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

We investigated the association with Yersinia infection in patients with arthropathies in our region. To assess the reactivity to articular antigens, the correlation of anti-Yersinia with anti-type I and type II collagen antibodies was studied. Sera from 124 patients with musculoskeletal symptoms, and 47 synovial fluids (SF) from patients with rheumatoid arthritis (RA), spondyloarthopathies (SpA) or osteoarthritis (OA) were examined. Immunoglobulins against Yersinia enterocolitica, type I and type II collagens were determined by enzyme-linked immunosorbent assay. Immunoglobulin (Ig) A to Yersinia lipopolysaccharide (LPS) was present in 13/124 sera (10%) and 3/47 SF (6%). By Western blot, IgA to Yersinia outer proteins (Yops) was found in 14/124 sera (11%) and 2/47 SF (4%). Yersinia DNA from SF was not amplified by polymerase chain reaction. We found a significant correlation with anti-collagen type I but not type II antibodies. These results suggest different reactivity to articular collagen in patients with Yersinia antibodies.
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PMID:Correlation between Yersinia enterocolitica and type I collagen reactivity in patients with arthropathies. 1714 98

Rheumatoid arthritis (RA) is characterized by infiltrations of inflammatory cells accompanied by neovascularization in the joint. We hypothesized that cell activation via the toll-like receptor (TLR) may be involved in the induction of angiogenic molecules, which are relevant to the pathogenesis of RA. RA fibroblast like synoviocytes (FLS) were stimulated with TLR-2 ligand bacterial peptidoglycan (PGN), TLR-4 ligand lipopolysaccharide (LPS) and various cytokines. Vascular endothelial growth factor (VEGF) and IL-8 were measured by ELISA in culture supernatants; mRNA levels were assessed by RT-PCR and real time PCR. The levels of TLR-2, VEGF and IL-8 were analyzed by dual immunohistochemistry in RA synovium and compared with osteoarthritis (OA). Regulation of MyD88, IRAK4, IRAK1, IRAK-M and TRAF-6 mRNA expression levels by PGN were analyzed by RT-PCR. Phosphorylation of I kappa B alpha was evaluated by western blotting. Levels of VEGF and IL-8 were upregulated in culture supernatants of RA FLS stimulated with PGN, similar to the levels of IL-1beta and IL-17 stimulation. Neutralization of TLR-2 with a blocking monoclonal antibody significantly reduced both VEGF and IL-8 levels (P<0.05), which reflected the functional relevance of TLR-2 activation to the induction of VEGF and IL-8 production. Downstream intracellular signaling following TLR-2 stimulation involved MyD88-IRAK-4-TRAF-6 pathways, resulting in NF-kappaB activation. Thus, TLR-2 activation in RA FLS by microbial constituents could be involved in the induction of VEGF and IL-8 and thereby promote inflammation either directly or via angiogenesis. This possibly contributes to the perpetuation of synovitis in patients with RA.
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PMID:Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. 1718 9

Toll-like receptors (TLRs) are pattern-recognition receptors that connect innate and adaptive immunity. Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector functions in inflammatory synovitis of rheumatoid arthritis (RA). The aim of this study was to clarify whether stimulation of TLR2 and TLR4 by their specific ligands induces the production of IL-15 in fibroblast-like synoviocytes (FLS) from RA patients. FLS were isolated from RA synovial tissues and stimulated with the TLR2 ligand bacterial peptidoglycan (PGN) and the TLR4 ligand lipopolysaccharide (LPS). IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real time PCR. The expression of TLR2, TLR4, and IL-15 in the RA synovium was quantified by immunohistochemistry and compared with values obtained in osteoarthritis synovium. IL-15 production increased in culture supernatants of RA FLS stimulated with PGN or PGN plus LPS, and this was upregulated at the transcriptional level. In contrast, LPS did not increase the level of IL-15 although it augmented the stimulatory effect of PGN on IL-15 production. Inhibition of nuclear factor (NF)-kappaB with a specific inhibitor abrogated the stimulatory effect of PGN or PGN plus LPS on IL-15. Neutralization of TLR2 with a blocking monoclonal antibody significantly reduced IL-15 production (P<0.05), reflecting the functional relevance of TLR2 activation in the induction of IL-15 production. These data suggest that TLR2 activation in RA FLS by microbial constituents is involved in the induction of IL-15 and that TLR2 promotes inflammation through NF-kappaB. TLR4 augmented the stimulatory effect of TLR2 on IL-15, possibly contributing to the maintenance of synovitis in patients with RA.
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PMID:Toll-like receptor 2 and 4 combination engagement upregulate IL-15 synergistically in human rheumatoid synovial fibroblasts. 1728 61

Previously, we reported that cartilage is an estrogen receptor (ER) positive tissue and that mRNA levels of ERbeta increase in postmenopausal women with osteoarthritis. Based on our findings and those of other investigators, we hypothesized that local rather than circulating estrogen levels negatively affect chondrocyte metabolism and that selective ER modulators (SERM) augment cartilage health. To test the latter part of our hypothesis, we explored the role of genistein, a naturally occurring SERM with high affinity to bind ERbeta, in inhibiting the lipopolysaccharide (LPS)-stimulated cyclooxygenase (COX)-2 in chondrocytes. Primary cultures of normal human chondrocytes were treated with three levels of genistein (0, 50, and 100 microM). After 1 h, the genistein-treated cells were stimulated by 1 microg/ml LPS for 24 h. Cells were then harvested, and the cytosolic fraction was isolated for assessment of COX-1 and COX-2 protein levels using Western analysis. Nitric oxide (NO), interleukin-I beta (IL-1beta), and human cartilage glycoprotein 39 (YKL-40) production was also measured in cell supernatants. NO and IL-1beta were measured as markers of inflammation, and YKL-40 was assessed as a marker of cartilage catabolism. Genistein had no significant effect on either YKL-40 or IL-1beta levels. Our data indicate that the LPS-stimulated increases in COX-2 protein level and NO in supernatant are reduced by pretreatment of genistein, whereas COX-1 protein level is not affected by genistein. The ability of genistein to suppress COX-2 but not COX-1 is advantageous because suppressing COX-2 can lead to suppression of proinflammatory molecules. Although genistein suppresses COX-2 production, it does not affect the production of COX-1 enzyme, which is responsible for releasing prostaglandins involved in cellular house-keeping functions such as the maintenance of gastrointestinal integrity and vascular homeostasis.
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PMID:Genistein reduces the production of proinflammatory molecules in human chondrocytes. 1736 82

Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.
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PMID:A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis. 1738 41

Matrix metalloprotease-13 (MMP-13) is induced by pro-inflammatory cytokines and increased expression is associated with a number of pathological conditions such as tumor metastasis, osteoarthritis, rheumatoid arthritis and periodontal diseases. MMP-13 gene regulation and the signal transduction pathways activated in response to bacterial LPS are largely unknown. In these studies, the role of the mitogen-activated protein kinase (MAPK) pathways in the regulation of MMP-13 induced by lipopolysaccharide was investigated. Lipopolysaccharide from Escherichia coli and Actinobacillus actinomycetemcomitans significantly (P < 0.05) increased MMP-13 steady-state mRNA (average of 27% and 46% increase, respectively) in murine periodontal ligament fibroblasts. MMP-13 mRNA induction was significantly reduced by inhibition of p38 MAP kinase. Immunoblot analysis indicated that p38 signaling was required for LPS-induced MMP-13 expression. Lipopolysaccharide induced proximal promoter reporter (-660/+32 mMMP-13) gene activity required p38 signaling. Collectively, these results indicate that lipopolysaccharide-induced murine MMP-13 is regulated by p38 signaling through a transcriptional mechanism.
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PMID:Transcriptional activation of MMP-13 by periodontal pathogenic LPS requires p38 MAP kinase. 1762 49

Growth and differentiation factor 5 (GDF5) has been implicated in chondrogenesis and joint formation, and an association of GDF5 and osteoarthritis (OA) has been reported recently. However, the in vivo function of GDF5 remains mostly unclarified. Although various human GDF5 mutations and their phenotypic consequences have been described, only loss-of-function mutations that cause brachypodism (shortening and joint ankylosis of the digits) have been reported in mice. Here, we report a new Gdf5 allele derived from a large-scale N-ethyl-N-nitrosourea mutagenesis screen. This allele carries an amino acid substitution (W408R) in a highly conserved region of the active signaling domain of the GDF5 protein. The mutation is semi-dominant, showing brachypodism and ankylosis in heterozygotes and much more severe brachypodism, ankylosis of the knee joint and malformation with early-onset OA of the elbow joint in homozygotes. The mutant GDF5 protein is secreted and dimerizes normally, but inhibits the function of the wild-type GDF5 protein in a dominant-negative fashion. This study further highlights a critical role of GDF5 in joint formation and the development of OA, and this mouse should serve as a good model for OA.
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PMID:A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. 1765 74

Clinical studies have demonstrated that SKI306X, a purified preparation of three medicinal plants, relieves joint pain and improves functionality in osteoarthritis patients. To study the biological action of SKI306X, bovine cartilage explants and human peripheral blood mononuclear cells (PBMC) were stimulated with IL-1 beta and lipopolysaccharide (LPS) respectively, in the presence or absence of SKI306X and its individual composites. All tested compounds inhibited dose-dependently IL-1 beta-induced proteoglycan release and nitric oxide production by cartilage, indicating cartilage protective activity. SKI306X and two of its compounds inhibited PGE(2), TNF-alpha and IL-1 beta production by LPS-stimulated PBMC, indicating anti-inflammatory activity. These results demonstrate that the biological effect of SKI306X is at least bipartite: (1) cartilage protective and (2) anti-inflammatory. The observed anti-inflammatory effects may provide an explanation for the outcome of the clinical studies. Long-term clinical trails are necessary to elucidate whether the in vitro cartilage protective activity results in disease-modifying effects.
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PMID:The multicomponent phytopharmaceutical SKI306X inhibits in vitro cartilage degradation and the production of inflammatory mediators. 1794 60

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine produced by epithelial cells and triggers dendritic cell-mediated Th2 type allergic inflammatory responses. This study investigated whether Toll-like receptor (TLR) ligands, lipopolysaccharide (LPS) and poly-IC affect TSLP production in synovial fibroblasts. Enzyme-linked immunosorbent assay showed that LPS and poly-IC upregulated TSLP production in synovial fibroblasts obtained from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, we found that nuclear factor (NF)-kappaB inhibitor IMD-0354, dexamethasone, and interferon (IFN)-gamma inhibited the LPS- and poly-IC-induced TSLP production in RA and OA synovial fibroblasts. Thus, LPS and poly-IC can upregulate TSLP via a NF-kappaB pathway in synovial fibroblasts, which is downregulated by dexamethasone and interferon (IFN)-gamma. The current findings suggest that TSLP may be involved in the pathophysiology of inflammatory arthritis as well as allergic disease.
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PMID:Thymic stromal lymphopoietin secretion of synovial fibroblasts is positively and negatively regulated by Toll-like receptors/nuclear factor-kappaB pathway and interferon-gamma/dexamethasone. 1808 96

Since recent evidences point out the potential involvement of Toll-like receptors (TLRs) in the therapeutic effect of vasoactive intestinal peptide (VIP), the purpose of this study is to elucidate the role of VIP as a negative regulator of TLR-signaling. To this aim, we analyzed in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), the expression profile of TLR-pathway related molecules, as well as the alterations induced by LPS stimulation in RA-FLS and the effect of VIP treatment. Cultured FLS were obtained from patients with RA or OA. RA-FLS were next stimulated with lipopolysaccharide (LPS) in presence or absence of VIP. The gene expression profiling of molecules involved in LPS-mediated TLR4-signaling was studied by cRNA microarray analysis. Twenty three molecules involved in TLR signaling resulted over-expressed at mRNA level in basal RA-FLS compared to OA-FLS. Moreover, in RA-FLS, 23 of the analyzed genes were found to be up-regulated by LPS stimulation whereas 30 were not affected. VIP down-regulated the LPS-induced RNA expression of molecules involved in TLR signaling pathway. Up-regulation of RNA expression of CD14, MD2, TRAM, TRIF, IRAK4, TAB2, TRAF6 and TBK1 was corroborated by RT-PCR as well as the VIP regulatory effect. Increased protein levels of TRAF6, TBK1 and pIRAK1 after exposure to LPS, and the inhibitory effect of VIP, were described by Western blotting. As functional consequences, it was observed the VIP-induced impaired production of IL-6 and RANTES/CCL5 after LPS stimulation. In conclusion, VIP acts as a negative modulator of the TLR4-signaling by overturning the production of several checkpoints molecules of the cascade and thus, widening its potential therapeutic effects.
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PMID:VIP reverses the expression profiling of TLR4-stimulated signaling pathway in rheumatoid arthritis synovial fibroblasts. 1845 92


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