Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In this study the IL-6 production was studied by synovial cells isolated from patients with either rheumatoid arthritis (RA) or osteoarthritis (OA). The kinetics of spontaneous IL-6 production differs in both groups. Furthermore, the induction of IL-6 by bacterial lipopolysaccharide (LPS) in synovial cell cultures of RA is much more rapid than in those of OA patients. On the other hand, more PGE2 was detected in culture supernatants from synovial adherent cells of OA than in those of RA patients. We also compared the IL-6 production and the amount of IL-6 mRNA in fragments derived from the areas of synovial tissue showing macroscopic signs of intensive inflammation (area A), with those from relatively intact (area B) synovial sites. In synovial fragments, but not in isolated adherent cells at area A the in vitro IL-6 production starts earlier in RA than in OA. In the area A, significantly more CD14+, CD43+ and HLA-DR+ cells were detected than in the other compartment less involved in local inflammatory events.
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PMID:Dissimilar biosynthesis of interleukin-6 by different areas of synovial membrane of patients with rheumatoid arthritis and osteoarthritis. 137 92

We examined the prostaglandin E (PGE) synthesis of cultured adherent synovial fibroblast-like cells (SFC) from patients with osteoarthritis (OA) in the noninflammatory state as well as with rheumatoid arthritis (RA). In cells from RA patients the spontaneous PGE release was generally higher compared to that of OA patients, but decreased fast with time in culture. After cell passage, similar PGE baseline levels were seen in cells of the two patient groups. The cells could then be stimulated by the terminal complement components C5b-9 or C5b-8. PGE synthesis was also stimulated by the platelet-derived growth factor (PDGF), interleukin-1 (IL-1), or lipopolysaccharide (LPS). The amount of PGE synthesis after incubation with PDGF, LPS and IL-1 was comparable to that released after C5b-9. Thus, like other inflammatory mediators C5b-9 and PDGF trigger the increased PGE production by SFC and thus may participate in the development of synovial inflammation and contribute to the pathogenesis of RA.
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PMID:Effect of the late complement components C5b-9 and of platelet-derived growth factor on the prostaglandin release of human synovial fibroblast-like cells. 251 62

Classically, osteoarthritis (OA) has been considered a noninflammatory disease. However, the detection of selected inflammatory mediators in osteoarthritic fluid, in the absence of significant inflammatory cell infiltrate, is increasingly appreciated. We sought to identify the inflammatory component in human OA-affected cartilage that may be involved in cartilage damage/destruction. Using Western blot analysis and an antibody to the conserved region of nitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the "key players" of inflammation, in chondrocytes of OA-affected patients. Remarkably, none of the cartilage samples examined from normal joints demonstrated detectable amounts of this NOS. Western blot analysis using the same alpha-NOS antibody indicated that this NOS from OA-affected cartilage (OA-NOS) was larger in size than (and distinct from) transfected human hepatocyte or murine inducible NOS (iNOS) (150 versus 133 kD) and similar in size to neuronal constitutive NOS (ncNOS). Antibodies specific for iNOS showed binding to murine and human iNOS but not to OA-NOS, endothelial constitutive NOS, or ncNOS. Antibodies specific for ncNOS bound to ncNOS and also to OA-NOS, but not to murine or human iNOS or endothelial constitutive NOS. Incubation of OA cartilage in serum-free medium resulted in spontaneous release, for up to 72 h, of substantial amounts of nitrite (up to approximately 80 microM/100 mg wet tissue), which could be inhibited by at least 80% with various inhibitors of iNOS, including inhibitors of protein synthesis and transcription factor NF-kappa B, but which (unlike murine macrophage iNOS) was not sensitive to hydrocortisone or TGF-beta. Exposure of OA-affected cartilage to interleukin 1 beta, tumor necrosis factor-alpha, and lipopolysaccharide resulted in approximately 20-50% augmentation of nitrite accumulation, which was also sensitive to cycloheximide and pyrrolidine dithiocarbamate. Hence, our data indicate that OA-NOS (based on immunoreactivity and molecular weight) is similar to ncNOS and that it releases nitric oxide, which may contribute to the inflammation and pathogenesis of cartilage destruction in OA.
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PMID:The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. 750 55

The aim of this study was to determine whether the cytokine macrophage inflammatory protein-1 beta (MIP-1 beta) is present and functionally active in the arthritic joint. We used immunoassays and bioassays to assess the presence and function of MIP-1 beta using samples obtained from 62 arthritic patients. MIP-1 beta levels were increased in synovial fluids (SFs) from patients with osteoarthritis (OA) (18.0 +/- 8.9 ng/ml) (SD) compared to patients with rheumatoid arthritis (RA) 6.1 +/- 2.9 ng/ml) or other forms of arthritis (10.4 +/- 7.0 ng/ml) (P < 0.05). Levels of OA SF MIP-1 beta were significantly greater than OA or normal serum levels of MIP-1 beta. Anti-MIP-1 beta neutralized 28% of the chemotactic activity for monocytes found in OA SFs. Isolated OA synovial tissue fibroblasts did not constitutively produce MIP-1 beta but could be induced to express this chemokine upon exposure to tumor necrosis factor-alpha, interleukin-1 beta, or lipopolysaccharide. Synovial tissue immunohistochemical staining revealed that the main immunopositive cells in OA were the lining cells as well as vascular smooth muscle and endothelial cells. A minority of macrophages were immunopositive as well. In this study, we identify MIP-1 beta as a unique cytokine increased in OA compared to RA SF. We conclude that MIP-1 beta may play a role in the ingress of monocytes into the OA joint.
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PMID:Macrophage inflammatory protein-1 beta: a C-C chemokine in osteoarthritis. 758 41

Synovial fluid (SF) mononuclear cells (MNC) from 13 patients with rheumatoid arthritis (RA) and 12 patients with other arthritic diseases (OD) including osteoarthritis (OA), gout and spondyloarthritis (SA) were cultured in the presence of collagen types I and II or lipopolysaccharide (LPS) for 24 h. Interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha) in the SF and culture supernatants were assayed using ELISA. The results showed that one-half of the RA patients with high SF monocyte count had high SF IL-6 levels that coincided with the high spontaneous release of IL-6 by SF MNC. In the other RA patients with lower SF monocyte count, type II collagen induced significantly higher IL-1 beta than the medium control levels by SF MNC (P < 0.01) or that of the other diseases (P < 0.01). Similarly, type II collagen-induced IL-6 and TNF-alpha production rose significantly (P < 0.01) from SF MNC of RA but less from OD (P < 0.05). In addition, type I collagen could also induce IL-1, IL-6 and TNF-alpha in these samples from RA and OD patients but was less potent than type II collagen. Our results indicate that collagen-induced cytokines may be important in the pathogenesis of the disease.
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PMID:Collagen induces cytokine production by synovial fluid mononuclear cells in rheumatoid arthritis. 762 81

We investigated the nature of cytokines synthesized by human osteoarthritic (OA) synovium, particularly interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) to block the synthesis of metalloproteases (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthritis (OA) synovium. Human OA synovium were incubated in the presence or absence of lipopolysaccharide (LPS) or increasing concentrations of rhIL-1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-1ra in culture medium were carried out using specific ELISA. Although both IL-1 isoforms and TNF alpha could be produced by OA synovium, IL-1 beta was the predominant cytokine synthesized either in the presence or absence of LPS. Treatment of the OA synovium with an increasing concentration of rhIL-1ra (0-10 micrograms/ml) showed a dose dependent reduction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated synovium also showed a consistent suppression of metalloproteases and IL-6, although a higher IL-1ra concentration was required. Conversely, IL-1 beta production was not inhibited by IL-1ra, irrespective of the concentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine involved in the stimulation of metalloproteases and IL-6 synthesis in OA synovium.
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PMID:Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. 775 12

The objective of this study is to determine whether soluble intercellular adhesion molecule-1 (sICAM-1) is found in rheumatoid arthritis (RA) and other inflammatory disorders and to identify which cells are responsible for sICAM-1 production. Synovial fluid, blood and cells isolated from RA synovial fluids, and synovial tissues from 59 patients were studied. In addition, normal peripheral blood was obtained. sICAM-1 was assayed by an enzyme-linked immunoabsorbent assay. Synovial fluids from patients with RA and other inflammatory arthritides had significantly higher sICAM-1 levels than did osteoarthritis (OA) synovial fluids. Synovial fluid sICAM-1 levels were significantly positively correlated with synovial fluid leukocyte counts. RA synovial tissue fibroblasts released low levels of sICAM-1. Neutrophils (PMNs) isolated from synovial fluids of RA patients spontaneously released sICAM-1. However, mononuclear cells isolated from RA synovial fluid produced the largest quantities of sICAM-1. Phytohemagglutinin but not lipopolysaccharide enhanced mononuclear sICAM-1 release. sICAM-1 was increased in synovial fluids from RA compared to OA. This sICAM-1 may be important in modulating the trafficking of inflammatory leukocytes into diseased RA synovial tissue and fluid.
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PMID:Soluble intercellular adhesion molecule-1 in arthritis. 791 Jan 25

We and others have shown that cells obtained from inflamed joints of rheumatoid arthritis (RA) patients produce interleukin-8, a potent chemotactic cytokine for neutrophils (PMNs). However, IL-8 accounted for only 40% of the chemotactic activity for PMNs found in these synovial fluids. Currently, we have examined the production of the novel PMN chemotactic cytokine, epithelial neutrophil activating peptide-78 (ENA-78), using peripheral blood, synovial fluid, and synovial tissue from 70 arthritic patients. RA ENA-78 levels were greater in RA synovial fluid (239 +/- 63 ng/ml) compared with synovial fluid from other forms of arthritis (130 +/- 118 ng/ml) or osteoarthritis (2.6 +/- 1.8 ng/ml) (P < 0.05). RA peripheral blood ENA-78 levels (70 +/- 26 ng/ml) were greater than normal peripheral blood levels (0.12 +/- 0.04 ng/ml) (P < 0.05). Anti-ENA-78 antibodies neutralized 42 +/- 9% (mean +/- SE) of the chemotactic activity for PMNs found in RA synovial fluids. Isolated RA synovial tissue fibroblasts in vitro constitutively produced significant levels of ENA-78, and this production was further augmented when stimulated with tumor necrosis factor-alpha (TNF-alpha). In addition RA and osteoarthritis synovial tissue fibroblasts as well as RA synovial tissue macrophages were found to constitutively produce ENA-78. RA synovial fluid mononuclear cells spontaneously produced ENA-78, which was augmented in the presence of lipopolysaccharide. Immunohistochemical localization of ENA-78 from the synovial tissue of patients with arthritis or normal subjects showed that the predominant cellular source of this chemokine was synovial lining cells, followed by macrophages, endothelial cells, and fibroblasts. Synovial tissue macrophages and fibroblasts were more ENA-78 immunopositive in RA than in normal synovial tissue (P < 0.05). These results, which are the first demonstration of ENA-78 in a human disease state, suggest that ENA-78 may play an important role in the recruitment of PMNs in the milieu of the inflamed joint of RA patients.
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PMID:Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. 808 42

The effects of inflammation on the biochemical and biomechanical properties of articular cartilage at two sites (dorsal and palmar) from the radial facet of the equine third carpal bone were examined in response to a synovitis induced with Escherichia coli lipopolysaccharide (LPS). Four groups were studied. In group 1 synovitis was induced at time zero and evaluated at week 6. Group 2 was the sham-treated control for group 1. In group 3 synovitis was induced at time zero and evaluated at week 2. Group 4 was the sham-treated control for group 3. There was a significant increase (P < 0.05) in newly synthesized proteoglycan PG from both sites in group 3 as compared to the sham-treated groups and group 1. No significant difference in the endogenous PG concentration between groups or sites was detected. Sepharose CL-2B revealed two peaks of newly synthesized PG in all groups; an early peak (Kav 0.11-0.13) and a late peak (Kav 0.48-0.64). Newly synthesized PG profiles from sham-treated groups and group 3 were similar, but the group 3 PG profile exhibited a more pronounced early peak. Conversely, the PG profile from group 1 demonstrated a more prominent late peak. Electrophoresis and Western blot analysis of the pooled late PG peak fractions from the sham-treated and group 1 showed a single toluidine blue stained band from both sites which reacted with monoclonal antibody (MAb) 1C6. By contrast, the late peak from the palmar site in group 3 showed an additional faster moving component on composite gels which did not react with MAb 1C6. There was a significant decrease in Poisson's ratio and a significant increase in cartilage thickness in groups 1 and 3 which had received synovitis. The increase in cartilage thickness of groups 1 and 3 was also significantly affected by site (dorsal > palmar). There was no significant difference in aggregate modulus or permeability constant among groups. Primary joint inflammation induced by LPS alters the biochemical and biomechanical properties of the articular cartilage as a function of time and site. An increase in chondrocyte PG synthesis in the early period following synovitis may be a reparative response to the inflammatory insult. Continued alterations in the qualitative PG composition in the later period following synovitis may represent a shift in chondrocyte metabolism to repopulate the existing cartilage matrix.
Osteoarthritis Cartilage 1996 Jun
PMID:Biochemical and biomechanical alterations in equine articular cartilage following an experimentally-induced synovitis. 880 14

Tetracyclines have recently been shown to have "chondroprotective" effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1 beta-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline > or = doxycycline inhibited both lipopolysaccharide- and interferon-gamma-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of L-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for beta-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of beta-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.
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PMID:A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. 894 52


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