Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial lipopolysaccharide (LPS) plays a central role in the pathogenesis of gram-negative sepsis and shock. The glycosylphoshatidyl inositol (GPI) anchored glycoprotein CD14 on mononuclear cells binds LPS, especially in the presence of an LPS binding serum protein, activating the production of pro-inflammatory cytokines, i.e. TNF-alpha. However, since GPI anchorage to the cell membrane lacks the intracellular signalling capacity, the existence of at least a second receptor has been postulated. In attempt to identify additional LPS receptors, we used the human myelomonocytic cell line THP-1. This undifferentiated cell line did not respond to LPS in terms of TNF-alpha release, but when induced with 250 U/ml of IFN-gamma for 48 h, the cells released TNF-alpha (174 +/- 58.6 U/ml. L929 cell bioassay) in response to 10 vg/ml of E. coli 0111 LPS, in the absence of serum. Blockade of either HLA-DR or CD14 receptors with specific MAbs did not reduce the amount of cytokine released. However, when both the receptors were sequentially blocked involved on the effector cells a remarkable inhibition of TNF-alpha release was observed (8.6 +/- 1.4). It seems therefore, that HLA-DR receptor may be with CD14 in triggering TNF-alpha release by IFN-gamma, induced THP-1 cells.
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PMID:The release of tumor necrosis factor alpha (TNF-alpha) by interferon gamma (IFN-gamma) induced THP-1 cells stimulated with smooth lipopolysaccharide is inhibited by MAbs against HLA-DR and CD14 receptors on the effector cell. 903 62

Individuals with a consistently lower immune response may be more susceptible to infection but less prone to autoimmune disease or severe sepsis. The molecular mechanisms determining the low responder status are, however, unclear. We have screened 60 male donors for tumour necrosis factor (TNF) protein levels after stimulation of monocytes with lipopolysaccharide (LPS). Among these we identified three donors each that consistently had a level of less than 20% (low responders; LR) or of more than 80% (high responders; HR) of the maximum response seen in this population. Northern blot analysis of TNF mRNA after LPS stimulation revealed lower transcript levels in LR. Half life determination after actinomycin D blockade showed a similar decay rate for LR and HR and after blockade of degradation by cycloheximide treatment mRNA levels increased but LR remained lower compared to HR. These data indicate that the lower TNF mRNA levels in LR are not due to a more rapid mRNA degradation but rather a result of lower transcription. Transcripts for interleukin 6 (IL-6) were also low in LPS-stimulated monocytes of LR. Because expression of the LPS receptor CD14 was similar in LR and HR monocytes, our data suggest that differences in signal transduction account for the LR and HR phenotype.
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PMID:TNF gene expression in monocytes of low and high responder individuals. 912 9

The microvascular endothelial cell (MVEC) is a major target of inflammatory cytokines overproduced in conditions such as sepsis and infectious diseases. We addressed the direct and indirect effects of tumor necrosis factor (TNF) on endothelial cells that can be relevant for the pathogenesis of septic shock, with particular attention to the acute respiratory distress syndrome (ARDS) and to cerebral malaria (CM). To identify functional and phenotypical changes occurring in MVEC during sepsis, we isolated these cells from the lungs of patients who died of ARDS. The constitutive expression of ICAM-1 and, to a lesser extent, VCAM-1, CD14, and TNFR2 were significantly increased on MVEC isolated from ARDS patients compared with control MVEC, whereas ELAM-1 and TNFR1 were not increased. We found that lung MVEC from ARDS patients present a procoagulant profile and a higher production capacity of interleukin-6 (IL-6) and IL-8 when compared with those from controls. As in pulmonary MVEC derived from ARDS patients, the only TNFR type found up-regulated in brain microvessels during CM was TNFR2. This increase in TNFR2 expression only occurred in CM-susceptible mice at the onset of the neurological syndrome. We therefore investigated the role of TNFR2 in the development of this brain pathology by comparing the incidence of CM in wild-type and TNF receptor knock-out mice. Unexpectedly, the genetic deficiency in TNFR2, but not in TNFR1, conferred protection against CM and its associated mortality. No ICAM-1 up-regulation was detected in the brain of Tnfr2 knockout mice, indicating a close correlation between protection against CM-associated brain damage, absence of TNFR2, and absence of ICAM-1 up-regulation in the brain. Our results in ARDS and CM indicate a specific up-regulation of TNFR2, but not of TNFR1, on lung and brain MVEC, respectively. This increased expression leads to a reduced sensitivity toward TNFR1-mediated phenomena, such as the sensitized TNF cytolytic activity on lung MVEC. In contrast, the sensitivity toward TNFR2-mediated effects, such as ICAM-1 induction by membrane-bound TNF, is increased on brain and lung MVEC expressing increased levels of TNFR2. Therefore, the ICAM-1-inducing effect, rather than the direct cytotoxicity of inflammatory cytokines, such as TNF, appears to be crucial in ARDS and CM-induced endothelial damage, and TNFR2 seems to play an important role in this activity in vivo.
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PMID:TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria. 912 3

Interleukin(IL)-13, a cytokine produced by T helper 2 (Th2) cells, is a powerful inhibitor of macrophage functions, including surface expression of CD14 and production of IL-1 and tumor necrosis factor (TNF)-alpha. We tested the effects of recombinant mouse(m)IL-13 in a neonatal mouse model of endotoxin shock; this is a macrophage-dependent condition, which is a model of neonatal sepsis in humans. mIL-13 (0.5 microgram/mouse) dramatically reduced the lethal effects of lipopolysaccharide (LPS) if administered either 24 or 4 h prior to or concomitantly with LPS challenge. This action might be mediated by multiple modulatory activities of IL-13 on LPS-induced cytokine secretion since, relative to control animals, the mice treated with mIL-13 had eight times lower peak blood levels of TNF. The IL-1 beta levels were also decreased, whereas increased levels of IL-6 and IL-10 were observed at several time points after LPS challenge.
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PMID:Prevention of endotoxin-induced lethality in neonatal mice by interleukin-13. 920 14

Although glycosylphosphatidyl-inositol (GPI) linked membrane proteins do not possess transmembrane or cytosolic sequences they elicit transmembrane signals. Using microscopic fluorescence imaging and resonance energy transfer (RET) techniques we have shown that certain pro-inflammatory GPI-linked membrane proteins can interact with leukocyte beta 2 integrins (complement receptor type 3 (CR3) and 4 (CR4) and the leukocyte function-associated antigen-1 (LFA-1)). For example, physical associations between CR3 and Fc gamma RIIIB, CR3 and urokinase receptors, and CR3 and CD14 (lipopolysaccharide receptor) have been found. Although Fc gamma RIIIB appears to be constitutively associated with CR3, urokinase receptors and CD14 associations with CR3 are influenced by their ligation status and cell function (e.g. adherence and locomotion). CR3-to-urokinase receptor interactions have been confirmed by immunoprecipitation techniques. Immunoprecipitation of CR3 from Brij-58 lysates after biotinylation of neutrophil membranes revealed proteins of M(r) = 40,000, 50,000, 74,000 and 120,000, in addition to bands corresponding to the integrin alpha and beta chains. Cell functions such as transmembrane signaling and superoxide release/priming have been linked to these interactions. Importantly, reagents that affect the lectin-like site of CR3, such as N-acetyl-D-glucosamine, alpha-methyl-D-mannoside and beta-glucan alter these interactions and, in parallel, leukocyte functions. Thus, the interactions of GPI-linked proteins and integrins can be highly dynamic events linked to cell activities. Our studies suggest that it may be possible to develop new drugs directed at the lectin-like site of beta 2 integrins that block GPI-linked protein-to-integrin coupling thereby controlling inflammatory cell processes including cell adherence, locomotion and activation. Such drugs may be useful in clinical conditions such as ischemia-reperfusion injury, sepsis, arthritis and others.
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PMID:Ectodomain interactions of leukocyte integrins and pro-inflammatory GPI-linked membrane proteins. 922 70

The rate of oxygen consumption in the human acute monocytic leukemia-derived cell line, Mono Mac 6, in response to lipopolysaccharide (LPS) in vitro was measured by electron paramagnetic resonance spectroscopy using an oxygen-sensitive spin-label, 4-oxo-2,2,6,6-tetramethylpiperidine-d16-1-oxyl (15N-PDT). Lipopolysaccharide impaired oxygen consumption in a dose-dependent manner which was shown to be mediated by mitochondrial dysfunction and could be augmented by pretreatment of the cells with interferon-gamma. Treatment of the cells with anti-CD14 monoclonal antibody failed to inhibit the LPS-induced effects on cellular respiration. These results suggest that LPS can directly reduce normal cellular oxygen consumption possibly via a CD14-independent pathway. This alteration of mitochondrial function by LPS may be responsible for the observed cell damage during sepsis.
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PMID:Lipopolysaccharide decreases oxygen consumption by Mono Mac 6 cells; an electron paramagnetic resonance oximetry study. 924 68

The accumulation of sCD14 shed from human monocytes in vivo might correlate with other inflammatory parameters and could be of importance in overcoming a sepsis situation. The development of the sCD14 titer in the supernatant of monocyte-enriched MNC cultures isolated from healthy volunteers was studied utilizing a commercially available sCD14 ELISA. These culture experiments revealed the prolonged liberation of sCD14 into the supernatant during a period of several days. A medium-exchange schedule of 2-3 days was found to be superior to a longer incubation period with respect to the sCD14 yield. PMA initially enhanced the CD14 shedding slightly, but after a few hours it strongly repressed the process. Such a reduction was also achieved by protein synthesis inhibitors (cycloheximide, actinomycin D). Additionally, we monitored the concentration of sCD14, CRP, IL-6 and IL-8 in human sera from healthy persons or patients suffering from severe burn injuries with or without sepsis. Our results indicate that sCD14 is strongly correlated with IL-6, but not with IL-8. sCD14 titers were higher in the group of patients with both burn injuries and sepsis. From experiments with monocyte-enriched MNC cultures isolated from healthy volunteers and medium supplemented with sera containing sCD14 as well as radiolabeled LPS, we conclude that the enhanced shedding of CD14 in vivo during sepsis is probably not able to reduce the binding of LPS to monocytes.
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PMID:Characteristics of CD14 shedding from human monocytes. Evidence for the competition of soluble CD14 (sCD14) with CD14 receptors for lipopolysaccharide (LPS) binding. 926 97

Alveolar macrophages, which play a central role in lung defense, produce cytokines that help orchestrate local inflammatory responses. In sepsis and other pathological conditions, bacterial lipopolysaccharide endotoxin can induce alveolar macrophages (AM) to release proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1, and interleukin-6. Studying the mechanisms that control alveolar macrophage cytokine production may lead to better therapies for conditions involving inflammatory lung injury. We and others have noted significant differences between alveolar macrophages and peritoneal macrophages, but large numbers of human or murine alveolar macrophages are rarely available for detailed mechanistic studies. We have obtained three murine alveolar macrophage cell lines (AMJ2C8, AMJ2C11, and AMJ2C20) and have begun to characterize their cytokine responses to proinflammatory stimuli. We measured the effects of endotoxin, interferon gamma, and the combination of the two on production of tumor necrosis factor, interleukin-1 beta, and interleukin-6 in each line. We also studied the expression of the endotoxin receptor CD14 by these cells, and investigated the effect of serum on their endotoxin responsiveness. We show here that all three of the cell lines responded in a manner comparable to that of primary murine alveolar macrophages. Observed variations between these lines may reflect the documented heterogeneity seen in populations of primary alveolar macrophages. These cell lines should expand the repertoire of tools available to investigators studying regulation of murine alveolar macrophage responses.
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PMID:Characterization of proinflammatory cytokine production and CD14 expression by murine alveolar macrophage cell lines. 933 48

Exaggerated responses by phagocytes to bacterial endotoxin [lipopolysaccharide (LPS)] may result in the sepsis syndrome. While a number of LPS-binding proteins have been identified on immune cells, only CD14 has been definitively shown to be involved in signal transduction in response to LPS. The beta2 leukocyte integrins are a family of transmembrane receptors whose expression is restricted to leukocytes. Among their many functions, the beta2 integrins are phagocytic receptors that bind a variety of bacterial products, including LPS. We hypothesize that this binding results in signal transduction. Chinese hamster ovary (CHO) fibroblast cell lines expressing the CD11a/CD18 or CD11b/CD18 antigen were engineered by gene transfection. The cell lines were stimulated with LPS. LPS-induced nuclear translocation of nuclear factor kappa B (NF-kappaB) was analyzed by electrophoretic mobility shift assay. Heterologous expression of CD11a/CD18 and CD11b/CD18 in otherwise LPS-nonresponsive fibroblasts imparted the ability to respond to LPS. Responses to LPS were observed at levels of LPS of 100 ng/ml, as were responses to whole Gram-negative bacteria. The CD11/CD18 leukocyte integrins mediate cellular responses to the LPS component of Gram-negative bacteria. CD11/CD18-mediated responses of cells to LPS are likely to affect the phagocytosis, intracellular trafficking, and killing of invading bacteria as well as to help mediate cytokine responses during endotoxemia. The development of novel therapies to prevent the end-organ damage frequently observed during sepsis will require an understanding of these complex cellular events.
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PMID:CD11/CD18 leukocyte integrins: new signaling receptors for bacterial endotoxin. 944 98

Cell wall compounds of gram-positive bacteria are capable of inducing the biosynthesis of proinflammatory cytokines in CNS cells in a similar way as lipopolysaccharide (LPS) of gram-negative bacteria does. Astrocytes, which lack the CD14 LPS receptor, have also been shown to respond to LPS-stimulation by increased cytokine synthesis. However, almost nothing is known about signaling steps involved in this process. We have therefore examined signaling events in primary cultures of rat astrocytes and the human astrocytoma cell line U373MG, brought about by LPS and pneumococcal cell walls (PCW). Of particular interest to us was the tyrosine phosphorylation patterns and activation states of three members of the mitogen activated protein kinase (MAPK) family, i.e., extracellular signal-regulated protein kinase (erk)-1, erk-2, and the recently identified p38. We show that LPS and PCW initiate tyrosine phosphorylation and activation of erk-1, erk-2, and p38 in a dose-dependent fashion. Inhibitors of tyrosine phosphorylation were able to alleviate this effect and also blocked cytokine production of astrocytes. Both, LPS- and PCW-induced responses of astrocytic cells required the presence of soluble CD14 (sCD14) present in serum. Unraveling the signaling steps induced by bacterial compounds in cells of the CNS may potentially help to elucidate the pathomechanisms of meningitis and central nervous complications of sepsis and may offer options for novel treatment strategies.
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PMID:Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. 948 15


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