Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxin shock is not only the reflexion of Gram-negative focal infection but also the consequence of dysfunction of the intestinal mucous barrier and a decline of the detoxication capacity, in particular of the hepatic mesenchymal phagocytic system during a critical state. Cytokines and the primary LPS complex and its lipid A resp. are of basic importance. They start the release of a large amount of TNF alpha, IL-1, IL-6, IL-8 and other cascades. Acute shock is controlled nowadays more frequently than in the past, however, there is a high risk of a very adverse reaction of remote organs, which is very adverse from the prognostic aspect. A series of laboratory markers has a greater validity than the clinical picture alone. For screening derived markers are used not primary markers. Despite this they provide adequate information. Prophylaxis and treatment include selective bacterial decontamination, or active or passive immunization (PSAEVA, hyperimmune sera), minidoses of dopamine in a continuous infusion, early enteral nutritional intervention, in particular enteral nutrition containing glutamine. Monoclonal and polyclonal antibodies against the LPS complex and cytokines are tested, blocking their receptors or possibly early plasmapheresis. Permanent pillars of therapeutic tactics are still a radical and early elimination of possible infectious foci and targeted administration of antibiotics and maintenance of the perfusion pressure and adequate oxygenation.
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PMID:[New findings in emergency care and resuscitation in patients at risk for endotoxic shock]. 133

Trypanothione reductase is a member of the structurally and functionally well-characterized family of flavoprotein reductases, which catalyze the reduced pyridine nucleotide dependent reduction of their disulfide, peroxide, or metal ion substrates. Trypanothione reductase is found in a wide variety of Trypanosoma species, where the enzyme serves physiologically to protect the organism from oxidative stress and assists in maintaining low intracellular levels of hydrogen peroxide. The redox potential of the flavin and the hydride ion transfer reaction of the pro-S hydrogen of NADPH to N5 of FAD have been proposed to be influenced by the presence of a conserved Lys-Glu (K60-E201) ion pair at the bottom of the nicotinamide binding pocket. We have evaluated this hypothesis by making modest substitutions for both the Lys and Glu residues using site-directed mutagenesis. Replacement of the K60 residue with an arginine led to a poorly expressed, and completely inactive, enzyme. Replacement of the Glu201 residue with either a glutamine (E201Q) or an aspartate (E201D) residue led to expressed enzymes which could be readily purified in > 20 mg amounts using protocols developed for the WT enzyme, and which had significant residual trypanothione-reducing activity. These enzymes have now been characterized to determine their redox potentials, catalytic activities, and nucleotide specificities. Relative to the WT enzyme, both E201D and E201Q exhibit ca. 5% of WT trypanothione-reducing activity using NADPH as reductant, but significantly enhanced quinone reductase activity. The oxidase activity of both mutants is enhanced by over 50-fold compared to that of the WT. The redox potential of the WT enzyme has been determined to be -273 mV, while both the E201D and E201Q exhibit more positive redox potentials (-259 and -251 mV, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Catalytic and potentiometric characterization of E201D and E201Q mutants of Trypanosoma congolense trypanothione reductase. 754 22

The proliferation of human myeloid progenitor cells is negatively regulated in the presence of certain members of the chemokine family of molecules. This includes interleukin 8 (IL-8) and platelet factor 4 (PF4), which in combination are able to synergize, resulting in cell suppression at very low concentrations of these molecules. A series of PF4 and IL-8 mutant proteins were analyzed in an in vitro colony formation assay for myeloid progenitor cells to assess domains of these proteins that are required for activity. Mutation of either of the two DLQ motifs within PF4 resulted in an inactive protein. Perturbations within the IL-8 dimer interface region also resulted in mutants that were incapable of suppressing colony formation. A class of chimeric mutants consisting of domains of either PF4 and IL-8, Gro-alpha and PF4, or Gro-beta and PF4 were observed to inhibit myeloid cell proliferation at concentrations which were between 500- and 5000-fold lower than either the IL-8 or PF4 wild-type proteins alone. These chimeric mutants possessed activities that were comparable to or better than the activity observed when IL-8 and PF4 were added together in vitro. One of these highly active chimeric proteins was observed to be 1000-fold more active than either IL-8 or PF4 alone in suppressing not only the proliferation but also the cell cycling of myeloid progenitor cells following intravenous injection of the mutant into mice. Examination of additional IL-8-based mutants in the colony formation assay, which centered on the perturbation of the amino-terminal "ELR" motif, resulted in the observation that the highly active IL-8 mutant required both aspartic acid at amino acid residue 4 and either glutamine or asparagine at residue 6. Single mutations at either of these positions resulted in mutants with myelosuppressive activity equivalent to wild-type IL-8. Mutants such as IL-8M1 and IL-8M10 were observed to be significantly reduced in their ability to activate isolated human neutrophils, suggesting that separate mechanisms may exist by which myeloid progenitor cells and neutrophils are affected by chemokines.
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PMID:High activity suppression of myeloid progenitor proliferation by chimeric mutants of interleukin 8 and platelet factor 4. 755 82

Physiological levels of human fibrinogen markedly inhibited the chemotactic activity of human neutrophils triggered by zymosan-activated serum (ZAS), C5a, or IL-8 in a Boyden chamber assay. Fibrinogen also slightly inhibited the N-formyl-methionyl leucyl-phenylalanine (FMLP)-induced migration of human neutrophils. Albumin was devoid of the inhibitory activities displayed by fibrinogen in this system. The inhibition of chemotaxis by fibrinogen was dose-dependent and saturable. Fibrinogen placed in the upper compartment of the Boyden chamber produced a larger inhibition than that obtained with fibrinogen placed in the lower compartment. Lysine as well as the lysine analog 6-aminohexanoic acid (AHA) decreased the inhibitory capacity of fibrinogen. In contrast, both arginine and glutamine failed to suppress the fibrinogen-mediated inhibition of neutrophil chemotaxis. AHA counteracts the inhibition of ZAS-induced chemotaxis by anti-CD18 monoclonal antibody, suggesting that lysine binding sites are required for integrin function in chemotaxis. Fibrinogen also inhibited, in a dose-dependent manner, the oxygen consumption of neutrophils activated by opsonized zymosan. Taken together, the present results indicate that fibrinogen modulates neutrophil functions and suggest that in addition to its role in blood coagulation, circulating fibrinogen may be involved in regulation of the inflammatory response.
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PMID:Inhibition of neutrophil activation by fibrinogen. 784 97

The beneficial effects of glutamine on immune function in vitro have been well described. Severely ill surgical patients undergo glutamine depletion and this has been implicated as a cause of immune dysfunction in vivo. With the introduction of the stable dipeptides of glutamine into total parenteral nutrition (TPN) regimens, the clinical effects of glutamine on the immune system have taken on an increased relevance and importance. In a randomized clinical trial, we have shown that glutamine-supplemented TPN increased the T cell mitogenic response in patients undergoing colorectal resection. This was not associated with an altered production of the pro-inflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor (TNF). In a subsequent clinical trial comparing glutamine-supplemented TPN with control TPN in patients with severe acute pancreatitis there was a similar modest enhancement of the T cell response in the glutamine-supplemented group. Although Il-6 and TNF production were again unchanged, there was a significant reduction in IL-8 production in the glutamine-supplemented group. Glutamine may exert its immunological effects by a direct action on the cells of the immune system. Possible indirect mechanisms by which glutamine may influence the immune system include the maintenance of gut barrier function, or the preservation of action of the antioxidant glutathione.
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PMID:Effect of glutamine on immune function in the surgical patient. 897 26

Neutrophils play an important role in host defense by phagocytosing and destroying invading bacteria. A recent investigation revealed that glutamine (Gln) augmented the in vitro bactericidal activity of neutrophils from burn patients. However, it is unclear whether Gln enhances the function of neutrophils in postoperative patients. This study was designed to investigate the effect of Gln on the in vitro Escherichia coli-killing activity of neutrophils from postoperative patients. Nine randomly selected patients were included in this study. On the morning of the first postoperative day, blood was drawn and neutrophils were isolated. Eight healthy volunteers served as controls. E. coli was opsonized with pooled normal serum. Neutrophils (5 x 10(6)), together with opsonized E. coli (5 x 10(5)), were incubated for 2 h at 37 degrees C in Hanks' balanced salt solution supplemented with 0, 100, 500, or 1000 nmol/mL of Gln. The bactericidal function of neutrophils was determined by counting the number of viable bacteria. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-8, and granulocyte elastase levels in the cell culture supernatant were measured. Plasma C-reactive protein (CRP), cortisol, and amino acids were also analyzed. The plasma concentration of Gln was significantly lower in the postoperative patients than in the controls. Following culture with patient neutrophils, the number of viable E. coli decreased by 26% as the in vitro Gln concentration was increased from 500 to 1000 nmol/mL (P < 0.01). We defined the Gln 1000/Gln 500 ratio of the number of viable bacteria as the number of viable E. coli at an in vitro Gln concentration of 1000 nmol/mL divided by the number of viable E. coli at an in vitro Gln concentration of 500 nmol/mL. A positive correlation was thus demonstrated between the plasma Gln level and the Gln 1000/Gln 500 ratio of the number of viable bacteria in the patients (r = 0.69, P = 0.04). This finding indicated that as plasma Gln fell, there was an enhancement of neutrophil E. coli-killing activity by neutrophils in in vitro tests when the Gln concentration was increased from 500 to 1000 nmol/mL. Gln supplementation caused no appreciable changes in TNF-alpha, IL-1 beta, IL-8, or granulocyte elastase levels in cell culture supernatants. A negative correlation was recognized between the patient plasma Gln level and the Gln 1000/Gln 500 ratio of the cell culture supernatant IL-8 level (r = -0.73, P = 0.025). In conclusion, Gln supplementation enhanced the in vitro bactericidal function of neutrophils from postoperative patients.
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PMID:Glutamine-enhanced bacterial killing by neutrophils from postoperative patients. 935 31

Glutamine, a conditionally essential amino acid, is important for immune function. It is now being formulated for incorporation into total parenteral nutrition (TPN). The aims of this study were to examine the effect of glutamine administration on lymphocyte proliferation and proinflammatory cytokine release in patients with severe acute pancreatitis. Fourteen patients were randomized (in a double-blind fashion) to receive either conventional or isocaloric, isonitrogenous glutamine-supplemented (0.22 g glutamine x kg(-1) x d(-1) as glycyl-glutamine) TPN for 7 d. DNA synthesis (index of lymphocyte proliferation) and the 24-h release of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 from peripheral blood mononuclear cells were measured in vitro on days 0, 4, and 7. Thirteen patients completed the study protocol (6 glutamine TPN, 7 conventional TPN). Glutamine supplementation increased median DNA synthesis by 3099 cpm over the study period against 219 cpm in the conventional group (increase not significantly different between the two groups) . Glutamine supplementation did not significantly influence TNF or IL-6 release, but, in contrast, median IL-8 release was reduced by day 7 in the glutamine group while it was increased in the conventional group (-17.7 ng/mL (median change over study period) versus +43.3 ng/mL, respectively; P=0.045). Small patient numbers and substantial interindividual variation limit the conclusions, but there is a trend for the glutamine group to have improved lymphocyte proliferation, and in the case of IL-8, reduced proinflammatory cytokine release.
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PMID:Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis. 958 68

Glutamine (Gln) supplementation has been shown to decrease production of pro-inflammatory cytokines by the human intestinal mucosa. The mechanism of this is poorly understood. We hypothesize that Gln down-regulates lipopolysaccharide (LPS)-stimulated pro-inflammatory cytokine production in Caco-2 cells by nuclear factor-kappa B (NF-kappaB). Caco-2 cells were incubated with different concentrations of Gln with or without methionine sulfoximine (MS, an inhibitor of glutamine synthetase) before stimulation with LPS. IL-6, IL-8, IL-10 and TNF-alpha protein and mRNA level were determined. NF-kappaB translocation was determined using an ELISA-based kit. IL-8 was the only detectable cytokine/chemokine. The largest amount of IL-8 was secreted by cells in the presence of MS with no Gln in the medium after exposure to LPS. LPS increased IL-8 production, peaking 10h after LPS administration. The addition of Gln (0.5 or 5.0mM) decreased IL-8 peptide and mRNA expression. LPS increased NF-kappaB nuclear translocation in the presence or absence of MS. Neither Gln nor MS altered NF-kappaB nuclear translocation. These results indicate that the lack of glutamine increases IL-8 production by Caco-2 cells after LPS stimulation. However, the glutamine-mediated decrease in LPS-stimulated IL-8 production is not associated with NF-kappaB p50 nuclear binding.
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PMID:Glutamine decreases lipopolysaccharide-induced IL-8 production in Caco-2 cells through a non-NF-kappaB p50 mechanism. 1284 6

The mechanism of glutamine (Gln)-mediated down-regulation of inflammation in the intestine is poorly understood. We hypothesize that Gln down-regulates lipopolysaccharide (LPS)-stimulated IL-8 production in intestinal epithelial cells via transcription factors that counteract the effect of LPS-mediated increase in IL-8. Caco-2 cells were incubated with different doses of Gln with or without methionine sulfoximine (MS), an inhibitor of glutamine synthetase for 24 h before stimulation by LPS (100 microg/ml for 24 h). Inhibitors of the mitogen activated protein kinase (MAPK) family were added to cells for 1.5 h following stimulation by LPS. The p38 inhibitor SB 203580 resulted in a significant decrease in IL-8 peptide production (p < 0.01). However, p38 MAPK activity increased with Gln (p < 0.05), suggesting that this was not involved with Gln-mediated down-regulation of IL-8. Screening of 54 transcription factors demonstrated that STAT-4 was the only inflammation-related transcription factor that was up-regulated by Gln depletion and down-regulated with Gln supplementation (2-fold increase), paralleling IL-8 production. EMSA analysis confirmed these findings (3.5-fold increase). These results indicate that Gln deprivation enhances IL-8 production by Caco-2 cells after LPS stimulation and that down-regulation of IL-8 production with Gln is associated with alterations in STAT-4 transcription factor binding.
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PMID:Mechanism of glutamine-mediated amelioration of lipopolysaccharide-induced IL-8 production in Caco-2 cells. 1505 Jun 5

Vascular endothelial growth factor (VEGF) and interleukin-8/CXCL8 (IL-8) are prominent pro-angiogenic and pro-metastatic proteins that represent negative prognostic factors in many types of cancer. Hypoxia is thought to be the primary environmental cause of VEGF and IL-8 expression in solid tumors. We hypothesized that a lack of nutrients other than oxygen could stimulate the expression of these factors and previously demonstrated that expression of VEGF and IL-8 is responsive to amino acid deprivation. In the present study, we examined the effect of glutamine availability on the expression of these factors as well as the role of transcription factors NFkappaB and activating protein-1 (AP-1) in the response of TSE human breast carcinoma cells to glutamine deprivation. VEGF and IL-8 secretion and mRNA levels were dramatically induced by glutamine deprivation. mRNA stabilization contributed to this response. Glutamine deprivation increased NFkappaB (p65/p50) and AP-1 (Fra-1/c-Jun+JunD) DNA-binding activities. Blocking NFkappaB and AP-1 activation with curcumin as well as expression of dominant inhibitors, inhibitor of nuclear factor-kappaB (IkappaB) super repressor (IkappaBM), and a mutant form of c-Fos (A-Fos) demonstrated that the activation of NFkappaB and AP-1 transcription factors was necessary for the induction of IL-8 expression but dispensable for the induction of VEGF expression. A macro-array containing 111 NFkappaB target genes identified a total of 17 that were up-regulated 2-fold or more in response to glutamine deprivation. These included growth regulated oncogene alpha (GROalpha/GRO1/CXCL1), another neutrophil chemoattractant implicated in tumor angiogenesis and metastasis.
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PMID:Expression of angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 is highly responsive to ambient glutamine availability: role of nuclear factor-kappaB and activating protein-1. 1525 56


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