Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor (NF)-kappa B regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. In the anti-Thy 1.1 rat model, gliotoxin (75 micro g/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 micro g/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappa B activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. In cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-kappa B activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines, by blocking the phosphorylation/degradation of the I kappa B(alpha) subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappa B activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.
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PMID:Nuclear factor-kappa B inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis. 1236 22

A gene delivery system using bone marrow-derived CD11b(+)CD18(+) cells and their interaction with adhesion molecules was established. After transplantation into mice, these vehicle cells may be recruited into glomeruli upon lipopolysaccharide (LPS) treatment, and the number of recruited cells corresponds to the expression of intercellular adhesion molecule-1 (ICAM-1) in glomeruli. Using this system, interleukin-1 receptor antagonist (IL-1Ra) was delivered into animal models of glomerulonephritis evoked by anti-glomerular basement membrane antibody (anti-GBM nephritis). Urinary albumin excretion and the serum creatinine level were significantly elevated after anti-GBM antibody injection in mock-treated mice, whereas they were suppressed in the IL-1Ra-treated mice. Histological analysis revealed that glomerular injuries were also suppressed in IL-1Ra-treated mice. We further confirmed that specificity for inflamed glomeruli was significantly enhanced by a combination of the Cre/loxP system with the IL-1beta promoter. These data suggested that our novel system may be used as a therapeutic intervention for glomerulonephritis.
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PMID:Inflamed site-specific delivery of bone marrow-derived cells carrying IL-1Ra. 1238 2

1. In inflammatory kidney diseases procoagulatory activity (PCA) becomes evident. Glomerular fibrin deposits and capillary microthrombi are histopathological hallmarks in most forms of glomerulonephritis. 2. Therefore in this study the expression of tissue factor (TF) as the main inducer of thrombogenesis was examined in cultured human mesangial cells (MC) in response to proinflammatory stimuli such as interleukin-1 (IL-1 beta), tumour necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS). Also main signalling pathways were investigated. 3. IL-1 beta, TNF-alpha and LPS induced TF in MC in a time and dose dependent manner on mRNA and protein levels. Highest activity was found after 12 h of stimulation. Induction of TF was completely blockable by BAPTA-AM, a chelator of intracellular [Ca(2+)](i) as well as calphostin, a protein kinase C (PKC) inhibitor. Activation of the protein kinase A (PKA) pathway had no influence on basal TF expression, but down-regulated cytokine-induced TF. The PKA blocker, KT5720, increased TF formation significantly. Since TF exerts its activity primarily on the surface of cells and after release of encrypted receptors we further tested TF activity in MC supernatants. IL-1 beta did not significantly increase TF activity in supernatants of intact cells. However, when MC were rendered apoptotic by oxidative metabolites, IL-1 beta treated MC released highly stimulated TF activity into the supernatants, suggesting that a paracrine activation of the coagulatory cascade can take place under such conditions. 4. Inflammatory mediators up-regulate TF expression in MC by a PKC dependent pathway whereas PKA can serve as a negative feed-back link. Apoptosis of inflammatory MC may trigger to spread PCA.
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PMID:Protein kinase C (PKC) dependent induction of tissue factor (TF) by mesangial cells in response to inflammatory mediators and release during apoptosis. 1242 85

Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.
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PMID:[Pharmacological study on the effects of the adenosine uptake inhibitor KF24345 on inflammatory diseases]. 1289 Aug 98

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Here, we identify a cDNA encoding a novel mucin protein, shown previously to be up-regulated in IgAN patients, from a human kidney cDNA library. This protein contains a mucin tandem repeat of 19 amino acids consisting of many threonine, serine, and proline residues and likely to be extensively O-glycosylated; thus, this gene was classified in the mucin family and named MUC20. The human MUC20 gene contains at least four exons and is localized close to MUC4 on chromosome 3q29. We found variations in repeat numbers in the mucin tandem domain, suggesting polymorphism of this region. Northern blot and reverse transcription-PCR analyses revealed that human MUC20 mRNA was expressed most highly in kidney and moderately in placenta, colon, lung, prostate, and liver. Immunohistochemical analysis of human kidney revealed that MUC20 protein was localized in the proximal tubules. Immunoblotting analysis of MUC20 proteins produced in Madin-Darby canine kidney and HEK293 cells indicated the localization of MUC20 protein in a membrane fraction and extensive posttranslational modification. Immunoelectron microscopy of MUC20-producing Madin-Darby canine kidney cells demonstrated that MUC20 protein was localized on the plasma membrane. Expression of MUC20 mRNA in a human kidney cell line was up-regulated by tumor necrosis factor-alpha, phorbol 12-myristate 13-acetate, or lipopolysaccharide. Two species of MUC20 mRNA (hMUC20-L and hMUC20-S), resulting from alternative transcription, were identified in human tissue, whereas only one variant was observed in mouse tissues. Mouse MUC20 mRNA was expressed in the epithelial cells of proximal tubules, and the expression increased dramatically with the progression of lupus nephritis in the kidney of MRL/MpJ-lpr/lpr mice. Moreover, the expression of mouse MUC20 was augmented in renal tissues acutely injured by cisplatin or unilateral ureteral obstruction. These characteristics suggest that the production of MUC20 is correlated with development and progression of IgAN and other renal injuries.
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PMID:Molecular cloning, genomic structure, and expression analysis of MUC20, a novel mucin protein, up-regulated in injured kidney. 1456 53

The wide diversity of the T and B Ag receptor repertoires becomes even more extensive postneonatally due to the activity of TdT, which adds nontemplated N nucleotides to Ig and TCR coding ends during V(D)J recombination. In addition, complementarity-determining region 3 sequences formed in the absence of TdT are more uniform due to the use of short sequence homologies between the V, D, and J genes. Thus, the action of TdT produces an adult repertoire that is both different from, and much larger than, the repertoire of the neonate. We have generated TdT-deficient nonobese diabetic (NOD) and MRL-Fas(lpr) mice, and observed a decrease in the incidence of autoimmune disease, including absence of diabetes and decreased pancreatic infiltration in NOD TdT(-/-) mice, and reduced glomerulonephritis and increased life span in MRL-Fas(lpr) TdT(-/-) mice. Using tetramer staining, TdT(-/-) and TdT(+/+) NOD mice showed similar frequencies of the diabetogenic BDC 2.5 CD4(+) T cells. We found no increase in CD4(+)CD25(+) regulatory T cells in NOD TdT(-/-) mice. Thus, TdT deficiency ameliorates the severity of disease in both lupus and diabetes, two very disparate autoimmune diseases that affect different organs, with damage conducted by different effector cell types. The neonatal repertoire appears to be deficient in autoreactive T and/or B cells with high enough affinities to induce end-stage disease. We suggest that the paucity of autoreactive specificities created in the N region-lacking repertoire, and the resultant protection afforded to the newborn, may be the reason that TdT expression is delayed in ontogeny.
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PMID:Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in diabetes-prone nonobese diabetic mice and lupus-prone MRL-Fas(lpr) mice. 1503 81

We have suggested that renal tubular synthesis of C3 and its activation in the cortical interstitium is a mechanism for the progression of glomerulonephritis to interstitial injury. To test this hypothesis, immune complex glomerulonephritis was induced in C57BL/6 mice by intraperitoneal injections of horse spleen apoferritin and lipopolysaccharide (HSA/LPS). When compared to wild-type (WT) animals, C3 knockout (C3KO) mice had glomerular changes that were identical. Morphometric analysis of the cortical interstitium, however, showed marked differences. WT mice had more interstitial inflammation, edema, and tubular atrophy, when compared to C3KO mice. At the end of the experiment, WT animals also had significantly more proteinuria than did C3KOs. These experiments provide further evidence of a role of locally synthesized complement in the progression of glomerular disease.
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PMID:C3 is central to the interstitial component of experimental immune complex glomerulonephritis. 1587 25

Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs). Clinical and experimental evidence indicates that ANCA and proinflammatory stimuli of infectious origin act synergistically to cause vasculitis. We tested this hypothesis in a recently developed mouse model of anti-MPO IgG-induced glomerulonephritis by using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. Systemic administration of LPS dose dependently increased renal injury induced by anti-MPO IgG as demonstrated by increased glomerular crescent formation and glomerular necrosis. In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. Furthermore, a transient induction of circulating tumor necrosis factor (TNF)-alpha levels, followed by a marked increase in circulating MPO levels, was observed on administration of LPS. In vitro, anti-MPO IgG induced a respiratory burst in murine neutrophils only after priming with TNF-alpha. Finally, anti-TNF-alpha treatment attenuated, but did not prevent, the LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis. In conclusion, our study demonstrates that ANCA and proinflammatory stimuli act synergistically to induce vasculitic disease and suggests potential benefits of inhibiting TNF-alpha bioactivity in treating human ANCA-associated necrotizing crescentic glomerulonephritis.
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PMID:Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. 1597 51

Skeletal demineralization is a frequent accompaniment of chronic renal disease and is likely multifactorial. We studied the role of inflammation in stimulating bone resorption in a rat model of glomerulonephritis (GN). Three-week-old Sprague-Dawley rats received either saline (n = 8) or horse spleen apoferritin and lipopolysaccharide (HSA/LPS, n = 8) by intraperitoneal injection, for 6 weeks; afterward, they were observed for either an additional 3 weeks (9 weeks total; n = 4 from each group) or 14 weeks (20 weeks total; n = 4 from each group). Kidneys were analyzed by histomorphometry, and blood and urine samples were obtained to assess bone resorption. Whole-body and isolated femur Dual-Energy X-ray Absorptiometry (DEXA) scans were performed at the end of each study. HSA/LPS-treated animals developed a proliferative GN by 9 weeks, which is associated with proteinuria but no change in renal function. Between 9 and 20 weeks, there was evidence of an increasing interstitial inflammation (1381 +/- 67 interstitial cells/mm(2) at 9 weeks and 1818 +/- 28 interstitial cells/mm(2) at 20 weeks.) There was also evidence of bone resorbing activity as assessed by experimental/control (E/C) < 1.0 at 9 (E/C plasma = 0.66 +/- 0.05) and 20 (E/C plasma = 0.52 +/- 0.04) weeks. Parathyroid hormone (PTH) levels were normal at all time points, and no differences in bone mineral density were found. This model produces not only an immune glomerular/tubular injury, but also a stimulus for bone resorption that is related to objective measures of inflammation severity. The bone resorption is not caused by renal insufficiency, hyperparathyroidism, or steroid therapy. This model will prove useful in other studies of the role of renal inflammation in skeletal disorders.
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PMID:Nonparathyroid hormone-mediated calcium resorption in a rat model of immune glomerulonephritis. 1613 56

That both infiltrating macrophages and resident mesangial cells express inducible nitric oxide synthase (iNOS) and produce nitric oxide (NO) excessively is crucial to the progress of glomerulonephritis. Although several reports have mentioned the protective impacts of conjugated linoleic acid (CLA) in stimulated macrophages, the role of CLA in glomerular mesangial cells is unknown. The aim of the present study was to explore the ability of CLA to regulate iNOS expression and NO production in stimulated glomerular mesangial cells. Additionally, we evaluated the effect of CLA on activation of transcription factors which mediate iNOS expression. Exogenous CLA dose-dependently diminished iNOS mRNA and protein expression as well as NO production in lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma)-stimulated SV-40-transformed mouse mesangial cells. Electrophoretic mobility shift assay experiments demonstrated that CLA (100 microM) dramatically reduced activation of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1) and cAMP response element binding protein (CREB) induced by LPS/IFN-gamma. Moreover, addition of 100 microM CLA significantly diminished LPS-IFN-gamma-induced protein degradation of inhibitor kappaB-alpha (IkappaB-alpha) and the protein expression of phosphorylated IkappaB-alpha in the cytosolic fraction as well as nuclear p65 expression (P < 0.05). In summary, inhibition of NF-kappaB, AP-1 and CREB activation by CLA may be associated with the molecular basis for which CLA suppresses iNOS expression and NO production in stimulated mesangial cells.
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PMID:Contribution of conjugated linoleic acid to the suppression of inducible nitric oxide synthase expression and transcription factor activation in stimulated mouse mesangial cells. 1618 63


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