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)

Type I IFNs induce differentiation of dendritic cells (DCs) with potent Ag-presenting capacity, termed IFN-alpha DCs, that have been implicated in the pathogenesis of systemic lupus erythematosus. In this study, we found that IFN-alpha DCs exhibit enhanced migration across the extracellular matrix (ECM) in response to chemokines CCL3 and CCL5 that recruit DCs to inflammatory sites, but not the lymphoid-homing chemokine CCL21. IFN-alpha DCs expressed elevated matrix metalloproteinase-9 (MMP-9), which mediated increased migration across ECM. Unexpectedly, MMP-9 and its cell surface receptors CD11b and CD44 were required for enhanced CCL5-induced chemotaxis even in the absence of a matrix barrier. MMP-9, CD11b, and CD44 selectively modulated CCL5-dependent activation of JNK that was required for enhanced chemotactic responses. These results establish the migratory phenotype of IFN-alpha DCs and identify an important role for costimulation of chemotactic responses by synergistic activation of JNK. Thus, cell motility is regulated by integrating signaling inputs from chemokine receptors and molecules such as MMP-9, CD11b, and CD44 that also mediate cell interactions with inflammatory factors and ECM.
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PMID:Costimulation of chemokine receptor signaling by matrix metalloproteinase-9 mediates enhanced migration of IFN-alpha dendritic cells. 1667 Mar 11

The aim of this study was to determine if macrophage inflammatory protein (MIP) 1alpha, MIP-1beta, and RANTES (regulated upon activation normally T-cell expressed and secreted) serum concentrations are associated with clinical manifestations, disease activity, and damage accrual in patients with systemic lupus erythematosus (SLE). A cross-sectional study was performed in 62 SLE patients (per American College of Rheumatology criteria) participating in a longitudinal study and 20 healthy subjects. MIP-1alpha, MIP-1beta, and RANTES serum concentrations were determined by enzyme-linked immunosorbent assay. Demographic parameters, clinical manifestations, serologic features, pharmacologic treatments, disease activity, and damage accrual were determined at study visit. Disease activity was assessed with the Systemic Lupus Erythematosus Activity Measure (SLAM), and disease damage was assessed with Systemic Lupus International Collaborating Clinic Damage Index (SDI). The relation between the variables was studied with the Student t test and the Pearson r correlation test. SLE patients were more likely to have higher concentrations of MIP-1beta and RANTES than healthy individuals. In addition, they had a trend to have higher concentrations of MIP-1alpha. Patients with discoid lupus were more likely to have higher levels of MIP-1alpha. Elevation of MIP-1beta correlated with higher SDI score. No association was found between serum chemokines levels and disease activity. In conclusion, SLE patients have higher serum levels of MIP-1beta and RANTES than healthy individuals. MIP-1alpha is associated with discoid lupus, and MIP-1beta correlates with damage accrual in SLE. This study suggests that chemokines may have a role in the pathogenesis of SLE.
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PMID:Association of serum MIP-1alpha, MIP-1beta, and RANTES with clinical manifestations, disease activity, and damage accrual in systemic lupus erythematosus. 1692 94

The TNF superfamily cytokine TWEAK induces mesangial cells, podocytes, and endothelial cells to secrete pro-inflammatory chemokines including MCP-1, IP-10 and RANTES, which are crucial in the pathogenesis of lupus nephritis (LN). As TWEAK regulates the secretion of these inflammatory mediators, we studied whether urinary TWEAK (uTWEAK) levels might be predictive and/or diagnostic in LN. In a cross-sectional study of a large, multi-center cohort of systemic lupus erythematosus (SLE) patients, uTWEAK levels were higher in patients with active as compared to never or non-active nephritis (median (IQR): 16.3 (9.9-23.0) versus 5.5 (2.3-16.8) pg/mg creatinine, p=0.001), and levels of uTWEAK correlated with the renal SLE disease activity index (rSLEDAI) score (r=0.405, p<0.001). uTWEAK levels were higher in patients undergoing a flare as compared to patients with chronic stable disease (11.1 (8.1-18.2) and 5.2 (2.3-15.3) pg/mg creatinine, respectively; p=0.036). Moreover, uTWEAK levels were significantly higher in patients undergoing a renal flare, as opposed to a non-renal flare (12.4 (9.1-18.2) and 5.2 (3.0-11.9) pg/mg creatinine, respectively; p=0.029). An accurate, non-invasive method to repeatedly assess kidney disease in lupus would be very helpful in managing these often challenging patients. Our study indicates that urinary TWEAK levels may be useful as a novel biomarker in LN.
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PMID:Urinary TWEAK and the activity of lupus nephritis. 1725 12

Glomerulonephritis is an important cause of end-stage renal failure, yet the pathogenetic mechanisms of most forms of glomerulonephritis are not clear. Renal fibrosis is the final common pathway for many kidney lesions that lead to chronic progressive organ failure. Recent study suggests that chemokines and chemokine receptors are involved in the resolution or progression of renal diseases. In view of the above we detected using immunohistochemistry the expression of RANTES, CCR5+ cells,TGF-beta1, alpha-SMA in renal biopsy specimens in 17 patients with IVG A/C class of lupus nephritis and in 10 normal kidneys. The correlative study was undertaken to evaluate the possible relationships between the immunoexpression of RANTES, the number of CCR5+ cells, the immunoexpression of TGF-beta1, alpha-SMA, the value of interstitial cortical volume and the serum creatinine level in patients with lupus nephropathy. Statistical analysis revealed significant increase in tubulointerstitial RANTES immunoexpression in lupus nephritis as compared to normal controls. In our study CCR5+ cells were detected in the interstitium in tissue samples in patient with lupus nephritis, meanwhile no CCR5+ cells were documented in normal controls. We found a strong positive correlation between tubulointerstitial immunoexpression of RANTES and the number of interstitial CCR5+ cells as well as between immunoexpression of RANTES and the immunoexpression of TGF-beta1, alpha-SMA, renal cortical volume and serum creatinine in patients with lupus nephritis. Moreover, the number of interstitial CCR5+ cells was positively correlated with tubulointerstitial alpha-SMA immunoexpression and renal cortical volume. In summary, the results suggest that in lupus nephritis RANTES may participate in interstitial lesions via CCR5+ cells.
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PMID:The significant role of RANTES and CCR5 in progressive tubulointerstitial lesions in lupus nephropathy. 1758 40

TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.
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PMID:TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. 1802 43

To elucidate the molecular mechanism of glomerular events in lupus nephritis, we performed genome-wide mRNA expression analysis of glomeruli microdissected from lupus mice. MRL/lpr mice (12-week-old) were orally given vehicle or prednisolone (10 mg/kg per day) for 4 weeks. Renal histology of MRL/lpr mice revealed mesangial proliferative glomerulonephritis with cellular infiltration of macrophages, T cells, and neutrophils. We identified 567 up-regulated genes in MRL/lpr glomeruli compared to control congenic mice. Those included complement components, adhesion molecules, chemokines and their receptors, and molecules related to antigen presentation. Over 130 genes were considered preferentially or exclusively expressed in hematopoietic cell lineages possibly reflecting leukocytes accumulation. Of note is the finding that chemokines and chemokine receptors (CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11, CXCL16, CCR5, CXCR3, and CXCR6) that are related to T helper 1 (Th1) cells accumulation were up-regulated concomitantly with increased expression of Ebi3, a subunit of IL-27 that plays a role in Th1 predominance. These changes were accompanied by increased mRNA expression of many genes that were inducible by Th1 cytokine interferon-gamma. Prednisolone markedly attenuated glomerular lesion and leukocyte influx parallel with the reduction of enhanced gene expression. The present study shows additional evidence supporting glomerular Th1 cells accumulation and their role. Our data also provide an important resource in seeking new therapeutic targets to lupus nephritis. Supplemental table: available only at http://dx.doi.org/10.1254/jphs.FP0071337.
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PMID:Microarray analysis of glomerular gene expression in murine lupus nephritis. 1818 31

Chemokines and cytokines play an important role in the inflammatory development and progression of autoimmune diseases. The aim of the present study was to evaluate the role of MCP-1, SDF-1, and RANTES polymorphisms as susceptibility markers for systemic lupus erythematosus (SLE) in a group of Mexican patients. MCP-1-2518, SDF-1 G801A, and RANTES-28 polymorphisms were determined in 242 patients with SLE and 220 ethnically matched healthy controls by the polymerase chain reaction-restriction fragment length polymorphism technique. The differences between patients and healthy controls were evaluated by chi(2), Fisher's exact test, and Woolf method for odds ratio. A moderately increased frequency of MCP-1-2518 A allele (p = 0.033, pC = NS) and AA genotype (p = 0.017, pC = NS) existed in SLE patients compared with healthy controls. There was a relationship between polymorphisms and some clinical and laboratory characteristics. SLE patients with and without antiphospholipid syndrome demonstrated different distribution of SDF-1 G801A genotype frequencies. On the other hand, patients with leukopenia, anti-dsDNA, and antiphospholipid autoantibodies demonstrated different MCP-1-2518 genotype distribution compared with patients without these features. Our results suggest that MCP-1 polymorphism is moderately associated with the genetic susceptibility to SLE in Mexican individuals. The polymorphisms could be related to specific clinical and laboratory characteristics in these patients.
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PMID:MCP-1, RANTES, and SDF-1 polymorphisms in Mexican patients with systemic lupus erythematosus. 1819 26

Lupus nephritis is one manifestation of systemic lupus erythematosus (SLE). Interleukin (IL)-10 is involved in the pathogenesis of SLE. To determine whether IL-20, a member of the IL-10 family, is associated with lupus nephritis, we analyzed the expression of IL-20 and its receptors in mesangial cells derived from SLE-prone, NZB/W, and DBA/W mice. IL-20 and its receptors were upregulated in mesangial cells from NZB/W mice. Incubating IL-20 with mesangial cells upregulated the transcripts of CCL2 (MCP-1), CCL5 (RANTES), CXCL10 (IP-10), IL-6, iNOS, and ROS, all of which are involved in the pathogenesis of lupus nephritis. IL-20 specifically activated the downstream signal ERK 1/2. We also detected human IL-20 protein in both mesangial cells and inflammatory cells in kidney biopsies of patients with lupus nephritis. Our results reveal the novel effects of IL-20 on mesangial cells and its association with lupus nephritis.
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PMID:Interleukin-20 targets renal mesangial cells and is associated with lupus nephritis. 1877 58

Members of the TNF-ligand and receptor superfamilies are important in the pathogenesis of lupus nephritis, a major cause of mortality and morbidity in SLE. TWEAK, a member of the TNF-ligand superfamily, is markedly increased in urine from patients with active lupus nephritis, and urinary TWEAK levels significantly correlate with renal disease activity. To support a possible role of TWEAK in the pathogenesis of lupus nephritis and other inflammatory nephritides, we examined the effects of TWEAK in human kidney mesangial cells, podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. We found that TWEAK induces human kidney cells to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1alpha, ICAM-1, and VCAM-1. Cytokine production is mediated through NF-kappaB activation, and is inhibited by anti-TWEAK monoclonal antibodies. TWEAK stimulated chemokines induced migration of human PBMC, particularly monocytes/macrophages. Furthermore, we found that TWEAK promotes kidney infiltration of inflammatory cells, and stimulates proliferation of kidney cells in vitro and in vivo. Thus, TWEAK may play an important pathogenic role in the development of glomerulonephritis by promoting a local inflammatory environment and inducing kidney cell proliferation. Blocking TWEAK/Fn14 interactions may be a promising therapeutic target in immune-mediated renal diseases.
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PMID:TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. 1923 85

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with aberrant activation of T and B lymphocytes for the production of inflammatory cytokines and autoreactive antibodies. Animal studies of SLE have indicated that Toll-like receptors (TLR) are important in the pathogenesis of murine lupus. In the present clinical study, differential protein expressions of TLR-1-9 of monocytes and different lymphocyte subsets from patients with SLE and normal control subjects were determined by flow cytometry. Results showed that the expression of intracellular TLRs (TLR-3, -8, -9) and extracellular TLRs (TLR-1, -2, -4, -5, -6) were elevated in monocytes, CD4(+) T lymphocytes, CD8(+) T lymphocytes and B lymphocytes of SLE patients compared to control subjects (all P < 0.001). Moreover, cell surface expression of TLR-4 on CD4(+) T lymphocytes and CD8(+) T lymphocytes, and TLR-6 on B lymphocytes, were correlated positively with SLE disease activity index (SLEDAI) (TLR-4 on CD4(+) T lymphocytes and CD8(+) T lymphocytes: r = 0.536, P = 0.04; r = 0.713, P = 0.003; TLR-6 in B lymphocytes: r = 0.572, P = 0.026). In concordance with the above results, there is an observable increased relative induction (%) of inflammatory cytokine interleukin (IL)-1beta, IL-6, IL-10 and IL-12, chemokines CCL2, CXCL8, CCL5 and CXCL10 from peripheral blood mononuclear cells (PBMC) upon differential stimulation by PolyIC (TLR-3 ligand), lipopolysaccharide (TLR-4 ligand), peptidoglycan (TLR-2 ligand), flagellin (TLR-5 ligand), R837 (TLR-7 ligand) and CpG DNA (TLR-9 ligand) in SLE patients compared to controls. These results suggest that the innate immune response for extracellular pathogens and self-originated DNA plays immunopathological roles via TLR activation in SLE.
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PMID:Activation profile of Toll-like receptors of peripheral blood lymphocytes in patients with systemic lupus erythematosus. 1984 90


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