Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of the cytokine interleukin-10 (IL-10) have been reported in patients with active systemic lupus erythematosus (SLE). Any role for IL-10 in the pathogenesis of SLE is likely to involve the activation of expression of specific genes within its target cells. We have previously reported elevated levels of the 90 000 MW heat-shock protein (hsp 90) and autoantibodies to hsp 90 in patients with SLE. Recent studies have shown that the cytokine IL-6 activates hsp 90 gene expression via specific transcription factors that include STAT-3 (signal transducer and activator of transcription 3). In view of the known role of STAT proteins in IL-10 signalling pathways, we have investigated the effect of IL-10 on hsp 90 gene expression. Here we report that IL-10 enhances the expression of hsp 90 in both a human hepatoma cell line (HepG2) stably expressing the human IL-10 receptor and peripheral blood mononuclear cells (PBMC). In reporter gene assays IL-10 is able to activate both the hsp 90alpha and hsp 90beta promoters directly. Furthermore, a short region of the hsp 90beta promoter which is activated in response to IL-10, contains a STAT-3 binding site. This element but not a mutant derivative unable to bind STAT-3, is able to confer a response to IL-10 on a heterologous promoter. These results may be understood in terms of the shared signalling mechanisms of IL-10 and IL-6 and provide evidence of a role for IL-10 in the overexpression of hsp 90 in SLE, with possible pathological consequences.
 ...
PMID:Interleukin-10 activates heat-shock protein 90beta gene expression. 1044 36

Interleukin 12 (IL-12) is a heterodimer comprising p35 and p40 subunits which are encoded and regulated separately. The authors previously demonstrated deficient IL-12 production in SLE which correlates negatively with disease activity. The present study was designed to determine whether deficiency of IL-12 and excess production of IL-10 and IL-6 in systemic lupus erythematosus (SLE) are due to aberrant regulation at the gene level. Using semiquantitative RT-PCR assay, it was shown that constitutive expression of IL-12 p35 gene is somewhat impaired in SLE compared with controls and that IL-12 p40 mRNA, which was present at low levels in controls, was undetectable in unstimulated SLE peripheral blood mononuclear cells (PBMC). Gene expression of IL-12 p35 and p40 was significantly increased in response to SAC, with significantly lower SAC-induced expression of p40 in SLE patients than controls. SAC-stimulated IL-12 p35 and p40 mRNAs were significantly augmented by interferon gamma (IFN-gamma). Exogenous IL-12 or IFN-gamma significantly inhibited IL-10 gene expression, without affecting IL-6 mRNA or other proinflammatory cytokine mRNA levels. These observations were further confirmed by studies of protein production at the single cell level using ELISPOT assay. Downregulation of IL-12 p40 expression appears to be the cause of IL12 p70 deficiency in SLE. If this defect could be repaired, normalization of IL-12 and IFN-gamma production should reduce excessive IL-10 and prevent pathology.
 ...
PMID:Impaired production of IL-12 in systemic lupus erythematosus. III: deficient IL-12 p40 gene expression and cross-regulation of IL-12, IL-10 and IFN-gamma gene expression. 1052 20

Anti-CD4 antibodies have been recently introduced into the therapy of various autoimmune diseases, among them systemic lupus erythematosus (SLE). Their modes of action are not yet fully understood. Interference with cytokine release may be one possible mechanism. Therefore, the effects of anti-CD4 antibodies on the cytokine release of IL-6 (interleukin-6) and TNF-alpha (tumor necrosis factor alpha) were investigated in a whole blood culture system. Basal and phytohemagglutin/lipopolysaccharide (PHA/LPS)-stimulated cytokine patterns were compared to cytokine release after the addition of anti-CD4 antibodies (MAX.16H5) or methylprednisolone in short time whole blood cell culture systems from 12 patients with active SLE, 23 patients with inactive SLE and 12 healthy volunteers. TNF-alpha and IL-6 concentrations were determined in the supernatants by ELISA. High disease activity correlated with an increased production of proinflammatory cytokines. Cell cultures of patients with inactive SLE showed a diminished capacity to respond to mitogenic stimulation. Anti-CD4 antibodies added in vitro suppressed significantly the unstimulated production of IL-6 (P<0.02) in the cell cultures of patients with active SLE and in the PHA/LPS-stimulated cell cultures from both groups of SLE patients (both P<0.001) and healthy volunteers (P<0.01). However, MAX.16H5 did not affect the release of TNF-alpha. In control samples methylprednisolone considerably reduced stimulated and unstimulated IL-6 and TNF-alpha production in all SLE patients, irrespective of the disease state, and in all healthy controls. These data indicate that the proinflammatory cytokines are involved in the pathogenesis of SLE. It is assumed that anti-CD4 antibodies, which can be effective in the treatment of highly active lupus patients, may act via their influence on cytokine release. The decrease of the proinflammatory cytokines IL-6 under therapy with MAX.16H5 could explain the observations of clinical trials and animal studies which showed a reduction of inflammatory parameters and diminished production of autoantibodies following treatment with anti-CD4 antibodies.
Lupus 1999
PMID:Effects of anti-CD4 antibodies on the release of IL-6 and TNF-alpha in whole blood samples from patients with systemic lupus erythematosus. 1060 44

To date no specific serological parameter is available to assess disease activity in SLE. Soluble serum thrombomodulin is a new marker of endothelial cell injury and vasculitis. The objective of this study was to compare in vivo soluble thrombomodulin as marker of disease activity in SLE with established and recent serological parameters. One hundred and twenty-four sera of 30 patients with proven SLE with different disease activities were tested for serum levels of thrombomodulin, intercellular adhesion molecule-1 (ICAM-1), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), IL-2R, IL-6, IL-10, dsDNA by ELISA and dsDNA additionally by radioimmunoassay (RIA). C-reactive protein (CRP), complement component C3, IgG, creatinine, anti-nuclear antibodies (ANA) and intermediate filament antibodies were measured by standard laboratory tests. The clinical disease activity was evaluated by the Systemic Lupus Activity Measure (SLAM). Correlations of the different serological SLE disease activity parameters with the SLAM scores revealed the highest significance for serum thrombomodulin (correlation coefficient 0.82). This was further confirmed by the intra-individual analysis of follow-up sera. In addition, a moderate correlation could be found for IL-6, IL-10, ICAM-1, CRP and erythrocyte sedimentation rate (ESR). In summary, soluble thrombomodulin is the most important serological parameter of disease activity in SLE currently available, as shown by the in vivo studies. Soluble thrombomodulin might be a valuable serological parameter for therapeutical considerations.
 ...
PMID:Serum thrombomodulin-a reliable marker of disease activity in systemic lupus erythematosus (SLE): advantage over established serological parameters to indicate disease activity. 1060 82

We estimated the serum levels of IL-6, TNF-alpha and IL-10, and generation of superoxide radicals, as well as their mutual dependence, in 63 SLE patients at various stages of disease activity. Our results indicate a statistically significant increase of the serum levels studied, and an increase of superoxide anion generation by granulocytes, in correlation with SLE activity. These results indicate that oxygen metabolism and the examined cytokines play an important role in pathogenesis of SLE. The assessment of these parameters can be useful in the estimation of disease activity.
 ...
PMID:Estimation of SLE activity based on the serum level of chosen cytokines and superoxide radical generation. 1070 46

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.
 ...
PMID:Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha from normal human mononuclear cells involving in the lupus pathogenesis. 1071 64

Primary heart tumors are rare. The most common one is myxoma. It may synthetize IL-6 and frequently shown systemic clinical manifestations that confuse the diagnosis. Primary heart sarcomas are even more rare, as far as we know they have been not associated with systemic illnesses. We observed two cases with a presumptive diagnosis of systemic lupus erythematosus who were identified as primary sarcomatous heart neoplasms after surgical excision.
 ...
PMID:[Does heart sarcoma mimick lupus erythematosus and vasculitis? Report of 2 cases]. 1074 54

Although most published epidemiological studies have found little evidence of systemic autoimmune disease associated with silicone breast implants, there still remains a question of whether silicones can cause local and/or systemic immune dysfunction. This study further investigates the effects of silicones on autoantibody and immunoglobulin production and macrophage activation in female A.SW mice. Sixty mice were divided among four treatment groups receiving a 0.5-ml intraperitoneal injection of either phosphate-buffered saline (PBS), pristane, silicone gel, or silicone oil. Test bleeds were taken periodically for 6 months. In contrast to pristane, neither silicone gel nor silicone oil induced lupus-associated antinuclear autoantibodies (immunoglobulin G [IgG] anti-nRNP/Sm, Su, and ribosomal P) or lupus nephritis. However, serum IgM became elevated persistently within 1 month of silicone gel or silicone oil administration. Also, the level of IgG3 was clearly elevated in silicone oil-treated mice. In contrast, IgG1, IgG2a, and IgG2b levels were not affected greatly by either silicone gel or oil. Furthermore, peritoneal macrophages from silicone- and pristane-treated mice produced higher levels of interleukin-1beta (IL-1beta) and IL-6 than those from PBS-treated mice after lipopolysaccharide stimulation. These results suggest that silicone gels and oils are capable of inducing hypergammaglobulinemia and activating macrophages in female A.SW mice.
 ...
PMID:Induction of hypergammaglobulinemia and macrophage activation by silicone gels and oils in female A.SW mice. 1079 47

Tubulointerstitial nephritis is a less frequently recognized but important complication of systemic lupus erythematosus. We have investigated the cytokine beta2-microglobulin (beta2M) and Tamm-Horsfall glycoprotein (THG) excretions in the urine of systemic lupus erythematosus patients to identify indices for evaluation of tubulointerstitial inflammation in lupus nephritis (LN). Daily urine was collected from 15 patients with active LN, from 12 patients with inactive LN, and from 17 normal subjects. The amounts of soluble interleukin (IL) 2 receptor, IL-6, IL-8, beta2M, and THG in urine were measured. Beta2M and THG were regarded as indicators of proximal and distal renal tubule function, respectively. The urinary excretions of IL-6 and IL-8 were significantly higher in patients with active LN than in those with inactive LN and in normal individuals. The excretion of soluble IL-2 receptor in all three groups of subjects was not significantly different. On the other hand, the excretion of beta2M in patients with LN was significantly higher than that in normal individuals. The excretion of beta2M in patients with active or inactive LN was not significantly different. The THG excretion was lower in patients with active LN and tubulointerstitial inflammation as compared with patients with inactive LN or normal individuals. Six patients underwent pulse cyclophosphamide therapy during the course of experiments. Five of them showed a decrease in IL-8 and IL-6 excretions in urine after the treatment. The excretions of beta2M and THG in urine, in addition to IL-6 and IL-8, can reflect the renal inflammatory activity in patients with lupus tubulointerstitial nephritis as well as in those having lupus glomerulonephritis.
 ...
PMID:Increased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. 1086 35

Mutations of Fas (lpr) or Fas ligand (gld) cause a limited lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized lupus syndrome reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/lpr and B6/gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/lpr and B6/gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/lpr or B6/gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.
 ...
PMID:Fas and Fas ligand mutations inhibit autoantibody production in pristane-induced lupus. 1087 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>