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)

In heart muscle, the cytokine-inducible isoform of nitric oxide synthase (NOS2) is expressed in both cardiac myocytes and microvascular endothelial cells (CMEC). mRNA levels for both NOS2 and for osteopontin, a multifunctional extracellular matrix phosphoprotein containing and RGD integrin binding domain, are increased in cardiac muscle following intraperitoneal injection of adult rats with lipopolysaccharide. In vitro, interleukin-1 beta and interferon-gamma increased osteopontin mRNA levels in CMEC as well as NOS2 expression in both CMEC and cardiac myocytes. However, osteopontin mRNA levels in heart muscle in vivo, and in cardiac myocytes and CMEC in vitro, also are increased 10-30-fold by the synthetic glucocorticoid dexamethasone, an agent that suppresses cytokine induction of NOS2 in both cell types. The hexapeptide GRGDSP, which interrupts binding of RGD-containing proteins to cell surface integrins, increased NOS2 mRNA, while a synthetic osteopontin peptide analogue decreased NOS2 mRNA and protein levels in both cytokine-pretreated cardiac myocytes and CMEC cultures. Also, transfection with a full-length antisense-osteopontin cDNA in cytokine-pretreated CMEC decreased endogenous osteopontin mRNA and increased NOS2 mRNA levels. These results suggest that osteopontin could regulate the location and extent of NOS2 induction in the heart. Increased expression of osteopontin also may be one mechanism by which glucocorticoids suppress NOS2 activity in cardiac myocytes and microvascular endothelial cells.
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PMID:Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. 749 54

We report that osteopontin (OPN), a secreted, Arg-Gly-Asp-containing phosphoprotein expressed at high levels in the kidney, suppresses nitric oxide (NO) synthesis induced by the inflammatory mediators gamma-interferon and lipopolysaccharide in primary mouse kidney proximal tubule epithelial cells. Northern blot and immunofluorescence analyses of inducible nitric oxide synthase (iNOS) expression revealed that the inflammatory mediators increased iNOS mRNA and protein levels. Recombinant human OPN (purified from both mammalian cells and from Escherichia coli) inhibited this response by a process that was blocked by anti-OPN antiserum and by the peptide GRGDS, but not GRGES. The data suggest that inhibition of NO synthesis by OPN in these kidney cells is mediated by an integrin, possibly the alpha v beta 3 integrin, which is known to be an OPN receptor. NO is believed to control blood flow through the glomerulus, regulating salt and water balance, and to be important as a defense against tumor cells and infecting microorganisms. The ability of OPN to inhibit the induction of iNOS suggests that OPN may be an important regulator of the NO signaling pathway and NO-mediated cytotoxic processes.
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PMID:Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. 750 62

Osteopontin (OPN), a secreted acidic phosphoglycoprotein found in many tissues and body fluids, is produced in increased amounts in response to certain infections and after malignant transformation. In this study we examined the action of OPN on macrophage cytotoxicity and nitric oxide (NO) synthesis. A human OPN cDNA was cloned into the bacteriophage T7-based vector, pET8C, and the encoded protein purified from an induced culture of Escherichia coli carrying the plasmid. Recombinant OPN inhibited NO production by macrophage-like RAW264.7 cells stimulated with lipopolysaccharide plus interferon-gamma. OPN also inhibited the cytolytic activity of the activated macrophages toward NO-sensitive P815 mastocytoma cells, an action that was blocked by the NO synthase inhibitor, NG-monomethyl-L-arginine. Inhibition of NO production correlated with an OPN-dependent decrease in the abundance of inducible NO synthase mRNA. The shape of the dose-response curve, with a maximal effect over a narrow range of OPN concentrations, suggested a complex interaction of OPN with cell surface receptors. Our data support the hypothesis that tumor-cell-derived OPN functions to protect the tumor cells from macrophage-mediated destruction.
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PMID:Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW264.7 macrophages. 883 Jul 97

Osteopontin (OPN) is a secreted phosphoprotein found in body fluids (e.g. plasma, urine, milk) and in mineralized tissues. Its expression is increased in many transformed cells and in normal cells exposed to various cytokines. When stimulated with the inflammatory mediators lipopolysaccharide and interferon-gamma, mouse macrophages secrete nitric oxide (NO) as a cytotoxic agent effective against microbial invaders and tumour cells. This report documents (1) that thioglycollate-elicited peritoneal macrophages, activated with the inflammatory mediators, produced less NO and exhibited reduced cytotoxicity towards target cells when they were obtained from old animals than when they were obtained from young animals; and (2) that OPN was able to inhibit both the induced NO synthesis and cytotoxicity, but more effectively in macrophages from the young animals than those from the old animals. This may be due to the observed higher level of OPN expression in macrophages from old animals.
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PMID:Differential effects of osteopontin on the cytotoxic activity of macrophages from young and old mice. 888 70

Osteopontin is a secreted phosphoprotein that is expressed in the normal kidney and induced during various pathologic conditions associated with tubulointerstitial injury. However, the exact cellular location of osteopontin in the kidney has been a matter of controversy, and little is known about the role of osteopontin in the kidney. The purpose of this study was to establish the cellular and intracellular distribution of osteopontin in the rat kidney under normal conditions and after injection of a bacterial endotoxin lipopolysaccharide (LPS). Animals received injections of LPS or vehicle at different time intervals from 4 to 20 h before sacrifice. Kidneys were preserved by in vivo perfusion with paraformaldehyde-lysine-periodate (PLP) and processed for light and electron microscope immunocytochemistry using monoclonal antibodies to rat osteopontin. By light microscopy, immunostaining was observed in the descending thin limb and the papillary surface epithelium of both control and LPS-treated animals. After injection of LPS, osteopontin immunostaining was observed throughout the distal nephron and was also present in segments of the proximal tubule, where it was distributed in a punctate pattern. Staining was already present 4 h after injection of LPS and was maximal 6 h after injection. Electron microscopy revealed that osteopontin immunoreactivity in the descending thin limb and distal tubule cells was located in the Golgi apparatus and in small cytoplasmic vesicles, whereas in the proximal tubule labeling was observed in the vacuolar-lysosomal system. Western blot analysis demonstrated a band at approximately 70 kD and confirmed the increase in osteopontin expression after administration of LPS. These results demonstrate that osteopontin is constitutively expressed in cells of the descending thin limb and papillary surface epithelium and is induced throughout the distal tubule after administration of LPS.
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PMID:Ultrastructural localization of osteopontin in the kidney: induction by lipopolysaccharide. 921 53

To investigate whether MCP-1, CINC, RANTES, osteopontin and ICAM-1 mRNA could be induced in cultured rat mesangial cells by interleukin-1beta(IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS), and whether MCP-1 and CINC gene expression could be modulated by dexamethasone, Northern blot assays were performed. IL-1beta induced MCP-1, CINC, RANTES and ICAM-1 gene expression in a time dependent manner. IL-1beta-induced MCP-1, CINC and ICAM-1 mRNA amount were maximal at 3 hours exposure around 14.5, 15.7, 2.2 folds increase and IL-1beta-induced RANTES mRNA at 24 hours around 2.0 folds. TNF-alpha and LPS also induced MCP-1 and ICAM-1 gene expression. TNF-alpha also induced RANTES gene expression but LPS did not. On the other hand, IL-1beta, TNF-alpha and LPS had little effect on osteopontin gene expression but fetal calf serum could increase osteopontin mRNA. Dexamethasone suppressed the IL-1beta-induced MCP-1 and CINC mRNA. These results suggest that, through these gene expressions, mesangial cells are able to communicate directly or indirectly with macrophages or neutrophils, which may lead to glomerulosclerosis.
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PMID:Chemokines, osteopontin, ICAM-1 gene expression in cultured rat mesangial cells. 961 Jun 17

We tested the hypothesis that osteopontin (OPN) can inhibit the induction of inducible nitric oxide synthase (iNOS) in vascular tissue. iNOS activity was induced in rat thoracic aortas by incubation of the tissue with lipopolysaccharide (LPS) and measured by conversion of L-[3H]arginine to L-[3H]citrulline. Addition of >/=1 nM recombinant OPN protein significantly reduced the LPS-induced increase in iNOS activity. Western blotting and the RT-PCR were used to determine the effect of LPS with and without OPN on tissue levels of iNOS protein and RNA, respectively. LPS resulted in an increase in iNOS protein and RNA, whereas OPN dose-dependently reduced tissue levels of iNOS activity, protein, and RNA. Mutated OPN proteins, in which the integrin-binding RGD amino acid sequence was deleted or mutated to RGE, resulted in complete and partial loss, respectively, of the ability of OPN to inhibit LPS-induced iNOS activity, implicating integrin binding in the effect. These results indicate that OPN can prevent induction of iNOS in vascular tissue.
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PMID:Osteopontin inhibits inducible nitric oxide synthase activity in rat vascular tissue. 984 27

Osteopontin has been shown to inhibit the induction of inducible nitric oxide synthase (iNOS, or NOS2) by lipopolysaccharide and interferon-gamma in the RAW264.7 mouse monocyte/macrophage line and in primary mouse proximal tubule epithelial cells. However, the RAW264.7 cells become refractory to the action of OPN after several subcultures or under dilute culture conditions, possibly because of changes in the composition of the extracellular matrix. We make this suggestion because if the cells are plated on a collagen type I or collagen type IV substrate the inhibitory action of OPN is completely suppressed; this is not the case on substrates consisting of laminin, fibronectin, poly-D-lysine, or poly-(2-hydroxyethylmethylacrylate). These observations imply that macrophages are sensitive to regulation by OPN only in certain physiological contexts. Both hyaluronate, which binds CD44, and rat IgGs are also able to inhibit the induction of NO synthesis by the inflammatory mediators. The similar actions of HA and OPN are consistent with the possibility that CD44 may be a receptor for OPN.
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PMID:Regulation of no synthesis induced by inflammatory mediators in RAW264.7 cells: collagen prevents inhibition by osteopontin. 1085 58

Nitric oxide (NO) produced by macrophages is thought to contribute to various pathological conditions. Osteopontin (OPN) is a phosphorylated glycoprotein produced principally by macrophages. OPN inhibits inducible nitric oxide synthase (iNOS), which generates large amounts of NO production. However, the relationship between NO and endogenous OPN in activated macrophages has not yet been elucidated. We therefore examined expression of endogenous iNOS and OPN in a murine macrophage cell line, RAW 264.7 cells, by treating the cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Treatment of cells with LPS and IFN-gamma resulted in an increase of iNOS mRNA to maximum at 12 h after stimulation. In contrast, OPN mRNA was induced more slowly than iNOS mRNA. Induction of both iNOS and OPN mRNA in RAW 264.7 cells was markedly suppressed by addition of the specific iNOS inhibitor S-2-aminoethyl isothiourea dihydrobromide. The NOS inhibitor NG-methyl-L-arginine also suppressed induction of OPN mRNA but hardly affected iNOS mRNA expression. The NO-releasing agent spermine-NONOate but not peroxynitrite enhanced induction of OPN mRNA. These results suggest that NO directly up-regulates the endogenous OPN in macrophages stimulated with LPS and IFN-gamma. This up-regulation of endogenous OPN may represent a negative feedback system acting to reduce iNOS expression.
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PMID:Osteopontin is induced by nitric oxide in RAW 264.7 cells. 1086 13

Rheumatoid arthritis is one of the most critical diseases that impair the quality of life of patients, but its pathogenesis has not yet been fully understood. Osteopontin (OPN) is an extracellular matrix protein containing Arg-Gly-Asp (RGD) sequence, which interacts with alpha(v)beta3 integrins, promotes cell attachment, and cell migration and is expressed in both synovial cells and chondrocytes in rheumatoid arthritis; however, its functional relationship to arthritis has not been known. Therefore, we investigated the roles of OPN in the pathogenesis of inflammatory process in a rheumatoid arthritis model induced by a mixture of anti-type II collagen mAbs and lipopolysaccharide (mAbs/LPS). mAbs/LPS injection induced OPN expression in synovia as well as cartilage, and this expression was associated with joint swelling, destruction of the surface structures of the joint based on scanning electron microscopy, and loss of toluidine blue-positive proteoglycan content in the articular cartilage in wild-type mice. In contrast, OPN deficiency prevented the mice from such surface destruction, loss of proteoglycan in the articular joint cartilage, and swelling of the joints even when the mice were subjected to mAbs/LPS injection. Furthermore, mAbs/LPS injection in wild-type mice enhanced the levels of CD31-positive vessels in synovia and terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive chondrocytes in the articular cartilage, whereas such angiogenesis as well as chondrocyte apoptosis was suppressed significantly in OPN-deficient mice. These results indicated that OPN plays a critical role in the destruction of joint cartilage in the rheumatoid arthritis model in mice via promotion of angiogenesis and induction of chondrocyte apoptosis.
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PMID:Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. 1193 8


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