Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multifunctional protein 14 (MFP-14) is a ubiquitous protein that inhibits the production of tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma), which are involved in the pathogenesis of sepsis. Here, lipopolysaccharide (LPS)-induced lethality in mice was markedly reduced by MFP-14. The treatment also lowered LPS-induced levels of TNF-alpha and IFN-gamma in the blood.
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PMID:Prevention and treatment of lethal murine endotoxemia by the novel immunomodulatory agent MFP-14. 1130 37

Tumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identified originally as a TNF-alpha and IL-1beta-stimulated gene from normal, human foreskin fibroblasts and vascular endothelial cells, respectively. TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a carboxy-terminal half that shares homology with the entire sequence of C-reactive protein (CRP) and serum amyloid P component (SAP), acute-phase proteins of the pentraxin family. Some experimental evidence suggests that TSG-14 plays a role in inflammation, yet its function and mechanism of action remain unclear. We have generated transgenic mice that overexpress the murine TSG-14 gene under the control of its own promoter. From eight transgenic founders, two lineages were derived and better characterized: Tg2 and Tg4, carrying two and four copies of the transgene, respectively. TSG-14 transgenic mice were found to be more resistant to the endotoxic shock induced by LPS and to the polymicrobial sepsis caused by cecal ligation and puncture (CLP). Moreover, macrophages derived from the transgenic mice produced higher amounts of nitric oxide in response to IFN-gamma, TNF-alpha, and LPS as compared with macrophages from wild-type animals, and the augmented response appears to be the consequence of a higher responsiveness of transgenic macrophages to IFN-gamma. The data shown here are the first in vivo evidence of the involvement of TSG-14 in the inflammatory process and suggest a role for TSG-14 in the defense against bacterial infections.
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PMID:TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis. 1140 78

To determine the relative contribution of lipopolysaccharide (LPS) and non-LPS components of Neisseria meningitidis to the pathogenesis of meningococcal sepsis, this study quantitatively compared cytokine induction by isolated LPS, wild-type serogroup B meningococci (strain H44/76), and LPS-deficient mutant meningococci (strain H44/76[pLAK33]). Stimulation of human peripheral-blood mononuclear cells with wild-type and LPS-deficient meningococci showed that non-LPS components of meningococci are responsible for a substantial part of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta production and virtually all interferon (IFN)-gamma production. Based on tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of LPS in proteinase K-treated lysates of N. meningitidis H44/76, a quantitative comparison was made between the cytokine-inducing capacity of isolated and purified LPS and LPS-containing meningococci. At concentrations of >10(7) bacteria/mL, intact bacteria were more potent cytokine inductors than equivalent amounts of isolated LPS, and cytokine induction by non-LPS components was additive to that by LPS. Experiments with mice showed that non-LPS components of meningococci were able to induce cytokine production and mortality. The principal conclusion is that non-LPS parts of N. meningitidis may play a role in the pathogenesis of meningococcal sepsis by inducing substantial TNF-alpha, IL-1beta, and IFN-gamma production.
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PMID:Contributions of Neisseria meningitidis LPS and non-LPS to proinflammatory cytokine response. 1149 21

Cerebral abscess is a rare complication of staphylococcal septicemia in infants associated with high mortality and morbidity. In the pathogenesis of abscess formation, S. aureus, one major causative agent, interacts with endothelial cells of the brain vessels before reaching the central nervous system. This study examined the growth of S. aureus in human brain microvascular endothelial cells (HBMEC) cultures stimulated with cytokines. IFN-gamma inhibited S. aureus replication by the induction of indoleamine 2,3-dioxygenase (IDO) in HBMEC. This activation of IDO in HBMEC could be shown by RT-PCR and by detection of kynurenine in culture supernatants of activated cells. Resupplementation of L-tryptophan abrogated the inhibitory effect of IFN-gamma on the growth of staphylococci, hence confirming the activation of indoleamine 2,3-dioxygenase as being responsible for the induced bacteriostasis. Addition of TNF-alpha enhanced the IFN-gamma mediated antibacterial effects, whereas TNF-alpha alone had no influence on staphylococcal growth. Stimulation of HBMEC with IFN-gamma failed to activate inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO). Thus, intra- and extracellular depletion of L-tryptophan seems to be an important process in the defense against staphylococcal brain abscesses by means of creating an unfavorable microenvironment.
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PMID:Potential role of human brain microvascular endothelial cells in the pathogenesis of brain abscess: inhibition of Staphylococcus aureus by activation of indoleamine 2,3-dioxygenase. 1157 1

IFN-gamma is a key immunoregulatory cytokine that plays a predominant role in innate immunity. By employing PCR-Select to search for genes differentially expressed in IFN-gamma/TNF-alpha stimulated macrophages, we identified a novel IFN-gamma-induced transcript designated PUMA-G (protein up-regulated in macrophages by IFN-gamma). PUMA-G codes for a protein with seven transmembrane helices, a feature commonly shared with the G protein-coupled receptor superfamily (GPCR). The PUMA-G protein is most similar to the human orphan GPCR HM74 (73 % identity) and GPR31 (30 % identity). PUMA-G mRNA was readily induced in macrophages after stimulation with IFN-gamma, LPS, polyIC and CpG oligonucleotides. In vivo PUMA-G was up-regulated in mice suffering from microbial sepsis or from Listeria monocytogenes infection. Characterization of the genomic locus revealed an intronless PUMA-G open reading frame. Genomic Southern blot analysis indicates that PUMA-G is a single-copy gene. PUMA-G maps to mouse chromosome 5F. Confocal microscopy of transiently transfected 264.7 RAW macrophages and 293T cells with a PUMA-G-EGFP fusion construct showed predominant fluorescence at the cell surface, suggesting a localization at the cell membrane. Taken together, our data indicate that PUMA-G is a new inducible representative of GPCR, with potential importance in macrophage functions.
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PMID:PUMA-G, an IFN-gamma-inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily. 1174 92

Lactoferrin (Lf) is an iron-binding protein of external secretions and neutrophil secondary granules with antimicrobial and immunomodulatory activities. To further define these properties of Lf, we have investigated the response to Staphylococcus aureus infection in transgenic mice carrying a functional human Lf gene. The transgenic mice cleared bacteria significantly better than congenic littermates, associated with a trend to reduced incidence of arthritis, septicemia, and mortality. We identified two pathways by which S. aureus clearance was enhanced. First, human Lf directly inhibited the growth of S. aureus LS-1 in vitro. Second, S. aureus-infected transgenic mice exhibited enhanced Th1 immune polarization. Thus, spleen cells from infected transgenic mice produced higher levels of TNF-alpha and IFN-gamma and less IL-5 and IL-10 upon stimulation ex vivo with the exotoxin toxic shock syndrome toxin-1 compared with congenic controls. To confirm that these effects of Lf transgene expression could occur in the absence of live bacterial infection, we also showed that Lf-transgenic DBA/1 mice exhibited enhanced severity of collagen-induced arthritis, an established model of Th1-induced articular inflammation. Higher levels of stainable iron in the spleens of transgenic mice correlated with human Lf distribution, but all other parameters of iron metabolism did not differ between transgenic mice and wild-type littermates. These results demonstrate that human Lf can mediate both antimicrobial and immunomodulatory activities with downstream effects on the outcome of immune pathology in infectious and inflammatory disease.
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PMID:Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice. 1193 51

Studies have shown that both animal tissue-fixed immune cells and human peripheral blood mononuclear cell (PBMC) functions are altered after burn injury. Additional studies suggest that the burn injury-induced alterations in these divergent cell populations from different species are similar. It remains unknown, however, whether the observed changes in animal tissue-fixed immune cell function following thermal injury also occurs to a similar extent in the PBMC population. The aim of our study was to compare PBMC and tissue-fixed immune cell functions from the same animal using a murine burn model. At 7 days post-burn, mice were more susceptible to sepsis and delayed type hypersensitivity responses were suppressed. Splenocytes isolated from injured mice displayed suppressed proliferation and increased IL-10 production. In contrast, PBMC from injured mice displayed suppressed proliferation, IL-2 and IFN-gamma production. Splenic macrophage nitric oxide, PGE(2), TNF-alpha, IL-6 and IL-10 production was enhanced post-burn and IL-12 production was suppressed. PBMC from such animals displayed enhanced PGE(2) production and suppressed IL-6 and IL-12 production. These results indicate that while an immunosuppressive Th(2) phenotype (increased IL-10 and/or suppressed IL-2, IFN-gamma) was induced in both the splenic and PBMC compartments post-injury, differential expression and dimorphism in the response also exists. Thus, the assessment of only PBMC function in burn patients may not accurately reflect the patient's actual immune status at the tissue level.
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PMID:Differential expression and tissue compartmentalization of the inflammatory response following thermal injury. 1202 8

The relationship between peaks of G-CSF serum concentrations and respiratory burst activity of polymorphonuclear cells (PMN) was investigated in patients with postoperative or post-traumatic severe sepsis and septic shock. Over a 12 month period, a longitudinal analysis of G-CSF, TNF-alpha and IFN-gamma serum concentrations, burst activity of PMN, and expression of CD64 on the surface of PMN, were performed by ELISA technique and flow cytometric analysis, respectively, in 58 patients admitted to the intensive care unit (ICU) on a daily basis until discharge from the ICU or death. Out of these 58 patients, 27 with proven infections were in septic shock for at least 4 days' duration. Seventeen of these patients survived, whereas ten died. In 15 out of these 27 patients, 26 episodes of G-CSF peaks were observed, which were followed in most patients (13/15) by an increase in PMN burst activity, from 28% up to 540% (median 188%). Following the G-CSF peaks, CD64 expression on PMN remained at an increased level, followed by a marked decline 3 days later. TNF-alpha serum concentrations were elevated in most episodes (22/26), whereas IFN-gamma serum concentrations were below the detection level in 23/26 episodes. Taken together, peaks in G-CSF serum concentrations are followed by enhanced CD64 expression and increased burst activity of PMN in most patients with severe sepsis and septic shock. Thus, endogenous G-CSF increases neutrophil function in patients with severe sepsis and septic shock, necessary for resolution of bacterial infections in these patients.
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PMID:Peaks of endogenous G-CSF serum concentrations are followed by an increase in respiratory burst activity of granulocytes in patients with septic shock. 1202 9

The role of IL-10 in experimental sepsis is controversial. The nontoxic immunomodulator, ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) has been previously shown to inhibit IL-10 expression at the transcriptional level. In this study, we show that in mice subjected to cecal ligation and puncture (CLP), treatment with AS101 12 h after, but not before, CLP significantly increased survival of septic mice. This was associated with a significant decrease in serum IL-10 and in IL-10 secretion by peritoneal macrophages 24-48 h after CLP. At that time, the ability of these cells to secrete TNF-alpha and IL-1beta was restored in AS101-treated mice. The increased survival of AS101-treated mice was due to the inhibition of IL-10, since cotreatment with murine rIL-10 abolished the protective activity of AS101. AS101 increased class II Ag expression on peritoneal macrophages, severely depressed in control mice, while it did not affect the expression of class I Ags. This was accompanied by a significant elevation in the level of IFN-gamma secreted by splenocytes. Moreover, AS101 ameliorated bacterial clearance in the peritoneum and blood and decreased severe multiple organ damage, as indicated by clinical chemistry. Furthermore, myeloperoxidase levels in the liver and lung of AS101-treated mice, an indirect means of determining the recruitment of neutrophils, were significantly decreased. We suggest that nontoxic agents such as AS101, with the capacity to inhibit IL-10 and stimulate macrophage functions, may have clinical potential in the treatment of sepsis, provided they are administered during the phase of sepsis characterized by immune suppression.
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PMID:Anti-IL-10 therapeutic strategy using the immunomodulator AS101 in protecting mice from sepsis-induced death: dependence on timing of immunomodulating intervention. 1207 68

Bacterial toxins, including endotoxin/LPS as well as superantigens, are major causative agents of multi-organ failure associated with sepsis and liver disease. However, the precise mechanisms initiating cell activation by the toxins have not been clarified. We compared lethal shock and cytokine production in response to LPS with responses to the superantigen staphylococcal enterotoxin B (SEB) in both LPS-responsive C3H/HeN mice and LPS-hyporesponsive C3H/HeJ mice treated with D-galactosamine (GalN). LPS was not lethal and did not induce production of TNF-alpha in C3H/HeJ mice. In contrast, SEB produced lethal shock associated with liver failure and induced cytokines such as TNF-alpha, IFN-gamma, and IL-2 in both C3H/HeN and C3H/HeJ mice. Peritoneal macrophages from C3H/HeJ mice did not produce TNF-alpha in vitro in response to SEB or LPS. However, no significant difference was observed in production of TNF-alpha in response to stimulation in vitro by SEB between C3H/HeN and C3H/HeJ splenic lymphocytes. We have demonstrated that SEB causes lethal toxicity associated with liver injury in LPS-hyporesponsive C3H/HeJ mice and that as the underlying mechanism, the normal T-cell function in these mice still maintained the sensitivity to SEB since the genetic defect of C3H/HeJ mice unresponsive to LPS and SEB is restricted in macrophages/monocytes and does not extend to T cells.
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PMID:Staphylococcal enterotoxin B induces hepatic injury and lethal shock in endotoxin-resistant C3H/HeJ mice despite a deficient macrophage response. 1223 Sep 15


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