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)

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.
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PMID:Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. 783 Dec 99

During early human pregnancy, fetal cytotrophoblasts rapidly invade the uterus. This process has many similarities to tumor invasion, except that the extent and the timing of cytotrophoblast invasion are carefully regulated. Therefore, this system is particularly useful for studying mechanisms that regulate invasive processes. Previously, we showed that production and activation of the 92-kDa type IV collagenase (matrix metalloproteinase(MMP)-9) is necessary for cytotrophoblast invasion in vitro. In other systems, interleukin (IL)-1 beta is an important regulator of matrix-degrading metalloproteinases. Therefore, we investigated trophoblast production of IL-1 beta and its receptors, as well as the effects of this cytokine on cytotrophoblast metalloproteinase activity and invasion. The results showed that release of IL-1 beta parallels the invasive potential of the cytotrophoblasts; the highest levels are produced by first trimester cells and the lowest levels by term cells. Immunoprecipitation showed that cytotrophoblasts express the 80-kDa type I IL-1 receptor, suggesting that autocrine effects are possible. IL-1 beta stimulated trophoblast MMP-9 secretion (by a mechanism that required nascent mRNA and protein synthesis) as well as metalloproteinase activity and invasion of Matrigel. Increasing (by lipopolysaccharide treatment) or decreasing (by glucocorticoid treatment) IL-1 beta production had parallel effects on MMP-9 secretion, metalloproteinase activity, and invasion. Because IL-1 beta and corticosteroids are present in high concentrations at the maternal-fetal interface, normal trophoblast invasion may be regulated, in part, by their opposing actions. In contrast, stimulation of cytotrophoblast IL-1 beta secretion by lipopolysaccharide may play a role in the sequela of infected fetal membranes.
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PMID:Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. 800 17

Gelatinase B is a regulated matrix metalloproteinase with an important role in the remodelling of extracellular matrices and of basement membranes. To study the structure and function of gelatinase B in the mouse, the cDNA was cloned from a macrophage cell line (WEHI-3). Using this cDNA, a cosmid clone with the mouse gene was isolated. The complete gene (8 kbp) was sequenced and compared with the human gene structure. There was 78% similarity at the cDNA level and the exon/intron structure of the murine gene was similar to the human counterpart. At the 5' untranslated side, 1200 bp of the promoter/enhancer region were sequenced and found to contain several transacting-factor-binding sites. The mRNA transcription-initiation site was determined by non-isotopic primer-extension analysis. Polymerase-chain-reaction amplification of cDNAs yielded indirect evidence for a reverse-transcription stop in WEHI-3 cell mRNA. The DNA-derived mouse-protein structure exhibited 82% similarity with the human one. This similarity was functionally reflected by cross-reactivity of the mouse protein with an antiserum against human gelatinase B. The production of murine gelatinase B was studied at the protein level by zymography and at the mRNA level by Northern blot analysis. In WEHI-3 cells the gelatinase B protein is induced by bacterial lipopolysaccharide, phorbol ester, double-stranded RNA and the cytokine interleukin-1. Regulation of activity and structural heterogeneity of gelatinase B in WEHI-3 cells were shown to occur at the gene regulatory level, by expression of the matrix metalloproteinase inhibitor TIMP-1, and by glycosylation of the secreted protein.
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PMID:Mouse gelatinase B. cDNA cloning, regulation of expression and glycosylation in WEHI-3 macrophages and gene organisation. 824 59

We recently demonstrated that stimulation of inducible nitric oxide synthase (iNOS) activity reduced the accumulation of collagen and fibronectin in cultured rat mesangial cells. Therefore, we examined whether nitric oxide (NO) influenced the activity of a 72 kDa neutral matrix metalloproteinase by these cells in vitro. Enzyme activity was assessed in a biotin-avidin ELISA and by zymography. Exposure of mesangial cells to the cytokines, interferon (IFN)-gamma and lipopolysaccharide (LPS), increased gelatinolytic activity by 325 +/- 60% (P < 0.025). Co-incubation with 20 mM L-arginine caused a further increase in matrix metalloproteinase levels. Addition of L-NAME, an inhibitor of iNOS, reversed the IFN-gamma/LPS-induced rise in gelatinolytic activity. Incubation with the exogenous NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), resulted in a dose dependent increase in metalloproteinase activity (P < 0.01). The NO-induced changes in metalloproteinase activity were also demonstrable by zymography. These data indicate that NO modulates the activity of a 72 kDa neutral matrix metalloproteinase and suggest that altered NO production may contribute to the development of glomerulosclerosis and tubulointerstitial fibrosis in chronic renal disease states.
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PMID:Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. 857 77

Chronic inflammation and degradation of connective tissue in the course of periodontitis are maintained by bacterial products such as lipopolysaccharides (LPS), which probably act via inflammation mediators, e.g. cytokines. We investigated the effects of lipopolysaccharide (LPS) from E. coli and mouse recombinant interleukin 1 alpha (mrIL-1) on chondrogenesis, endochondral mineralization, matrix metalloproteinase activation and matrix degradation in vitro using cartilage organoid cultures. Mesenchymal cells of limb buds from mouse embryos (day 12) were grown at high density on a membrane filter at the medium/air interphase for 14 days. Chondrogenesis occurred during the first 6 days of culture. Endochondral mineralization took place upon addition of 5 mM beta-glycerophosphate from day 7 to 14. Treatment of the cultures with LPS and mrIL-1 on days 2 to 14 and during mineralization on days 7 to 14 resulted in a marked decrease of types I and II collagen, matrix mineralization and proteoglycan content. In the medium, proteoglycan content and metalloproteinase activity were enhanced. LPS induced IL-1 alpha production and release into the medium. LPS antagonist polymyxin B partly abolished the LPS effect, whereas IL-1 receptor antagonist (IL-1ra) partly abolished both LPS and mrIL-1 effects. Reversal of LPS-induced effects by IL-1ra was comparable to the reversal of mrIL-1 effects, only the decrease in type II collagen after LPS treatment was abolished to a lesser extent by IL-1ra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of metalloproteinase activity, cartilage matrix degradation and inhibition of endochondral mineralization in vitro by E. coli lipopolysaccharide is mediated by interleukin 1 alpha. 858 63

In neurodegenerative disease or after brain injury, parenchymal cells in the central nervous system are activated to produce inflammatory mediators, mainly consisting of cytokine-induced factors, in a manner similar to, but clearly different from a peripheral inflammatory response. The upregulated expression of several extracellular matrix proteins in astrocytes located surrounding a neuritic plaque in Alzheimer's disease is a good example of such a response. A family of mediators which is cytokine-induced during an inflammatory response in the periphery are the matrix metalloproteinases. Matrix metalloproteinases are calcium-requiring, zinc-containing endopeptidases that constitute a major component of the enzyme cascade responsible for degradation of extracellular matrix proteins such as collagen, proteoglycan and laminin. Little is known about the cellular source or the function of matrix metalloproteinases in the central nervous system or how their expression is regulated in brain. Thus, it was of interest to determine which factors of the so-called 'brain inflammatory response' regulate the expression of these proteases in the nervous system. To this end, we measured the expression of matrix metalloproteinases in cultured rat astrocytes and microglia after treatment with various cytokines. Interleukin-1 beta, tumor necrosis factor-alpha and lipopolysaccharide were potent stimulators of matrix metalloproteinase-2 (gelatinase A) and matrix metalloproteinase-9 (gelatinase B) in cultured rat astrocytes; the effect of each secretagogue was inhibited in the presence of glucocorticoid. Interleukin-1 beta and lipopolysaccharide also stimulated the production of matrix metalloproteinase-3 (stromelysin-1) in astrocytes. In addition, activated microglia release matrix metalloproteinase-9. The 'coactivator' of monocytic phagocytes, interferon-gamma, rather than augmenting the response to lipopolysaccharide, inhibited it. Thus, cytokines appear to be potent regulators of matrix metalloproteinase production in astrocytes and microglia. The presence of these enzymes in 'inflamed' central nervous system may suggest their involvement in the pathogenesis or progression of neurodegenerative diseases which are associated with an inflammatory component. Much remains to be learned about the potential substrates for these enzymes and the mechanism of their activation in the central nervous system.
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PMID:Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. 894 20

The effect of neutrophil elastase on the functional status of gelatinases was studied in an hamster model developed by intratracheal administration of lipopolysaccharide followed by in situ cell activation with phorbol myristate acetate. This resulted in the production in bronchoalveolar lavage fluids, in addition to the matrix metalloproteinase MMP-9, of a 75 kDa gelatinase associated with collagenolytic activity. Treatment in vivo with an elastase inhibitor abolished the latter activity. Since, in addition, elastase activates in vitro purified MMP-9 gelatinase into a similar 75 kDa entity, these data suggest that elastase may be a physiological activator of MMP-9 in vivo.
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PMID:Activation of MMP-9 by neutrophil elastase in an in vivo model of acute lung injury. 903 77

CGP 42112, a high-affinity ligand for angiotensin II AT2 receptors, binds to rat macrophage/microglia lacking AT2 receptors. Here we report that CGP-42112 binds to human monocytes and exerts specific effects. Binding studies revealed a single site, highly specific for CGP-42112, not displaceable by angiotensin II, angiotensin fragments, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-4, IL-10, transforming growth factor-beta, or lipopolysaccharide (LPS). Incubation of purified human monocytes in serum-free medium with CGP-42112 enhanced, in a dose-dependent manner, cell attachment to fibronectin and collagen-coated dishes as well as matrix metalloproteinase-9 secretion. CGP-42112 did not promote cytokine secretion. In contrast, when added in the presence of low doses of LPS, CGP-42112 reduced the LPS-stimulated secretion of TNF-alpha, IL-1 alpha, IL-1 beta, and IL-6 without affecting IL-10 and decreased the LPS-stimulated matrix metalloproteinase-9 activity. Additionally, CGP-42112 inhibited the increase in protein kinase A activity produced by LPS. Our results indicate that CGP-42112 may modulate monocyte activation through binding to a novel receptor.
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PMID:CGP-42112 partially activates human monocytes and reduces their stimulation by lipopolysaccharides. 931 2

This study was conducted to examine of [4-(N-hydroxyamino)-2R-isobutyl-3S-(phenylthiomethyl)-succinyl]-L- phenylalanine-N-methylamide (GI 129471), a matrix metalloproteinase inhibitor, for its effects on increase of serum pro-inflammatory cytokine levels as well as hepatic injury in D-galactosamine plus lipopolysaccharide-injected mice. In vitro experiments showed that GI 129471 was able to inhibit the elevation of tumor necrosis factor-alpha (TNF-alpha) in LPS-stimulated human and mouse whole blood with IC50 values of 370 nM and 260 nM, respectively. When administrated i.p. at 40 mg/kg, GI 129471 significantly reduced serum TNF-alpha level but not other pro-inflammatory cytokines in D-galactosamine plus lipopolysaccharide-injected mice. Treatment of mice with GI 129471 also reduced biochemical indices of hepatic injury to the normal level. Histopathological findings indicated that GI 129471 treatment can prevent severe centrilobular necrosis in liver. These results suggest that release of TNF-alpha from lipopolysaccharide-stimulated cells is the critical step leading to hepatic injury in endotoxemia and that a matrix metalloproteinase inhibitor with an inhibitory action on this step may be a promising drug for the clinical treatment of endotoxemia accompanied by hepatic injury.
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PMID:Metalloproteinase inhibitor prevents hepatic injury in endotoxemic mice. 948 62

Tumor necrosis factor alpha (TNFalpha) is synthesized as a transmembrane precursor form that is proteolytically processed and released as the soluble mature form. In human monocytes and monocytic cell lines, the production, processing, and release of TNFalpha are co-induced by certain activators, such as lipopolysaccharide. To investigate the mechanism of TNFalpha processing and release, we established a cell line which constitutively produced TNFalpha, by transfecting the TNFalpha precursor form cDNA into NIH/3T3 cells. In these cells, the processing and release of TNFalpha were augmented by phorbol 12-myristate 13-acetate (PMA), mediated through a protein kinase C (PKC) signalling pathway. Various protease inhibitors were tested and it was found that matrix metalloproteinase (MMP) inhibitors blocked the processing and release of TNFalpha both in the absence and presence of PMA. This result is compatible with the recent reports that MMP are involved in the processing and release of TNFalpha. In contrast, 3,4-dichloroisocoumarin, N alpha-p-tosyl-L-phenylalanine chloromethane, iodoacetamide, and o-phenanthroline inhibited the processing and release of TNFalpha only in the presence of PMA, suggesting that serine proteases requiring SH for their activity, a combination of serine proteases and cysteine proteases, or MMP, may be involved in the PKC-mediated induction of TNFalpha processing and release.
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PMID:Processing and release of tumor necrosis factor alpha. 965 52


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