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)

Glucocorticoids almost completely inhibit the synthesis by isolated macrophages of cachectin/tumor necrosis factor (TNF), a cytokine implicated as a major endogenous mediator of septic shock. Despite this in vitro effectiveness, the clinical use of glucocorticoids has failed to demonstrate any clear benefit in the treatment of septic shock. In an effort to understand what other mechanisms might play a role in the patient with sepsis, we examined the effect of interferon-gamma (IFN gamma) on the synthesis of cachectin/TNF. We show here that IFN gamma, although unable by itself to induce cachectin/TNF synthesis, enhanced the endotoxin-induced production of cachectin/TNF in vitro. Furthermore, IFN gamma overcame the inhibition of cachectin/TNF synthesis caused by the glucocorticoid, dexamethasone. These effects of IFN gamma were accounted for by increased levels of cachectin/TNF mRNA. The in vivo implications of these studies are discussed with emphasis on their relevance in human sepsis.
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PMID:Interferon-gamma overcomes glucocorticoid suppression of cachectin/tumor necrosis factor biosynthesis by murine macrophages. 212 Feb 85

The etiology and mechanisms by which severe trauma or sepsis induce hepatic failure are unknown. Previously we showed that Kupffer cells (KC), the fixed macrophages of the liver, induce a profound decrease in hepatocyte (HC) total-protein synthesis when exposed to endotoxin. Furthermore we demonstrated that endotoxin-activated KCs induce these changes in HC protein synthesis through the induction of a novel L-arginine-dependent biochemical pathway within the HC. In this pathway, the guanido nitrogen of L-arginine is converted to the highly reactive molecule nitric oxide (NO.). To identify the KC factors that act as signals for induction of HC NO. biosynthesis, recombinant cytokines were added to HC cultures and HC nitrogen oxide production and protein synthesis levels were determined. We found that no single cytokine, but rather a specific combination of tumor necrosis factor, interleukin-1, interferon-gamma, and endotoxin, were required for maximal induction of HC nitrogen oxide production. This specific combination of cytokines induced a 248.8 +/- 26.0 mumol/L (micromolar) increase in HC nitrogen oxide production and simultaneously inhibited HC total protein synthesis by 36.1% +/- 3.1%. These data demonstrate that multiple cytokines, produced by endotoxin-activated KC, induce the production of NO. within HC, which in turn leads to the inhibition of HC total-protein synthesis.
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PMID:Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. 212 Nov 10

Traumatic injury and sepsis reduce HLA-DR expression on monocytes. This study assessed the effect of interferon-gamma (IFN-gamma) on the expression of HLA-DR on monocytes taken from severely injured patients. The mononuclear layer of each blood sample was incubated with either 500 units IFN-gamma or control media. The mean baseline HLA-DR expression of the trauma group (n = 11) was 32%, significantly less than the mean HLA-DR expression of 91% for the control group (n = 10). In the trauma group, HLA-DR expression after culturing with IFN-gamma was 81%, significantly greater than both the mean baseline HLA-DR expression (32%). In the control group, HLA-DR expression after culturing with IFN-gamma was 94%, similar to the mean baseline HLA-DR expression of 91%. These data confirm that HLA-DR on monocytes of severely injured patients is markedly reduced and show that it can be increased significantly in vitro by IFN-gamma.
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PMID:Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. 250 20

Cytokine-inducible nitric oxide (NO) production has been implicated in the pathogenesis of septic shock. The present study was designed to determine which cytokines induce expression of the NO synthase gene in rat aortic vascular smooth muscle cells (VSMC) in vitro and whether NO synthase gene expression is inducible in vivo. NO synthase mRNA appeared after 4-h exposure to interleukin-1 beta (IL-1 beta), and levels continued to increase up to 24 h. Levels of NO synthase transcripts were greatest in VSMC treated with IL-1 beta (1 nM), lower in VSMC treated with Escherichia coli lipopolysaccharide (LPS; 100 micrograms/ml), and just detectable in VSMC treated with tumor necrosis factor-alpha (TNF-alpha; 1 nM). IL-1 beta, TNF-alpha, and LPS each induced NO synthase activity, assessed by release of nitrite, conversion of L-arginine to L-citrulline, and increased levels of guanosine 3',5'-cyclic monophosphate, whereas IL-2, IL-6, and interferon-gamma were ineffective. IL-1 beta was more potent and effective than TNF-alpha; however, submaximal concentrations of TNF-alpha acted synergistically with IL-1 beta to induce NO synthase gene expression and activity. Inducible NO synthase mRNA was present in aorta from rats 6 h after treatment with LPS (5 mg/kg), but not at 24 h. Synergistic activation of NO synthase gene expression in VSMC by IL-1 beta and TNF-alpha may contribute to hypotension in sepsis.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells. 751 63

Stimulation with lipopolysaccharide (LPS) will lead to the expression of a variety of genes in CD14+ monocytes/macrophages, but also in CD14- fibroblasts and endothelial cells. Upon secondary LPS stimulation, the expression of many of these genes is only minimal. This applies to several cytokines, most prominent among them tumor necrosis factor (TNF). Induction of tolerance appears to require some degree of activation in the primary exposure, as partial structures of LPS induce tolerance, as long as they are able to activate cells. Studies on the mechanism of unresponsiveness in tolerant cells show that the CD14 LPS receptor is not downregulated but may even increase in number at the cell surface. Furthermore, this receptor appears to be functional in that mobilization of the transcription factor NF-kappa B does still occur. This NF-kappa B complex is composed primarily of p50p50 homodimers, that bind to the respective DNA motif in the promoter region of many proinflammatory genes, thereby blocking transactivation. However, LPS tolerance does not lead to downregulation of all kinds of response, as some genes are even increased in expression upon secondary stimulation; these include p50 of NF-kappa B, TNF receptor type II and interleukin-10 (IL-10). These gene products are involved in the downregulation of proinflammatory cytokines and may thereby be instrumental in the unresponsiveness observed. Hence, tolerance to LPS is not a passive process that occurs in an exhausted cell; rather, it is a well-controlled active response that is orchestrated in order to prevent excessive inflammation. Important modulators of tolerance are glucocorticoids, which result in a general decrease of gene expression, and interferon-gamma (IFN-gamma), which enhances expression of proinflammatory genes. LPS tolerance does occur in some clinical settings, as in hemodialysis, in sepsis and in patients treated repeatedly with LPS or other monocyte activators. In fact, LPS tolerance may be exploited for prophylaxis of severe sepsis in patients at risk.
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PMID:Molecular mechanism in tolerance to lipopolysaccharide. 758 50

We previously reported that sequential exposure of cultured porcine aortic endothelial cells to lipopolysaccharide (LPS) and then to inducers of the heat shock response resulted in lethal injury by programmed cell death. In these present experiments, we evaluated the ability of other mediators of sepsis to prime endothelial cells for subsequent injury upon heat shock induction. We used SVEC4-10 microvascular endothelial cells, a cloned SV40-transformed cell line derived from LPS-resistant C3H/HeJ mice. When these endothelial cells were treated first with tumor necrosis factor-alpha followed by induction of the heat shock response with either heat or sodium arsenite (As), a standard chemical inducer of the heat shock response in vitro, a tumor necrosis factor dose-dependent cytotoxicity was observed, similar to that which we had seen previously in porcine endothelial cells primed with LPS. Subsequent experiments found that priming with interferon-gamma produced a similar dose-dependent toxicity upon heat shock with either heat or As. The reducing agents dithiothreitol and n-acetylcysteine, which we have previously shown to inhibit heat shock-induced programmed cell death in LPS-primed porcine endothelial cells, were also effective in protecting against heat shock-induced death following cytokine-priming in this microvascular cell line, suggesting that the intracellular signaling pathways of these priming agents are somewhere convergent. These data suggest that both exogenous and endogenous mediators of inflammation can prime endothelial cells for subsequent injury upon induction of the heat shock response, and are consistent with the emerging concept of redundancy in inflammatory signaling.
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PMID:Heat shock-induced cell death in murine microvascular endothelial cells depends on priming with tumor necrosis factor-alpha or interferon-gamma. 774 56

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in sepsis and septic shock. Kupffer cells (KCs) are the resident macrophages of the liver and are potent producers of TNF-alpha in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon-gamma on TNF-alpha production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF-alpha synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS-induced KC TNF-alpha synthesis. Exogenous 8-BrcGMP and dbcGMP increased LPS-stimulated TNF-alpha synthesis but had no effect on KC TNF-alpha in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide-releasing substance that stimulates guanylate cyclase, increased TNF-alpha synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF-alpha synthesis. The inhibitory effect of methylene blue could be overcome with exogenous dbcGMP or SNP. Our results demonstrate that guanylate cyclase and cGMP mediate LPS-induced KC TNF-alpha synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli.
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PMID:Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-alpha synthesis. 785 45

The effects of recombinant murine interferon-gamma (rmIFN-gamma) on survival and host defense were studied during gut-derived sepsis that included transfusion-induced immunosuppression. Balb/c mice (n = 153) were transfused with allogeneic blood and then treated with different doses of rmIFN-gamma: 10, 100, 1000, 10,000 U, or sterile saline as control once daily for 3 days. Five days after transfusion they were gavaged with 10(10) Escherichia coli and given a 20% TBSA burn injury. Survival was significantly higher in groups receiving 10 U compared to control and the group receiving 10,000 U (P < 0.0001 and P = 0.02, respectively). Groups receiving 100 or 1000 U also showed an improvement of survival compared to nontreated control animals (P = 0.02). The effect of rmIFN-gamma on the degree of translocation and the host's ability to kill translocated organisms was also investigated. Mice were treated as described above, except they were gavaged with 111In oxine-labeled E. coli and then subjected to a 20% TBSA burn. Mesenteric lymph nodes (MLN), liver, and spleen were harvested aseptically. Less translocation to the liver was observed compared to the nontreated group (P = 0.002) to the MLNs and spleen of the group treated with 100 U rmIFN-gamma compared to controls and the group treated with 10 U (P < 0.005). Animals receiving 1000 U showed fewer bacteria in the liver and spleen compared to the control group (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IFN-gamma decreases translocation and improves survival following transfusion and thermal injury. 801 7

Following trauma and tissue injury, patients frequently suffer infections and septic complications. Tissue injury is associated with the induction of the hepatic acute-phase response, but how this phenotypic expression by hepatocytes influences their subsequent response to endotoxin (lipopolysaccharide, LPS) or inflammatory cytokines is unknown. We have shown that both rat and human hepatocytes maximally express the enzyme-inducible nitric oxide synthase (iNOS) in response to a combination of LPS and the cytokines tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), and interleukin-1. Furthermore, we have shown that the in vivo induction of the acute-phase response following tissue injury (hind limb turpentine injection) is not associated with hepatocyte iNOS expression. In this study, we show that the phenotypic change associated with the acute-phase response following tissue injury primes the hepatocyte to subsequently express iNOS in vitro in response to LPS alone as well as TNF and IFN-gamma. This expression of iNOS can be seen as early as 3 hr following the initial injury and lasts up to 24 hr. Early postinjury changes result in maximal expression following stimulation with TNF or IFN-gamma. Later (24 hr post-injury) changes reveal LPS to be the most potent inducer with as little as 0.01 microgram/ml LPS being required for iNOS mRNA expression. The in vivo correlate of tissue injury (turpentine injection) followed by sepsis (intraperitoneal LPS injection) resulted in a three- to fourfold rise in plasma levels of the stable end-products of nitric oxide production, nitrite, and nitrate (NO2- + NO3-), over levels seen in cases of sepsis alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Remote tissue injury primes hepatocytes for nitric oxide synthesis. 804 Nov 39

Mononuclear phagocytes (MO) secrete tumor necrosis factor-alpha (TNF) in response to inflammatory stimuli, most notably the bacterial product lipopolysaccharide (LPS). Cross-linking of MO Fc receptors also induces TNF release. Immunoglobulin for i.v. use is currently being investigated for the treatment and prophylaxis of neonatal sepsis and for the treatment of various syndromes of autoimmune dysfunction in children and adults. We examined the in vitro effect of immunoglobulin-gamma (IgG) on neonatal (cord blood) monocyte and adult MO TNF production. Kinetic studies were performed on MO incubated with IgG alone and on MO preincubated with IgG and stimulated with interferon-gamma/LPS. Incubation of MO in IgG (1-25 g/L) for 2, 6, and 24 h did not stimulate TNF secretion or production. However, enhanced TNF secretion was detected in MO preincubated in IgG and subsequently stimulated with interferon-gamma/LPS. TNF secretion by cord blood monocytes was increasingly enhanced by preincubation for 6 h with 1, 10, and 25 g/L IgG (2413.1 +/- 1389.4, p < 0.05; 4070.4 +/- 3069.2, p < 0.005; and 6383.7 +/- 2982.2, p < 0.005 versus 1215 +/- 575.9 ng/L, respectively, in cells preincubated in medium alone). Significant enhancement was also detected in cord blood monocytes preincubated in IgG for 2 h. TNF secretion by adult MO was similarly enhanced (6082.0 +/- 1732.8, p < 0.05; 7158.8 +/- 3938.2, p < 0.05; and 7302.7 +/- 3451.4, p < 0.05 versus 3353.2 +/- 2946.7 ng/L for 1, 10, and 25 g/L IgG, respectively, versus preincubation in medium alone). In additional experiments performed with Fc, Fab, and F(ab')2 fragments, only F(ab')2 fragments yielded positive results.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intravenous immunoglobulin modulates human mononuclear phagocyte tumor necrosis factor-alpha production in vitro. 804 75


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