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)

The met proto-oncogene encodes the cell surface receptor for hepatocyte growth factor (HGF) and transmits its multifunctional signals such as regulation of cell proliferation, motility, and morphogenesis. These pleiotropic actions attributable to HGF are mainly reported on cells of epithelial derivation which express the Met receptor. The HGF gene, on the other hand, is expressed in mesenchymally derived cells including peripheral blood leukocytes. Recently, we reported that Met receptor gene expression in epithelial cells is induced by inflammatory cytokines; currently, however, little is known concerning Met gene expression in mesenchymal cells. In the present study, we have explored the role of Met expression during monocyte-macrophage differentiation using THP-1 cells, a monocytic cell line, and monocytes freshly isolated from normal human peripheral blood. We have found that untreated monocytes do not express Met mRNA and protein. Upon incubation with differentiation inducers such as 12-O-tetradecanoylphorbol-13-acetate, lipopolysaccharide, a combination of interleukin (IL) 6 plus tumor necrosis factor (TNF) alpha, or IFN-gamma plus TNF-alpha, a pronounced increase in the amounts of Met mRNA and protein are seen in THP-1 cells. The expression of Met appears to correlate with the onset of differentiation of monocytes as noted by changes in cell morphology and adherence to culture plates, and the increased accumulation of Met protein was observed only in cells that differentiated and adhered to the culture dish. Moreover, Met was found to be phosphorylated on tyrosine residues, indicating that the receptor is potentially involved in signal transduction events. Addition of exogenous HGF to the activated cells resulted in the suppression of cell proliferation and an increase in cell motility. Reverse transcription-PCR and Western blot analyses revealed that untreated THP-1 cells contain HGF transcript and protein, and that HGF expression is inducible by addition of the differentiation agents such as 12-O-tetradecanoylphorbol-13 acetate or IL-6 plus TNF-alpha. Immune serum that is specific for neutralizing HGF activity markedly inhibited monocyte differentiation (50% reduction in cell attachment and process formation) induced by IL-6 and TNF-alpha. Moreover, we also found that the mRNA for Ron, which encodes a tyrosine kinase receptor for HGF-like protein (also known as macrophage-stimulating protein), is induced in THP-1 cells during the course of their differentiation to macrophages by IFN-gamma plus TNF-alpha. These findings indicate that the HGF and Met families may indeed be physiological regulators of monocyte-macrophage differentiation/maturation.
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PMID:Induction of met proto-oncogene (hepatocyte growth factor receptor) expression during human monocyte-macrophage differentiation. 878 Aug 95

Microglial cells respond to most pathological events by rapid transformation from a quiescent to an activated phenotype characterized by increased cytotoxicity and motile activity. To investigate the regulation of microglial motility by different inflammatory mediators, we studied cultured murine microglia by time-lapse video microscopy and a computer-based motility assay. Microglial cells exhibited a high resting motility. The acute application of complement 5a (C5a) immediately induced intense ruffling of microglial membranes followed by lamellipodia extension within few seconds, while formyl-Met-Leu-Phe-OH, bacterial endotoxin (lipopolysaccharide) or inflammatory cytokines did not increase motility. This process was accompanied by a rapid rearrangement of the actin cytoskeleton as demonstrated by labelling with fluorescein isothiocyanate-phalloidin and could be inhibited by cytochalasin B. A GTP-binding protein was involved in the signal cascade, since pertussis toxin inhibited motility and actin assembly in response to C5a. Chemotactic migration in a gradient of C5a was also completely blocked by pertussis toxin and cytochalasin B. The C5a-induced motility reaction was accompanied by an increase in intracellular calcium ([Ca2+]i) as measured by a Fluo-3 based imaging system. Ca2+ transients were, however, not a prerequisite for triggering the increase in motility; motility could be repeatedly evoked by C5a in nominally Ca(2+)-free solution, while Ca2+ signals occurred only upon the first stimulation. Moreover, conditions mimicking intracellular Ca2+ transients, like incubation with thapsigargin or Ca2+ ionophore A23187, were not able to induce any motility reaction, suggesting that Ca2+ transients are not necessary for, but are associated with, microglial motility. Motile activity was shown to be restricted to a defined concentration range of [Ca2+]i as revealed by lowering [Ca2+]i with BAPTA-AM or increasing [Ca2+]i with A23187. Since complement factors are released at pathological sites, this signal cascade could serve to increase motility and to direct microglial cells to the lesioned or damaged area by means of a G-protein-dependent pathway and via the rearrangement of the actin cytoskeleton.
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PMID:Complement 5a controls motility of murine microglial cells in vitro via activation of an inhibitory G-protein and the rearrangement of the actin cytoskeleton. 880 27

The kinetics of IL-8, tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta release by PMN adhered to fibronectin, laminin or plastic for 24 h in response to continuous stimulation with lipopolysaccharide (LPS; 50 ng/ml), N-formyl-Met-Leu-Phe (fMLP; 100 mM), or phorbol myristate acetate (PMA; 10 ng/ml), was investigated under altered oxygen tension conditions. Cell supernatants were sampled for cytokine content every 6 h and measured by ELISA. IL-8 was the most abundant cytokine, produced in a range of up to 5.4 ng/ml; TNF-alpha and IL-1 beta were produced in a range of up to 1 ng/ml. During normoxia, LPS was the most potent stimulus, inducing the release of each cytokine, while fMLP showed a less pronounced effect on IL-8 and IL-1 beta production and markedly inhibited TNF-alpha production. PMA markedly suppressed IL-8 and IL-1 beta release and failed to induce any release of TNF-alpha. Hypoxia had an overall inhibitory effect on cytokine release except for PMA-induced IL-1 beta release, and hypoxia/reoxygenation had a significant up-regulating effect except for a further inhibition of fMLP-induced release of TNF-alpha. Integrinmatrix protein ligation differentiated both spontaneous and externally induced cytokine release and its sensitivity to alteration in oxygen tension. Thus the process of PMN elaboration of inflammatory cytokines is controlled on multiple levels of signal transduction, differentiated by integrin-extracellular matrix interactions, and is sensitive to alterations in microenvironmental oxygen tension.
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PMID:Polymorphonuclear leucocyte (PMN)-derived inflammatory cytokines--regulation by oxygen tension and extracellular matrix. 897 28

Vascular adhesion protein-1 (VAP-1) is an endothelial molecule which mediates lymphocyte binding to endothelium in peripheral lymph nodes and at certain sites of inflammation. The expression of VAP-1 in vivo is strongly up-regulated in inflamed tissues, such as gut and skin. The purpose of this work was to examine the factors responsible for this induction of VAP-1. Since the expression of VAP-1 could not be induced in cultured endothelial cells with a large panel of mediators, we used an organ culture technique for the investigation of the regulation of VAP-1 expression in a more physiological micromilieu. Indeed, we found that the expression of endothelial VAP-1 could be up-regulated in human tonsillar tissue with interleukin (IL)-1, IL-4, tumor necrosis factor (TNF-alpha), interferon (IFN)-gamma and lipopolysaccharide, whereas histamine, thrombin, dibutyryl cAMP, N-formyl-Met-Leu-Phe (fMLP) and phorbol 12-myristate 13-acetate (PMA) had no effect. The induced VAP-1 protein was similar in molecular weight to the non-induced VAP-1, suggesting that VAP-1 synthesized de novo carries appropriate carbohydrate moieties. In contrast to tonsil organ culture, similar inductions performed with human appendix showed no up-regulation of VAP-1 expression, indicating that the regulation of VAP-1 expression exhibits organ-selective characteristics. Furthermore, in these tissues the smooth muscle cells, which constitutively express VAP-1, could not be stimulated to alter their level of expression of this molecule. In conclusion, the expression of VAP-1 can be markedly up-regulated with several mediators in tonsil but not in appendix organ culture, whereas cultured endothelial cells cannot be induced to express VAP-1. These results indicate that the expression of VAP-1 is regulated in a tissue- and cell type-selective manner, and a correct micromilieu is required for the up-regulation to occur.
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PMID:Organ-selective regulation of vascular adhesion protein-1 expression in man. 924 94

Low intravenous doses of endotoxin [lipopolysaccharide (LPS), 0.7 microgram/kg] induce monophasic fever, increase anterior and posterior pituitary hormone release, and enhance hypothalamic c-Fos expression in pigs, all of which can be prevented by indomethacin (Ind). The present study shows that the synthetic corticosteroid dexamethasone (Dex, 5 mg/kg) has a similar action to Ind and, when given alone, lowers core temperature. In addition, the corticosteroid synthesis inhibitor metyrapone (Met, 3.3 mg/kg, every one-half hour) reduces LPS fever and amplifies the effect of LPS on vasopressin, but not on oxytocin, release. The similar actions of Dex and Ind suggest that phospholipase A2 pathways controlling prostaglandin synthesis mediate the responses of prepubertal pigs to immunological challenge with LPS. The increased vasopressin release induced when animals receiving Met are also given LPS supports findings in other nonrodent species indicating an inverse relationship between cortisol and vasopressin. The attenuation of LPS fever by Met is suggestive of an endogenous antipyretic mechanism associated with enhanced neurohypophysial vasopressin secretion.
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PMID:Interrelated adrenocortical and neurohypophysial responses associated with fever in endotoxin-treated pigs. 932 84

Granulocyte apoptosis is an important mechanism underlying the removal of redundant neutrophils from an inflammatory focus. The ability of many proinflammatory agents to impede this event suggests that such agents act not only in a priming or secretagogue capacity but also increase neutrophil longevity by delaying apoptosis. We have examined whether this hypothesis holds true for all neutrophil priming agents, in particular tumor necrosis factor-alpha (TNF-alpha), which has been variably reported to either induce, delay, or have no effect on neutrophil apoptosis. After 20 hours coincubation TNF-alpha inhibited neutrophil apoptosis; however, more detailed analysis demonstrated its ability to promote apoptosis in a subpopulation of cells at earlier (2 to 8 hours) times. Formyl-Met-Leu-Phe, platelet-activating factor, inositol hexakisphosphate, lipopolysaccharide, leukotriene B4, and granulocyte-macrophage colony-stimulating factor all inhibited apoptosis at 6 and 20 hours. The early proapoptotic effect of TNF-alpha was concentration-dependent (EC50 2.8 ng/mL), abolished by TNF-alpha neutralizing antibody, and was not associated with any change in cell viability or recovery. Of relevance to the inflamed site, the ability of TNF-alpha to accelerate apoptosis was lost if neutrophils were primed with 1 micromol/L PAF or aged for 6 hours before TNF-alpha addition. The TNFR55-selective TNF-alpha mutants (E146K, R32W-S86T) induced neutrophil apoptosis but with a potency 14-fold lower than wild-type TNF-alpha. Although the TNFR75-selective mutant (D143F) did not induce apoptosis, blocking antibodies to both receptor subtypes abolished TNF-alpha-stimulated apoptosis. Hence, TNF-alpha has the unique ability to induce apoptosis in human neutrophils via a mechanism where TNFR75 facilitates the dominant TNFR55 death effect. This may be an important mechanism controlling neutrophil longevity and clearance in vivo.
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PMID:Regulation of neutrophil apoptosis by tumor necrosis factor-alpha: requirement for TNFR55 and TNFR75 for induction of apoptosis in vitro. 932 45

Tumor necrosis factor-alpha (TNF-alpha) induces a rapid increase in polymorphonuclear leukocyte (PMN) polyamine content which appears to be required for optimal priming of the respiratory burst. The objective of the present study was to determine whether inhibition of polyamine biosynthesis modifies PMN responses to lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony-stimulating factor (G-CSF). Treatment with alpha-difluoromethylornithine (DFMO), a selective inhibitor of the rate-limiting biosynthetic enzyme ornithine decarboxylase, produced dose-dependent inhibition of the respiratory burst in PMNs that were primed by these agents and subsequently activated by formyl-Met-Leu-Phe (fMLP). However, DFMO did not significantly inhibit fMLP-stimulated superoxide generation or alter the induction of PMN adhesion and interleukin-1 beta (IL-1 beta) mRNA expression by LPS or GM-CSF. Antagonism of priming by DFMO correlated with a dose-dependent attenuation of fMLP-induced intracellular Ca2+ mobilization (r > or = 0.96). Since Ca2+ plays an important role in modulating the respiratory burst in primed PMNs, this could, in part, account for the selective effects of DFMO.
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PMID:An inhibitor of ornithine decarboxylase antagonizes superoxide generation by primed human polymorphonuclear leukocytes. 936 91

The aim of this study was to evaluate the effects of [Met5]enkephalin, des-Met-[Met5]enkephalin, des-Tyr-[Met5]enkephalin, and Tyr-Gly-Gly on natural killer cytotoxic activity and on concanavalin A- and lipopolysaccharide-stimulated proliferation of B and T cells in mice. Single i.p. injections of [Met5]enkephalin, des-Met-[Met5]enkephalin, and Tyr-Gly-Gly increased both natural killer cytotoxicity and proliferation of mitogen-stimulated B and T cells. These effects were inhibited by naloxone pretreatment, which suggests the opioid mechanism of the peptides studied. The rate of lymphocytic proliferation increases not only after single injection of [Met5]enkephalin or its metabolites, but also after 3 or 7 days of treatment. Apart from the functional effects, [Met5]enkephalin, des-Met-[Met5]enkephalin, and Tyr-Gly-Gly increased the percentages of natural killer cells and T cells. The results of this study suggest that the immunomodulatory action of [Met5]enkephalin may be mediated or enhanced by its N-terminal metabolites des-Met-[Met5]enkephalin and Tyr-Gly-Gly.
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PMID:Immunologic action of [Met5]enkephalin fragments. 965 Aug 53

Neutrophil elastase degrades extracellular matrix components and is involved in tissue destruction in several inflammatory states. We examined the inhibition of the elastase activity derived from activated neutrophils in vitro and in vivo by FR134043, disodium-(Z,1S,15S,18S,24S,27R,29S,34S,37R)-29-b enzyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31, 37-dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,2 8,31,33-octaazatetracyclo[16.13.6.1(24,28).0(3,8)]octatriconta+ ++-3,5,7-trien-5,6-diyl disulfate, an elastase inhibitor with broad specificity, and elucidated the role of neutrophil elastase in pathogenesis of acute inflammation. In a culture of human neutrophils, phorbol myristate acetate (PMA) and calcium ionophore increased elastase activity in the supernatants, which was amplified by co-existing mononuclear leukocytes. Formyl-Met-Leu-Phe stimulated elastase release in the presence of, not without, mononuclear leukocytes. Intratracheal injection of lipopolysaccharide elevated the elastase activity in bronchoalveolar lavage fluid of rats. These elastase activities were significantly inhibited by FR134043. Intratracheal treatment with FR134043 in rats also inhibited the enzyme induced by lipopolysaccharide, though the maximum inhibition was 52%. Ear edema elicited by topical application of PMA in mice was significantly suppressed by pretreatment with FR134043 (38% inhibition at 1 mg/ear). In carrageenan-induced joint injury in rats, plasma extravasation into the synovial cavity was partially and significantly inhibited by FR134043 at 1 mg/knee, while an elastase-specific inhibitor showed no effect. These results suggest that neutrophil elastase is partially involved in tissue damage in acute inflammation provoked by irritants, but not in carrageenan-induced hyperpermeability.
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PMID:Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043. 1042 48

Inositol hexaphosphate (IP6) has anti-cancer properties, but recently other extracellular functions have been observed for IP6, including enhancing superoxide production and phagocytosis by neutrophils in the presence of microbial stimuli. This study investigated other inflammatory functions of IP6 on adherent neutrophils. The effect of IP6 on the release of IL-8, tumour necrosis factor (TNF-alpha) and IL-6 by neutrophils attached to either plastic or laminin for up to 6 hours in response to stimulation with lipopolysaccharide or N-formyl-Met-Leu-Phe (fMLP) was investigated. An increase in IL-8 secretion by stimulated cells occurred in the presence of IP6. The incubation of cells attached to laminin with IP6 alone (100-250 BM) did not effect cell morphology, but in the presence of 10(-7) M fMLP altered cell shape. A direct effect of IP6 on cell function was to trigger a sustained assembly of F-actin. Thus, exposure of neutrophils to low levels of IP6 appears to modulate selective neutrophil functions.
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PMID:Effect of IP6 on human neutrophil cytokine production and cell morphology. 1062 45


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