Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021311 (Infection)
 38,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infections with verocytotoxin (VT) producing Escherichia coli have been strongly implicated in the epidemic form of hemolytic uremic syndrome (HUS). Endothelial damage plays a central role in the pathogenesis of HUS. In vitro studies have shown that VT can damage endothelial cells after interaction with its cellular receptor globotriaosylceramide (GbOse3cer). Cytokines, such as tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) can potentiate the toxic effect of VT by inducing a protein-synthesis dependent increase in VT receptors on endothelial cells. In this study, the mechanisms underlying the increase in endothelial VT receptors induced by TNF alpha were studied in more detail. To investigate which proteins were involved in this induction, endothelial cells were incubated with and without TNF alpha in the presence of 14C-galactose or 14C-glucose. Thin-layer chromatography (TLC) analysis of the glycolipid extracts of these cells demonstrated a markedly enhanced incorporation of 14C-galactose in GbOse3cer and other galactose-containing glycolipids, suggesting that TNF alpha enhanced galactosyl-transferase activity. To examine the role of the two recently cloned TNF-receptors (TNFR-p75 and TNFR-p55) in the TNF alpha-induced increase in GbOse3cer in human endothelial cells, cells were incubated with TNF alpha, the TNFR-p55 selective R32W-S86T-TNF alpha-mutant, or the TNFR-p75 selective D143N-A145R-TNF alpha-mutant. The effect of TNF alpha activation, determined by binding-experiments with 125I-VT-1, could be largely, but not completely mimicked by R32W-S86T-TNF alpha. Although incubation of cells with D143N-A145R-TNF alpha did not show an increase in VT-1 binding, the monoclonal antibody utr-1, which prevents binding to TNFR-p75, decreased the TNF alpha-induced VT-1 binding. Activation of protein kinase C (PKC) by phorbol ester increases the expression of VT-1 receptors; this effect was prevented by the PKC inhibitor Ro31-8220 and by homologous desensitization by pretreatment with phorbol ester. In contrast, the presence of the protein kinase inhibitor Ro31-8220 or desensitization of PKC activity reduced the TNF alpha-induced increase in VT-1 receptors maximally by 50% and 24%, respectively. Comparable reductions in overall protein synthesis and the synthesis of E-selectin and plasminogen activator inhibitor-1 (PAI-1) were observed. This suggests an effect on general protein synthesis rather than a specific effect of PKC in the signal transduction pathway, by which TNF alpha induces VT-1 receptors. Our results indicate that TNF alpha can increase the VT-1 receptors on endothelial cells by inducing galactosyl-transferase activity, that this action of TNF alpha mainly occurs via the TNFR-p55; and that PKC activation increases expression of VT-1 receptors by a separate mechanism that acts additively to the TNF alpha-induced increase in VT-1 receptors.
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PMID:Tumor necrosis factor alpha induces endothelial galactosyl transferase activity and verocytotoxin receptors. Role of specific tumor necrosis factor receptors and protein kinase C. 753 May 4

A series of recombinant herpes simplex virus (HSV-1) vectors have been constructed that encode either the full-length cDNA of the human p75 NGF receptor (p75hNGFR) or truncated forms of the receptor. Infection of cultured fibroblast cells with viral stocks results in abundant expression of all three cDNAs, as detected by affinity cross-linking, immunoblot analysis, and equilibrium binding. Furthermore, viral infection of primary neuronal cultures gives easily detectable p75 expression by immunofluorescence and affinity cross-linking. When p75 was introduced by viral infection into fibroblast cells expressing the trk proto-oncogene, a new binding site was created, consistent with high-affinity NGF binding. This site is not created by the coexpression of truncated forms of p75 that lack either the extracellular ligand binding domain or the cytoplasmic domain of the receptor, suggesting that both of these regions of the receptor are required for the formation of the high-affinity NGF binding site. Hence, these HSV-1 vectors give rise to appropriate NGF receptor binding after viral infection. The application of these HSV-1 constructs to primary neuronal culture and in vivo models of p75NGFR function is discussed.
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PMID:HSV-1 vector-mediated gene transfer of the human nerve growth factor receptor p75hNGFR defines high-affinity NGF binding. 838 40

Two different receptors exist for tumor necrosis factor-alpha (TNF-alpha), designated as p55 (TNF-RI) and p75 (TNF-RII). Soluble (= s) forms of TNF-Rs are secreted after proteolytic cleavage and block the effects of TNF-alpha. sTNF-RI, sTNF-RII and the soluble interleukin 2 receptor (sIL-2R) were determined by ELISA in serum samples of HIV-infected children and adolescents. Twelve children with vertical HIV infection (mean age +/- SD, 5.9 +/- 3.8 years) and 17 horizontally infected patients (16.1 +/- 7.3 years) were classified according to the revised CDC criteria. Twenty healthy control persons (6.4 +/- 5.8 years) showed the following receptor concentrations (median): sTNF-RI 888 pg/ml, sTNF-RII 1,741 pg/ml, sIL-2R 94 pM. Compared to controls, horizontally HIV-infected patients had significantly (Mann-Whitney U test) higher levels for sTNF-RI (median 1,192 pg/ml), sTNF-RII (3,481 pg/ml) and sIL-2R (128 pM). For vertically infected children only sTNF-RII (2,944 pg/ml) was significantly elevated compared to controls. There were no differences in soluble receptor levels between vertical or horizontal transmission. Surprisingly, no significant differences for sTNF-RI, sTNF-RII and sIL-2R occurred when 19 patients in stage CDC I were compared to ten patients in stages II or III. The clearly elevated sTNF-RII levels in patients with horizontal and vertical HIV infection indicate the activation of the monocyte/macrophage system in both groups.
Infection
PMID:Increased serum levels of soluble tumor necrosis factor receptors (sTNF-Rs) in children and adolescents with vertically and horizontally transmitted HIV infection. 887 82

In 15 consecutive subjects hospitalized with nephropathia epidemica, a European form of hemorrhagic fever with renal syndrome, the plasma concentrations of nitrate plus nitrite, stable metabolites of nitric oxide, were determined. From day 3 of onset of disease the concentrations increased, peak levels being reached on days 5 to 7. Maximal plasma concentrations of nitrate plus nitrite were correlated to the degree of hypotension (r = -0.64, p = 0.02) and levels of tumor necrosis factor (TNF)-alpha (r = 0.51, p = 0.05) and soluble TNF receptors p55 and p75 (r = 0.58, p = 0.03 and r = 0.54, p = 0.04, respectively) but not to levels of interferon-gamma or interleukin-10 (p > 0.05). The results are compatible with the well-known capacity of TNF-alpha to enhance production of nitric oxide, and suggest that nitric oxide may be of physiologic importance in hemorrhagic fever with renal syndrome.
Infection
PMID:Increased production of nitric oxide in patients with hemorrhagic fever with renal syndrome--relation to arterial hypotension and tumor necrosis factor. 892 42

Infection of the dental pulp leads to an osteolytic lesion that results from a polymicrobial infection consisting largely of pathogenic anaerobes. Infection causes significant morbidity and mortality mediated by bacterial factors and in some cases by the up-regulation of inflammatory cytokines. The inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), in particular, play a complex and central role in the responses to microbial pathogens. However, relatively little is known about the significance of these cytokines in protecting the host from focal polymicrobial anaerobic infections. To establish the relative importance of IL-1 and TNF in mediating the response to a mixed anaerobic infection, we inoculated the dental pulp of mice with six anaerobic pathogens containing functional deletions of receptors to IL-1 (IL-1R1(-/-)), TNF (TNFRp55(-/-)-p75(-/-)), or both (TNFRp55(-/-)-IL-1RI(-/-)). The results indicate that IL-1 receptor signaling and TNF receptor signaling both play similarly important roles in protecting the host from local tissue damage. However, IL-1 receptor signaling is considerably more important than TNF receptor signaling in preventing the spread of infection into surrounding fascial planes, since IL-1R1(-/-) but not TNFRp55(-/-)-p75(-/-) mice exhibited significantly higher morbidity and mortality. Moreover, all of the fatal infections occurred in male mice, suggesting the importance of gender differences in limiting the impact of these infections.
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PMID:Interleukin-1 receptor signaling rather than that of tumor necrosis factor is critical in protecting the host from the severe consequences of a polymicrobe anaerobic infection. 1089 81

The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.
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PMID:Cholesterol and interleukin-6 concentrations relate to outcomes in burn-injured patients. 1279 32

In experimental murine trypanosomiasis, resistance is often scored as the capacity to control peak parasitemia levels, which results in prolonged survival. Infection-induced pathology has not systematically been used as a resistance criterion. Because this parameter could be the most relevant for comparative analysis of natural and experimental infections, as well as for understanding of pathology-associated immune alterations, we analyzed Trypanosoma brucei infections in 4 different established conventional mouse models, as well as in tumor necrosis factor (TNF)-deficient and TNF-receptor-deficient mice. Results indicate the following: (1) there is no correlation between peak parasitemia control or survival and the induction of infection-associated anemia, loss of body weight, liver pathology, reduced locomotor activity, and general morbidity; (2) serum levels of TNF, interferon- gamma, and interleukin-10, which are known to affect survival, do not correlate with induction of pathology; and (3) infection-induced occurrence of lipopolysaccharide hypersensitivity does not correlate with survival. However, one parameter that was found to correlate with the inhibition of trypanosomiasis-associated pathology in all models was the shedding of soluble p75 TNF-receptor during peak parasitemia stages. These results are important for future cytokine and trypanosomiasis pathology studies, because the interplay between TNF and the soluble receptors it sheds has not been considered in either human clinical sleeping sickness studies or in veterinary trypanosomiasis research.
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PMID:P75 tumor necrosis factor-receptor shedding occurs as a protective host response during African trypanosomiasis. 1474 12

Giving C57BL/6 mice 10(4) PFU of coxsackievirus B3 (H3 variant) fails to induce myocarditis, but increasing the initial virus inoculum to 10(5) or 10(6) PFU causes significant cardiac disease. Virus titers in the heart were equivalent at days 3 and 7 in mice given all three virus doses, but day 3 titers in the pancreases of mice inoculated with 10(4) PFU were reduced. Tumor necrosis factor alpha (TNF-alpha) concentrations in the heart were increased in all infected mice, but cytokine levels were highest in mice given the larger virus inocula. TNF-alpha(-/-) and p55 TNF receptor-negative (TNFR(-/-)) mice developed minimal myocarditis compared to B6;129 or C57BL/6 control mice. p75 TNFR(-/-) mice were as disease susceptible as C57BL/6 animals. No significant differences in virus titers in heart or pancreas were observed between the groups, but C57BL/6 and p75 TNFR(-/-) animals showed 10-fold more inflammatory cells in the heart than p55 TNFR(-/-) mice, and the cell population was comprised of high concentrations of CD4(+) gamma interferon-positive and Vgamma4(+) cells. Cardiac endothelial cells isolated from C57BL/6 and p75 TNFR(-/-) mice upregulate CD1d, the molecule recognized by Vgamma4(+) cells, but infection of TNF(-/-) or p55 TNFR(-/-) endothelial cells failed to upregulate CD1d. Infection of C57BL/6 endothelial cells with a nonmyocarditic coxsackievirus B3 variant, H310A1, which is a poor inducer of TNF-alpha, failed to elicit CD1d expression, but TNF-alpha treatment of H310A1-infected endothelial cells increased CD1d levels to those seen in H3-infected cells. TNF-alpha treatment of uninfected endothelial cells had only a modest effect on CD1d expression, suggesting that optimal CD1d upregulation requires both infection and TNF-alpha signaling.
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PMID:Roles of tumor necrosis factor alpha (TNF-alpha) and the p55 TNF receptor in CD1d induction and coxsackievirus B3-induced myocarditis. 1570 85

Infection by virulent Mycobacterium avium caused progressive severe lymphopenia in C57BL/6 mice due to increased apoptosis rates. T-cell depletion did not occur in gamma interferon (IFN-gamma)-deficient mice which showed increased T-cell numbers and proliferation; in contrast, deficiency in nitric oxide synthase 2 did not prevent T-cell loss. Although T-cell loss was IFN-gamma dependent, expression of the IFN-gamma receptor on T cells was not required for depletion. Similarly, while T-cell loss was optimal if the T cells expressed IFN-gamma, CD8(+) T-cell depletion could occur in the absence of T-cell-derived IFN-gamma. Depletion did not require that the T cells be specific for mycobacterial antigen and was not affected by deficiencies in the tumor necrosis factor receptors p55 or p75, the Fas receptor (CD95), or the respiratory burst enzymes or by forced expression of bcl-2 in hematopoietic cells.
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PMID:Gamma interferon-induced T-cell loss in virulent Mycobacterium avium infection. 1590 87

Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1beta, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-alpha, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p < 0.0001), as well as of IL-6 (p < 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.
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PMID:Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis. 1740 24


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