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

As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P < 0.005; 10 months: 53% vs. 80%) and significantly (P < 0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 +/- 3 vs. 127 +/- 42; 10 months, 53 +/-5 vs. 140 +/- 37 mg/dl). Appearance of anti-DNA antibodies was retarded and survival significantly (P < 0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7 - 12-fold in 8- 10-month-old mice vs. 2-month-old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies proteinuria and survival of lupus mice, in an additional group of animals (N = 16). Thus, at 14.5 months when all mice given bindarit alone died, 50% of mice on combined therapy were still alive (P < 0.023). Studies are needed to establish whether bindarit may function as a steroid sparing drug in human lupus.
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PMID:Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease. 950 20

A significant number of T cells and macrophages infiltrate the kidneys of patients with lupus nephritis. Chemotactic factors, especially monocyte chemoattractant factor-1 (MCP-1) and adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), cooperatively facilitate recruitment of mononuclear cells into inflamed tissue. Increased expression of class II MHC molecules and CD40 on renal tubular epithelial cells coupled with upregulation of CD40 ligand (CD40L) and interleukin-2 receptor on infiltrating T cells suggest ongoing cellular immune responses. Recent studies employing knockout mice suggest that the T(H)-1 cytokine interferon-gamma is an important cytokine in amplifying the local immune response of lupus nephritis. Infiltrating mononuclear cells exert their effects on resident renal cells through secretion of soluble factors and/or direct cell to cell contact. These interactions, among others, involve molecules such as CD40/CD40L and adhesion molecules. Studies to better define these molecules are in progress and may provide additional targets for therapeutic intervention. Thus, while autoantibody production and complement activation are the major players in initiating the inflammatory response in lupus nephritis, cellular immune mechanisms mediated through infiltrating mononuclear cells have an important role in its amplification and the progression of renal injury.
Lupus 1998
PMID:Cellular interactions in the pathogenesis of lupus nephritis: the role of T cells and macrophages in the amplification of the inflammatory process in the kidney. 988 96

The chemokine is a new class of cytokine. Now, more than 30 members of chemokine superfamily and 15 members of chemokine receptors (CXCR1-4, CCR1-8, CX3CR, CCR) have been identified. They were shown to be involved in the inflammatory response. The chemokine is classified into four subgroups (CXC, CC, C and CX3C). The local production of IL-8, MCP-1 and RANTES in rheumatoid inflamed joints has been reported. The predominance of several chemokines in other collagen diseases, such as SLE, systemic sclerosis and myositis is also described. Therefore, the inhibition of chemokines or chemokine receptors might be novel targets for various human disease, including collagen diseases.
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PMID:[Chemokines and Chemokine receptors in collagen diseases]. 1007 91

IFN-inducible protein-10 (IP-10) is supposed to act as a specific chemoattractant for Th(1)cells. Since Th(1)cells and IFN-gamma are shown to be important for developing systemic lupus erythematosus (SLE), we examined the relationship between serum IP-10 levels and the disease activity. Serum IP-10 levels were markedly increased in the SLE patients depending on the level of disease activity, whereas not in the patients with rheumatoid arthritis (RA). On the other hand, serum MCP-1 levels were increased to a similar extent both in RA and inactive SLE patients, and a little more elevated in active SLE patients. Serum IP-10 levels in SLE patients correlated positively and negatively with levels of anti-DNA antibody and complements, respectively, whereas MCP-1 levels correlated less or not at all. These results suggest that serum IP-10 levels could be a good indicator for the activity of SLE and that IP-10 could play an important immunological role in SLE.
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PMID:Serum levels of ifn-inducible PROTEIN-10 relating to the activity of systemic lupus erythematosus. 1102 74

The phosphorylation of p38 mitogen-activated protein kinase (MAPK) is responsible for the production and signal transduction of cytokines and chemokines. This study hypothesized that p38 MAPK activation is required for spontaneous autoimmune renal injury in MRL-Fas(lpr) mice, resembling human lupus erythematosus. FR167653, a specific inhibitor of p38 MAPK, is orally administrated from 3 or 4 mo of age in MRL-Fas(lpr) mice (at doses of 10 or 32mg/kg per day) until 6 mo of age. The phosphorylated p38 MAPK in kidneys of MRL-Fas(lpr) mice was evaluated. The number of phosphorylated p38 MAPK-positive cells was increased in diseased kidneys. The daily oral administration of FR167653 decreased p38 MAPK phosphorylation in kidneys, especially in a group of mice administered FR167653 (32 mg/kg per day) daily from 3 to 6 mo of age. FR167653 reduced the accumulation of macrophages and T cell and prevented kidney pathology, resulting in prolonged survival. In addition, FR167653 reduced expression of MCP-1 and TNF-alpha in the diseased kidneys and cultured tubular epithelial cells. Furthermore, FR167653 decreased IgG levels in the diseased kidneys and circulation. These results suggest that the phosphorylation of p38 MAPK is required for the pathogenesis of renal injury in MRL-Fas(lpr) mice followed by subsequent expression of renal cytokine/chemokine and IgG production. This study provides evidence that the regulation of p38 MAPK is a novel target for the therapy of renal injury in systemic lupus erythematosus.
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PMID:p38 Mitogen-activated protein kinase contributes to autoimmune renal injury in MRL-Fas lpr mice. 1250 38

The expression of chemokine receptors on T-cells and chemokine levels in the blood was studied in 23 patients with SLE (ACR criteria), seven patients with rheumatoid arthritis (RA) and in 15 healthy controls using flow cytometry, RT-PCR and ELISA. The cell surface expression of the chemokine receptors CXCR5 and CCR6 was decreased in SLE patients compared with controls (P = 0.051 and P = 0.002, respectively). The decrease of CXCR5 was confined to SLE patients with inactive disease (SLEDAI < 6) compared with active disease (SLEDAI > 6) and controls. CXCR2 and CCR1 were increased in patients with active SLE compared with patients with inactive disease (P = 0.001 and P = 0.01, respectively) and with controls (P = 0.02 and P = 0.053, respectively). The levels of the chemokines MIP-1alpha MCP-1, SDF-1alpha, IP-10 and RANTES were significantly elevated in SLE patients compared with controls. Patients with renal involvement had increased surface expression of CXCR3 and CCR3 (P = 0.04 in both) and a lower level of soluble IP-10 compared with patients without renal disease (P = 0.025) and compared with controls (P = 0.001). The ratio between CCR5 and CCR3 was significantly increased in RA patients compared with SLE patients and controls supporting a Th1 overweight in RA. In conclusion, patients with SLE showed abnormal T-cell expression of several chemokine receptors and levels of soluble chemokines in their plasma/serum.
Lupus 2003
PMID:Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus. 1459 26

How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll-like receptor (TLR)-9 activation by exogenous or endogenous CpG-DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG-oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli (E. coli) on the course of nephritis in MRL(lpr/lpr) mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG-ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL(lpr/lpr) mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL(lpr/lpr) mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up-regulated CCL5/RANTES mRNA upon stimulation with CpG-ODN in vitro. In vivo both E. coli DNA and CpG-ODN increased serum DNA autoantibodies of the IgG2a isotype in MRL(lpr/lpr) mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG-ODN increased renal CCL2/MCP-1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC-ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG-DNA-induced progression of lupus nephritis.
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PMID:Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. 1473 43

Interactions between members of the TNF ligand superfamily with their cognate TNF receptors play a crucial role in maintaining immune homeostasis in normal individuals, while dysregulation of certain TNF-ligands and receptors contributes to the pathogenesis of autoimmunity. Identification of novel members of the TNF ligand and receptor families will promote our understanding of the pathogenesis of systemic autoimmune diseases, thus facilitating the development of novel therapeutic approaches. TNF-like weak inducer of apoptosis (TWEAK), a recently identified member of the TNF ligand family, induces PGE2, MMP-1, IL-6, IL-8, RANTES, and IP-10 in fibroblasts and synoviocytes, and upregulates ICAM-1, E-selectin, IL-8, and MCP-1 in endothelial cells. The receptor for TWEAK, Fn14, is expressed in various organs including the kidney; it is intriguing that some of these chemokines induced by TWEAK are crucial in the pathogenesis of lupus nephritis. Furthermore, others have described upregulated TWEAK expression on the surface of T cells in human lupus. In this paper we review the possible roles of TWEAK/TWEAK receptor interactions in the pathogenesis of inflammatory and systemic autoimmune diseases, with particular focus on systemic lupus erythematosus. TWEAK blockade may be helpful therapeutically in restoration of tolerance, but is more likely to modify inflammatory damage in target organs.
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PMID:The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. 1535 86

Increased Fli-1 mRNA is present in PBLs from systemic lupus erythematosus patients, and transgenic overexpression of Fli-1 in normal mice leads to a lupus-like disease. We report in this study that MRL/lpr mice, an animal model of systemic lupus erythematosus, have increased splenic expression of Fli-1 protein compared with BALB/c mice. Using mice with targeted gene disruption, we examined the effect of reduced Fli-1 expression on disease development in MRL/lpr mice. Complete knockout of Fli-1 is lethal in utero. Fli-1 protein expression in heterozygous MRL/lpr (Fli-1(+/-)) mice was reduced by 50% compared with wild-type MRL/lpr (Fli-1(+/+)) mice. Fli-1(+/-) MRL/lpr mice had significantly decreased serum levels of total IgG and anti-dsDNA Abs as disease progressed. Fli-1(+/-) MRL/lpr mice had significantly increased splenic CD8(+) and naive T cells compared with Fli-1(+/+) MRL/lpr mice. Both in vivo and in vitro production of MCP-1 were significantly decreased in Fli-1(+/-) MRL/lpr mice. The Fli-1(+/-) mice had markedly decreased proteinuria and significantly lower pathologic renal scores. At 48 wk of age, survival was significantly increased in the Fli-1(+/-) MRL/lpr mice, as 100% of Fli-1(+/-) MRL/lpr mice were alive, in contrast to only 27% of Fli-1(+/+) mice. These findings indicate that Fli-1 expression is important in lupus-like disease development, and that modulation of Fli-1 expression profoundly decreases renal disease and improves survival in MRL/lpr mice.
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PMID:Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice. 1552 90

Monocyte chemoattractant protein-1 (MCP1) polymorphism has been reported to be associated with systemic lupus erythematosus (SLE). However, the correlation between the polymorphism and SLE is poorly understood. In this study we investigated the role of this polymorphism together with that of chemokine SDF1-3'A and chemokine receptor CCR2-V64I. The association between gene polymorphism and SLE was explored by way of a case-control study. In 143 patients with SLE and 157 healthy controls, the polymorphisms of SDF1-3'A, -2518MCP-1 and CCR2-V64I were determined using PCR-RFLP and an amplification-refractory mutation system, respectively. No significant difference was found in allelic and genotype frequency of SDF1-3'A, CCR2-V64I and -2518MCP-1 between SLE patients and controls. However, a significant increase in the frequency of the AG genotype of MCP-1 was found among patients with arthritis (P(c)=0.003, OR 3.08, 95%CI 1.27-7.57). The frequency of individuals having G at position -2518 of the MCP-1 gene was also increased among patients with arthritis (P(c)=0.028, OR 2.99, 95%CI 1.13-8.08). It is noteworthy that the frequency of -2518MCP-1G in the Chinese Han population was 64%. The results indicate an association between the presence of G at position -2518 in the MCP-1 promoter region and the presence of arthritis in patients with SLE.
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PMID:The correlation between monocyte chemoattractant protein-1 and the arthritis of systemic lupus erythematosus among Chinese. 1561 78


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