and growth-regulated oncogene-alpha (GRO-alpha), which are potent chemoattractants and activators for neutrophils, are elevated and whether they correlate with clinical features in patients with systemic sclerosis (SSc).. Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 36), limited cutaneous SSc (lSSc; n = 42), systemic lupus erythematosus (SLE; n = 15), dermatomyositis (DM; n = 15), and healthy controls (n = 35) were examined by ELISA.. Serum IL-8 was detected significantly more frequently in patients with dSSc (61%) and lSSc (55%) relative to healthy controls (6%), patients with SLE (7%), and those with DM (13%). Similarly, serum GRO-alpha concentrations in SSc patients were significantly increased compared with controls, patients with SLE, or those with DM. Elevated IL-8 concentrations significantly correlated with decreased % DLCO and rheumatoid factor positivity, while increased GRO-alpha levels were significantly associated with decreased % DLCO and % vital capacity, involvement of kidney and muscle, the presence of anti-topoisomerase I antibody, and increased serum IgG levels.. Our results suggest that the elevation of serum levels of the CXC chemokines IL-8 and GRO-alpha is specific to SSc and that the elevation of CXC chemokines, particularly GRO-alpha, correlates with the involvement of internal organs, especially pulmonary damage.

Topics: Adolescent; Adult; Aged; Chemokine CXCL1; Chemokines; Chemokines, CXC; Chemotactic Factors; Child; Dermatomyositis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Scleroderma, Systemic

Interleukin-8 (IL-8) is a potent neutrophil chemokine that has been implicated in the pathogenesis of renal inflammation in human glomerulonephritis. To explain inter-patient variations in renal inflammation during diseases such as systemic lupus erythematosus (SLE), it was postulated that the promoter region of the IL-8 gene contains polymorphic residues that influence the level of IL-8 expression in response to immune-complex deposition, and thereby affect the severity of renal injury. This study was undertaken to identify polymorphisms in the 5'-flanking region of the IL-8 gene that correlate with the severity of SLE nephritis.. A 1526 base pair segment of the IL-8 5'-flanking region was PCR amplified from the genomic DNA of 100 individuals and sequenced on an automated capillary electrophoresis system. Sequence data were compared with the published IL-8 sequence to identify polymorphisms. Allelic variations were verified by cloning and re-sequencing, and also by restriction enzyme analysis. Patients with SLE nephritis were genotyped for IL-8 polymorphisms, and associations between specific alleles and severity of SLE nephritis [based on the World Health Organization (WHO) classification] were determined.. Three single nucleotide polymorphisms were identified in the IL-8 flanking region. Labeled relative to the IL-8 translational start site, these are T-845C, T-738A, and A-353T. T-845C and T-738A are novel, and found primarily in African Americans. The C for T change at position -845 was found to be 3.6 to 7.5 times more frequent in African Americans with severe (WHO Class IV) SLE nephritis, than in African American controls, or patients with less severe forms of SLE nephritis, respectively.. IL-8-845C might predispose African Americans with SLE nephritis to more severe renal injury, perhaps by influencing IL-8 expression. Genotyping patients with glomerulonephritis for IL-8 polymorphisms may be useful in predicting disease outcome and individualizing immunosuppressive therapy.

Topics: Alleles; Asian People; Black People; Gene Frequency; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Polymorphism, Genetic; Polymorphism, Single Nucleotide; White People

To examine the effect of transfection of oligodeoxynucleotides (ODNs) containing a CpG motif (CpG-ODN), of which the sequence was derived from circulating DNA in the sera of patients with systemic lupus erythematosus (SLE), on the expression of intercellular adhesion molecule-1 (ICAM-1) and synthesis of mRNA for proinflammatory cytokines and ICAM-1 in human umbilical vein endothelial cells (EC).. A CpG-ODN or a control analogue, GpC-ODN, was transfected into EC. ICAM-1 expression was examined by flow cytometry, and expression of mRNA in EC encoding interleukin 1 (IL1), IL6, IL8, tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), and ICAM-1 was examined by semiquantitative reverse transcriptase-polymerase chain reaction.. The CpG-ODN augmented the expression of ICAM-1 on EC determined by flow cytometry and increased mRNA levels of IL6, IL8, TNFalpha, IFNgamma, and ICAM-1, but the GpC-ODN did not.. Synthesised DNA, with a sequence corresponding to that of the fragment containing the CpG motif, in sera of patients with SLE was found to enhance ICAM-1 expression on EC, suggesting the participation of circulating DNA fragments in the pathogenesis of vasculitis in SLE.

Topics: Cells, Cultured; CpG Islands; DNA; Endothelium, Vascular; Fatty Acids, Monounsaturated; Flow Cytometry; Fluorescent Dyes; Humans; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-1; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Quaternary Ammonium Compounds; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Immune imbalance in SLE increases the susceptibility to infectious diseases. The aim of this study was to analyze several mechanisms related to non-specific immunity in this autoimmune disorder. We studied in vivo CD11b expression, phagocytosis, and chemotaxis in polymorphonuclear cells (PMN) from SLE patients. All tests were also performed under hrIL-8 stimulating conditions and analyzed by flow cytometry. Intracellular leucocyte (monocytes and PMN) enzyme activity was evaluated using specific substrates for cathepsin B and D, collagenase, and oxidative burst by flow cytoenzymology. An exaggerated in vivo CD11b expression was observed on PMN from SLE patients without noticeably in vitro effect upon hrIL-8. Similarly both, phagocytosis and chemotaxis were diminished and showed no response to hrIL-8 stimulation. The opposite was found in PMN from controls. Intracellular enzyme activity was comparable between groups as far as cathepsin B and D are concerned. A tendency of decreased oxidative-burst induction was noted in monocytes and PMN from SLE patients, whereas collagenase activity was found clearly increased in both leucocyte subpopulations. Our results may represent a deficient ability of the innate immune mechanisms for the clearance of infectious agents, immune complexes, satisfactory resolution of inflammatory processes and tissue repair in SLE.

Topics: Adolescent; Adult; Cathepsin B; Cathepsin D; Chemotaxis, Leukocyte; Collagenases; Female; Flow Cytometry; Humans; Immunity, Innate; Interleukin-8; Lupus Erythematosus, Systemic; Macrophage-1 Antigen; Male; Middle Aged; Monocytes; Neutrophils; Phagocytosis; Recombinant Proteins; Respiratory Burst

To assess the changes of serum levels of interleukin-6(IL-6) and interleukin-8 (IL-8) in pregnant women with stationary phase systemic lupus erythematosus (SLE).. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum IL-6 and IL-8 from 14 pregnant women with stationary phase SLE (SLE group), 12 normal pregnant women (normal pregnant group) and 12 normal non-pregnant women (group normal non-pregnant). The later two groups are set as controls.. The IL-6, IL-8 levels in group SLE patients are (20.31 +/- 5.70) ng/L and (48.80 +/- 9.17) ng/L, significantly higher than those in normal pregnant group [IL-6, IL-8 levels are (8.40 +/- 2.49) ng/L and (21.15 +/- 5.21) ng/L, respectively, P < 0.01)] and normal non-pregnant group [IL-6, IL-8 levels are (6.14 +/- 0.86) ng/L and (17.71 +/- 4.43) ng/L, respectively, P < 0.01]. However, there's no significant difference between the normal pregnant group and normal non-pregnant group (P > 0.05).. Serum levels of IL-6, IL-8 may be helpful to monitor the progress of SLE during pregnancy.

Topics: Adult; Female; Humans; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Pregnancy; Pregnancy Complications

In our previous reports, we found polyclonal anti-double-stranded DNA antibodies (anti-dsDNA) purified from patients with active systemic lupus erythematosus (SLE) exerted inhibitory effect on [3H]thymidine incorporation of human mononuclear cells (MNC). However, the other immunological effects of anti-dsDNA on the functions of MNC have not yet been reported. In this study, two monoclonal antibodies, 12B3 and 9D7, with different anti-dsDNA activity were evaluated for their effects on the expression and release of different cytokines from human MNC. We confirmed absence of endotoxin in the two monoclonal antibody preparations and the used medium as detected by Limulus amoebocyte lysate test. The mRNA expression and release of different cytokines including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were measured. We found the two monoclonal anti-dsDNA not only dose-responsively suppressed the phytohaemagglutinin (PHA)-induced thymidine uptake of human MNC but stimulated the mRNA expression of IL-1beta, IL-6 and IL-8 in normal human MNC detected by reverse transcription-polymerase chain reaction (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) measurement of cytokines in MNC culture supernatants revealed that anti-dsDNA enhanced IL-1beta, IL-8, TNF-alpha and IL-10 release from resting MNC. These effects of anti-dsDNA antibodies were not affected by polymyxin B, a potent binder and neutralizer of lipopolysaccharide (LPS). These in vitro studies suggest that anti-dsDNA possess a dual effect on normal human MNC: (a) to enhance the release of proinflammatory cytokines (IL-1beta, IL-8 and TNF-alpha) from MNC to augment inflammatory reaction; and (b) to polarize the immune reaction towards the T helper 2 (Th2) (increased IL-10 production) pathway. This unique effect of anti-dsDNA may play a role in lupus pathogenesis by augmenting inflammatory reactions and autoantibody production which are commonly found in patients with active SLE.

Topics: Animals; Antibodies, Antinuclear; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Glomerular Mesangium; Humans; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Jurkat Cells; Leukocytes, Mononuclear; Lipopolysaccharides; Lupus Erythematosus, Systemic; Mice; Protein Binding; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Thymidine; Transcription, Genetic; Tumor Necrosis Factor-alpha

Symptoms originating from central nervous system (CNS) are frequently occuring in patients with systemic lupus erythematosus (SLE). Reliable diagnostic markers for this condition are presently lacking. Importantly, CNS involvement in lupus patients is associated with increased morbidity and mortality. The aim of this retrospective evaluate was to study the diagnostic value of cerebrospinal fluid (CSF) cytokine levels in SLE patients with CNS involvement. 34 patients with SLE were hospitalized and investigated for the presence of CNS lupus. These patients were evaluated clinically and with magnetic resonance imaging (MRI) and CSF analyses, as well as with neuropsychiatric tests. 13 patients were found to have CNS lupus whereas another four of the patients fulfilled the criteria for CNS involvement but were excluded from this group due to other causes of CNS involvement. Lastly, in 17 SLE cases, the diagnosis of CNS lupus could not be confirmed. CSF levels of interleukin-6 (IL-6) and IL-8, as well as the CSF/serum IL-6 ratio, were elevated in the CNS lupus group, compared with the 17 SLE patients not fullfilling a diagnosis of cerebral lupus. Interestingly, follow-up of five patients being successfully treated for CNS lupus revealed profound decrease of intrathecal IL-6 levels. These results indicate that analysis of CSF cytokine levels, especially IL-6 and IL-8, may be useful in the diagnostics and possibly follow-up of SLE patients with cerebral lupus.

Topics: Adolescent; Adult; Aged; Cytokines; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Lupus Erythematosus, Systemic; Lupus Vasculitis, Central Nervous System; Magnetic Resonance Imaging; Male; Middle Aged; Tumor Necrosis Factor-alpha

Our study aims to determine whether anti-dsDNA exerts any effect on the gene expression of IL-8 or TGF-beta in cultured HUVEC. Both cytokines have angiogenic effect on endothelial cells. IgG was purified from 19 patients with SLE and from 19 healthy controls. Anti-dsDNA-depleted polyclonal IgG was also prepared from serum IgG of lupus patients by affinity chromatography with DNA cellulose column. Compared with either control IgG or anti-dsDNA-dep-IgG, HUVEC incubated with anti-dsDNA-containing-IgG expressed higher levels of IL-8 mRNA (p = 0.0001) and TGF-beta 1 mRNA (p = 0.0014). We demonstrated a significant increase in the percentage of cells with fragmented DNA in HUVEC incubated with anti-dsDNA-containing-IgG compared with those incubated with anti-dsDNA-dep-IgG, supporting the notion that anti-dsDNA may exert a direct apoptotic effect on cultured endothelial cells. Our study provides in vitro evidence that anti-dsDNA could play an important pathogenetic role in inducing inflammatory injury of vascular endothelium in SLE.

Topics: Adult; Antibodies, Antinuclear; Apoptosis; Cells, Cultured; DNA; DNA Fragmentation; Endothelium, Vascular; Female; Flow Cytometry; Gene Expression Regulation; Humans; Immunoglobulin G; Interleukin-8; Lupus Erythematosus, Systemic; Male; Nitric Oxide Synthase; RNA, Messenger; Transforming Growth Factor beta; Umbilical Veins

Topics: Adolescent; Adult; Aged; Antibodies; Antibodies, Antinuclear; Autoantibodies; Autoimmune Diseases; Child; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged

A middle-aged woman with lupus cystitis showed no other symptoms of lupus vasculitis. Cystoscopic findings revealed mucosal hemorrhage and hyperemia. Histological studies of the bladder showed mucosal edema, inflammatory cellular infiltration and the deposition of immune complexes along the vessels. She was treated with a combination of intravenous methylprednisolone pulse therapy and oral prednisolone. Cystoscopy and histological findings showed appreciable improvement. Elevated urinary levels of chemokines such as interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF) decreased during convalescence. These results suggest that the early diagnosis and treatment with steroid pulse therapy achieves improvement of an unusual vasculitis symptom, lupus cystitis.

Topics: Anti-Inflammatory Agents; Chemokine CCL2; Cystitis, Interstitial; Drug Therapy, Combination; Edema; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Methylprednisolone; Middle Aged; Mucous Membrane; Prednisolone; Urinary Bladder Diseases

Cell surface expression of lysosome-associated membrane proteins (LAMPs) correlates with serum interleukin-8 (IL-8) levels, shorter disease duration, greater functional impairment from disease-related symptoms and soluble IL-2 receptor levels (sIL-2R) in patients with scleroderma. In this study of 46 patients with systemic lupus erythematosus (SLE), the relationship of serum IL-8 and cell surface LAMP to two clinical measures of disease activity, the SLEDAI and SLAM scales, was evaluated. IL-8 levels were determined on serum samples by the immunometric sandwich enzyme immunoassay technique. Cell surface LAMP expression was determined by flow cytometric quantitation of peripheral blood mononuclear cells with monoclonal antibodies directed against two of the major LAMP proteins, lamp1 and lamp2. The clinical disease activity scales correlated significantly with each other, with C3 levels, serum IL-8, C4, dsDNA and sIL-2R. Lamp1 and lamp2 expression correlated with the SLAM but not the SLEDAI scale. Serum IL-8 levels were elevated in 49 of 51 samples tested (44 of 46 patients) and had a stronger correlation with disease activity than C4, dsDNA and sIL-2R levels. Significantly higher levels of IL-8 were seen in patients with evidence of renal involvement. Serum IL-8 and cell surface LAMP expression may be useful indicators of disease activity in patients with SLE. The possible role of IL-8 in the pathogenesis of SLE requires further investigation.

Topics: Adolescent; Adult; Aged; Antibodies, Antinuclear; Antibodies, Monoclonal; Antigens, CD; Complement C3; Complement C4; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 1; Lysosomal-Associated Membrane Protein 2; Male; Membrane Glycoproteins; Middle Aged; Receptors, Interleukin-2; Severity of Illness Index