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)

Evidence is accumulating that the illness and pathology observed in malaria are not caused directly by parasite products, but by normal components of the immune response, mainly monokines such as tumor necrosis factor (TNF), produced in excess. These mediators are released from the host's monocytes and macrophages, apparently in response to stimulation by parasite products. Recombinant TNF, if injected into a range of animal species or into tumour patients, is demonstrably toxic, giving rise to changes typical of acute malaria, and several groups have detected circulating TNF in serum from patients acutely ill with malaria. The short serum clearance time of TNF and TNF tolerance have to be considered when interpreting such data. Current studies indicate that some malarial antigens, in the absence of lipopolysaccharide, can trigger release of TNF. This and other monokines could contribute to cerebral malaria in at least 2 ways: by increasing thrombospondin secretion, and hence favouring local sequestration of knob-bearing parasitized red cells, and, as has been demonstrated in clinical trials in tumour patients, by causing neurological symptoms directly. In addition, it seems that TNF does not act alone, but as part of an interdependent synergizing network of polypeptide mediators. These evidently act together to induce secretion of other cell products, such as platelet-activating factor, prostaglandins, reactive oxygen species and procoagulant activity, that actually cause illness, biochemical change and tissue damage. Understanding these processes should lead to a range of new therapeutic interventions.
 ...
PMID:Roles of tumour necrosis factor in the illness and pathology of malaria. 269 75

A major part of the anti-inflammatory effect of glucocorticoids is attributable to their attenuation of the induction of genes whose products mediate intercellular interactions, e.g. cytokines and the inducible forms of prostaglandin synthase and nitric oxide synthase. We hypothesized that (i) there exists a class of immediate-early/primary response genes whose induction by inflammatory agents, mitogens, and other stimuli is attenuated by glucocorticoids, and (ii) the products of these glucocorticoid-attenuated response genes (GARGs) function predominantly in paracrine cell processes. We constructed a lambda cDNA library from transforming growth factor beta 1-pretreated murine Swiss 3T3 cells stimulated with lipopolysaccharide (LPS) or serum in the presence of cycloheximide, screened 15,000 plaques by differential hybridization, and cloned 12 LPS-induced, dexamethasone-attenuated cDNAs. Seven were previously known. Six of these encode intercellular mediators (thrombospondin-1, MCSF, JE/MCP-1, MARC/fic/MCP-3, crg2/IP-10, and cyr61); one encodes a protein of unknown function (IRG2). Thus, a large majority of these GARG cDNAs encode intercellular mediators, as hypothesized. Of the five GARG cDNAs not previously known, one encodes a novel member of the CXC chemokine family, designated LIX (LPS-induced CXC chemokine). The predicted LIX protein has a 40-amino acid signal sequence and a 92-amino acid mature peptide with a distinctive COOH-terminal region. Surprisingly, segments of the 3'-untranslated regions of LIX and two other CXC chemokines have substantially greater nucleotide sequence homology than do their coding regions. These segments may perform an unknown regulatory function. The LIX message is strongly induced by LPS in fibroblasts, but not in macrophages, suggesting that LIX may participate in the recruitment of inflammatory cells by injured or infected tissue.
 ...
PMID:Glucocorticoid-attenuated response genes encode intercellular mediators, including a new C-X-C chemokine. 762 88

CD36 is an 88-kD integral membrane protein expressed on platelets, monocytes, macrophages, certain microvascular endothelia, and retinal pigment epithelium. It functions as an adhesive receptor for thrombospondin-1 (TSP-1), collagen, and malaria-infected erythrocytes and as a scavenger receptor for oxidized LDL and photoreceptor outer segments. The CD36-TSP-1 interaction plays a role in cell adhesion and the phagocytosis of apoptotic cells by macrophages. Because of the potential importance of the CD36-TSP-1 interaction in mediating atherogenic and inflammatory processes, we studied their expression in human peripheral blood monocytes exposed to soluble mediators known to regulate inflammation and atherogenesis. RNase protection assays showed 6- to 12-fold increases in CD36 mRNA in response to interleukin-4, monocyte colony-stimulating factor, and phorbol myristate acetate, while lipopolysaccharide and dexamethasone strongly downregulated CD36 mRNA. The downregulation of CD36 mRNA was associated with the disappearance of surface expression of CD36 antigen and loss of TSP-1 surface-binding capacity. Upregulation of CD36 mRNA was associated with a modest increase in surface antigen expression and a larger expansion of an intracellular pool of CD36. As with CD36, monocytes treated with monocyte colony-stimulating factor showed a rapid increase in TSP-1 mRNA expression. Moreover, while dexamethasone treatment decreased CD36 expression, it resulted in a rapid increase in TSP-1 mRNA, and while PMA increased CD36 mRNA, it rapidly decreased TSP-1 expression. Interferon gamma, which had no effect on CD36 mRNA, rapidly increased steady-state TSP-1 mRNA. Thus, expression of both CD36 and its ligand TSP-1 is regulated by soluble mediators, although certain mediators induce concordant changes and others discordant changes.
 ...
PMID:Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. 869 41

A cellular disintegrin and metalloproteinase (ADAM) is a new family of genes with structural homology to the snake venom metalloproteinases and disintegrins. We screened genes which were selectively expressed in the cachexigenic colon 26 adenocarcinoma subline in vivo. It was found that one novel cDNA clone, identified as a cachexigenic tumor selective gene, encodes a cysteine-rich protein which shows a sequence similarity to that of both the snake venom metalloproteinases and thrombospondins. We named this cDNA clone A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1). ADAMTS1 consists of six domains, 1) a pro- and 2) a metalloproteinase, 3) a disintegrin-like, 4) a thrombospondin (TSP) homologous domain containing TSP type I motif, 5) a spacer region, and 6) COOH-terminal TSP submotifs. Unlike other ADAMs, ADAMTS-1 does not possess a transmembrane domain and is a putative secretory protein. Therefore, ADAMTS-1 is a new type of ADAM family protein with TSP type I motifs. We demonstrated that the TSP homologous domain containing the TSP type I motif of ADAMTS-1 is functional for binding to heparin. ADAMTS-1 mRNA could be induced by stimulating colon 26 cells with an inflammatory cytokine, interleukin-1, in vitro. Moreover, intravenous administration of lipopolysaccharide in mice selectively induced ADAMTS-1 mRNA in kidney and heart. These data suggest that ADAM-TS-1 may be a gene whose expression is associated with various inflammatory processes as well as development of cancer cachexia.
 ...
PMID:Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. 899 97

Cellular disintegrin and metalloproteinases (ADAMs) are a family of genes with a sequence similar to those of snake venom metalloproteinases and disintegrins. The ADAMTS-1 gene encodes a new type of ADAM protein with respect to possessing the thrombospondin (TSP) type I motifs. Expression of the gene is induced in kidney and heart by in vivo administration of lipopolysaccharide, suggesting a possible role in the inflammatory reaction. In this study, we characterized the ADAMTS-1 gene product by using a transient expression system in COS-7 cells. We found that the precursor and processed forms of ADAMTS-1 were secreted from cells. Under normal growth conditions, little or none of both forms was detected in the cell culture medium, and instead the majority was found associated with the extracellular matrix (ECM). In addition, when cells were cultured in the presence of heparin, the mature form of ADAMTS-1 protein was detected in the cell culture medium, suggesting that binding of ADAMTS-1 to the ECM is mediated through sulfated glycosaminoglycans such as heparan sulfate. Analyses of deletion mutants of the ADAMTS-1 protein revealed that the spacer region as well as three TSP type I motifs in the carboxyl-terminal region of the ADAMTS-1 protein are important for a tight interaction with the ECM. These results suggest that the ADAMTS-1 is a unique ADAM family protein that anchors at the ECM.
 ...
PMID:ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region. 959 39

TGF-beta has been implicated in scarring and tissue fibrosis. Most cells secrete TGF-beta as a high molecular weight, latent complex that must be processed to a lower molecular weight, biologically active form. A number of molecules are involved in this activation step including the mannose 6-phosphate/insulin-like growth factor-II receptor, tissue transglutaminase, thrombospondin, plasmin, and others. Here we describe a rapid macrophage-based system for TGF-beta1 activation, which could be used for screening potential anti-fibrotic agents. The system employs transformed mouse peritoneal macrophages treated with lipopolysaccharide as a cell line capable of activating latent TGF-beta. The activation mechanism in our system involves mannose 6-phosphate/insulin-like growth factor-II receptor and transglutaminase. The activation of latent TGF-beta in this system can be prevented by the addition of mannose-6-phosphate but not mannose-1-phosphate. In addition, transglutaminase inhibitors, antibodies to thrombospondin, insulin-like growth factor-II in the presence of its binding protein IGFBP-2, but not IGFBP-1, suppressed the activation of TGF-beta. Anti-inflammatory molecules, such as hydrocortisone, when added to LPS-treated macrophages, inhibited TGF-beta activation by a mechanism, that may involve downregulation of transglutaminase expression. In summary, this new, rapid and reproducible system allows testing molecules for their ability to inhibit TGF-beta activation, thus providing a screening method for potential anti-scarring molecules.
 ...
PMID:Characterization of a macrophage-based system for studying the activation of latent TGF-beta. 1073 58

-CD36 is 1 of the class B scavenger receptor expressed on monocytes, monocyte-derived macrophages (Mphi), platelets, and adipocytes. In our previous studies, we reported that the uptake of oxidized low density lipoproteins (OxLDLs) is reduced by approximately 50% in Mphi from CD36-deficient patients compared with that in control subjects. Recently, we have shown that CD36 is highly expressed in human atherosclerotic aorta. Possibilities have been raised that besides the wide distribution and multifunctional characteristics of CD36, this molecule may also be involved in the mediation of intracellular signaling. The aim of the present study was to elucidate the role of CD36 in cytokine secretion and to investigate the CD36-mediated intracellular signaling stimulated by OxLDL. On addition of OxLDL or thrombospondin-1, the Mphi from CD36-deficient patients secreted significantly less amounts of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) compared with those from controls. RNase protection assay with multiprobe template sets demonstrated that after incubation with OxLDL, the mRNAs of a variety of cytokines, including genes encoding IL-1Ra, IL-1beta, IL-6, TNF-alpha and -beta, and interferon (IFN)-gamma and -beta, were significantly lower in the Mphi of patients. The addition of antibody against CD36 attenuated this OxLDL-induced response in controls. We also observed a reduced response in nuclear factor-kappa B (NF-kappa B) activity in OxLDL-stimulated Mphi from CD36-deficient patients. Unlike OxLDL, stimulation by lipopolysaccharide induced an increase in NF-kappa B activity in Mphi from CD36-deficient patients, suggesting that lipopolysaccharide-mediated signaling was conserved. These results demonstrate that in addition to the reduced OxLDL uptake that we reported previously, CD36-deficient patients may also have an impaired response of OxLDL-induced NF-kappa B activation and subsequent cytokine expression.
 ...
PMID:Oxidized LDL-induced NF-kappa B activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients. 1093 17

We have previously shown that the CD47-binding thrombospondin-1 (TSP-1)-derived peptide 4N1K induces a rapid apoptosis-like death of human monocytes and dendritic cells (DCs). However, not all cells were susceptible to the peptide-induced cell death and here, we have investigated whether surviving monocytes could differentiate into functionally normal DCs. We found that the cell-surface phenotype, the T-cell stimulatory capacity and the ability to undergo lipopolysaccharide (LPS)-induced maturation into CD83+ DCs were essentially identical in 4N1K-derived and control DCs. Interleukin-10 (IL-10) production was also normal, but a significant downregulation of the pro-inflammatory cytokines IL-12 and tumour necrosis factor-alpha (TNF-alpha) was observed in the 4N1K-derived DCs. To the contrary, simultaneous stimulation of control DCs with 4N1K and LPS + interferon-gamma did not alter IL-12 production. These results indicate that although activation of the TSP-1-binding region of CD47 on monocytes induces apoptosis in a large proportion of the cells, it does not hamper the overall capacity of the surviving cells to differentiate into DCs. Such DCs, however, have a reduced capacity for IL-12 and TNF-alpha production, and the possibility that this is linked to the uptake of apoptotic cells is discussed.
 ...
PMID:Ligation of CD47 during monocyte differentiation into dendritic cells results in reduced capacity for interleukin-12 production. 1472 21

Endothelial expression of matrix metalloproteinases has been implicated in angiogenesis and endothelial cell proliferation. Recently, it has been shown that high-density lipoproteins (HDLs) promote angiogenesis. In the present study, we investigated the effects of native HDLs on the expression of several proteases and their inhibitors in human umbilical vein endothelial cells. We show that ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motif) was potently induced by incubation with lipopolysaccharide or tumor necrosis factor-alpha and that the expression was significantly reduced in the presence of HDL subfraction 3. Since ADAMTS-1 has recently been shown to inhibit endothelial cell proliferation, the result of the present work may represent a new mechanism by which HDL could have a positive effect on endothelial cell and vascular wall function.
 ...
PMID:High-density lipoprotein subfraction 3 decreases ADAMTS-1 expression induced by lipopolysaccharide and tumor necrosis factor-alpha in human endothelial cells. 1499 35

Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 h after an injection of LPS/GalN (20 microg/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-alpha) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-alpha clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis.
 ...
PMID:Protective effect of dextromethorphan against endotoxic shock in mice. 1562 75


1 2 3 Next >>