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)

Using a THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype, we previously showed that tolerant cells remain responsive to LPS endotoxin with degradation of IkappaB in the cytosol and nuclear translocation and accumulation of p50 and p65 NF-kappaB transcription factors. Despite this, endotoxin-inducible NF-kappaB-dependent innate immunity genes, like IL-1beta, remained transcriptionally unresponsive in the tolerant phenotype, similar to the endotoxin tolerance observed in sepsis patients. In this study, we examined this paradox and found that RelB, another member of the NF-kappaB family, is induced during the establishment of tolerance. RelB expression correlated with IL-1beta repression, and sepsis patients showed increased RelB when compared with normal controls. Transient expression of RelB inhibited IL-1beta in endotoxin-responsive cells. In the inverse experiment, small inhibitory RNAs decreased RelB expression in tolerant cells and restored endotoxin induction of IL-1beta. When we examined tolerant cell extracts, we found transcriptionally inactive NF-kappaB p65/RelB heterodimers. Taken together, our findings demonstrate that RelB can repress proinflammatory gene expression, and suggest that RelB expression in sepsis patient blood leukocytes may play a role in the endotoxin-tolerant phenotype.
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PMID:Induction of RelB participates in endotoxin tolerance. 1695 72

Systemic inflammatory response syndrome (SIRS) and sepsis have been considered forms of hypercytokinemia in critically ill patients and immunocompromized hosts. It has been reported that some antimicrobial agents, including antifungal agents, not only have an antibiotic effect, but also they affect the host's immunological response. Immunofunctional cells, including monocytes and macrophages, were examined to determine whether they are influenced by the newly synthesized candin family antifungal agent micafungin (MCFG) using the human monocytic cell line THP-1 stimulated with lipopolysaccharide (LPS) as a model of hypercytokinetic conditions. LPS-induced production of TNF-alpha (tumor necrosis factor-alpha) and interleukin-8 (IL-8) in THP-1 cells was significantly suppressed dose-dependently by MCFG, although high concentrations of MCFG may reach toxic levels. It was clarified that MCFG inhibits the LPS-induced expression of TNF-alpha in THP-1 cells at the mRNA (messenger ribonucleic acid) level. In conclusion, administration of MCFG had an immunomodulatory effect on the host by reducing levels of TNF-alpha and IL-8. The effectiveness of MCFG in modulating hypercytokinemia is due not only to its direct antifungal effect, but also to the modulation of cytokine production in macrophages that regulates immunological activity and inflammation.
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PMID:Candin family antifungal agent micafungin (FK463) modulates the inflammatory cytokine production stimulated by lipopolysaccharide in THP-1 cells. 1700 23

Sepsis is characterized by a concurrent activation of inflammation and coagulation. Recently, recombinant human activated protein C was shown to decrease mortality in patients with severe sepsis presumably due to a combined anti-inflammatory and anticoagulant effect. These promising findings led to a search for other products that influence both the inflammatory and the procoagulant response to severe infection. Ethyl pyruvate (EP) was recently identified as an experimental anti-inflammatory agent during endotoxemia and sepsis. The aim of the present study was to investigate whether EP influences coagulation besides its anti-inflammatory effects. For this we investigated the effects of EP on the expression and function of tissue factor (TF), the principal initiator of coagulation activation in sepsis, in human monocytic (THP-1) cell cultures. EP dose-dependently inhibited the production of tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta by lipopolysaccharide (LPS)-stimulated THP-1 cells at mRNA and protein level, thereby confirming its anti-inflammatory properties in this in-vitro system. In addition, EP dose-dependently attenuated the increases in TF mRNA levels, TF-protein-surface expression and cell-surface-associated TF activity in LPS-stimulated THP-1 cells. These results demonstrate for the first time that EP is a compound with combined anti-inflammatory and anticoagulant effects.
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PMID:Ethyl pyruvate exerts combined anti-inflammatory and anticoagulant effects on human monocytic cells. 1713 74

Acinetobacter baumannii is a major nosocomial pathogen and frequent cause of hospital-acquired pneumonia, surgical wound infections and sepsis. As very little is known of the endotoxic potential of A. baumannii lipopolysaccharide (LPS) with respect to human cells or of its ability to stimulate inflammatory signalling via human Toll-like receptors (TLRs), the biological activity of these endotoxins was investigated in human monocytic THP-1 cells and in TLR-deficient HEK-293 cells transfected with human TLR2 and TLR4 constructs. Endotoxins derived from five clinical isolates of A. baumannii and one of Acinetobacter 'genomospecies 9' showed high potency, which was comparable to that of Escherichia coli strain R1 NCTC 13114 LPS, in the induction of the Limulus amoebocyte reaction and interleukin 8 and tumour necrosis factor alpha release from THP-1 cells. Whole UV-killed cells of A. baumannii and Acinetobacter 'genomospecies 9' stimulated both TLR2- and TLR4-dependent signalling, whereas pure endotoxins of all investigated strains induced signalling via TLR4, but not TLR2.
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PMID:Acinetobacter baumannii lipopolysaccharides are potent stimulators of human monocyte activation via Toll-like receptor 4 signalling. 1724 95

The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was recently shown to negatively regulate LPS-induced acute inflammatory responses. We previously observed that the metabolic thiol antioxidant alpha-lipoic acid (LA) inhibits LPS-induced expression of cellular adhesion molecules and adherence of monocytes to human aortic endothelial cells. Here we investigated the mechanism by which LA attenuates LPS-induced monocyte activation in vitro and acute inflammatory responses in vivo. Incubation of human monocytic THP-1 cells with LA induced phosphorylation of Akt in a time- and dose-dependent manner. In cells pretreated with LA followed by LPS, Akt phosphorylation was elevated initially and further increased during incubation with LPS. This LA-dependent increase in Akt phosphorylation was accompanied by inhibition of LPS-induced NF-kappaB DNA binding activity and up-regulation of TNFalpha and monocyte chemoattractant protein 1. Lipoic acid-dependent Akt phosphorylation and inhibition of NF-kappaB activity were abolished by the PI3K inhibitors LY294002 and wortmannin. Furthermore, LA treatment of LPS-exposed C57BL/6N mice strongly enhanced phosphorylation of Akt and glycogen synthase kinase 3beta in blood cells; inhibited the LPS-induced increase in serum concentrations and/or tissue expression of adhesion molecules, monocyte chemoattractant protein 1, and TNFalpha; and attenuated NF-kappaB activation in lung, heart, and aorta. Lipoic acid also improved survival of endotoxemic mice. All of these antiinflammatory effects of LA were abolished by treatment of the animals with wortmannin. We conclude that LA inhibits LPS-induced monocyte activation and acute inflammatory responses in vitro and in vivo by activating the PI3K/Akt pathway. Lipoic acid may be useful in the prevention of sepsis and inflammatory vascular diseases.
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PMID:Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. 1736 Apr 80

Tolerization with bacterial lipoprotein (BLP) affords a significant survival benefit in sepsis. Given that high mobility group box protein-1 (HMGB1) is a recognized mediator of sepsis-related lethality, we determined if tolerization with BLP leads to alterations in HMGB1. In vitro, BLP tolerization led to a reduction in HMGB1 gene transcription. This was mirrored at the protein level, as HMGB1 protein expression and release were reduced significantly in BLP-tolerized human THP-1 monocytic cells. BLP tolerance in vivo led to a highly significant, long-term survival benefit following challenge with lethal dose BLP in C57BL/6 mice. This was associated with an attenuation of HMGB1 release into the circulation, as evidenced by negligible serum HMGB1 levels in BLP-tolerized mice. Moreover, HMGB1 levels in peritoneal macrophages from BLP-tolerized mice were reduced significantly. Hence, tolerization with BLP leads to a down-regulation of HMGB1 protein synthesis and release. The improved survival associated with BLP tolerance could thus be explained by a reduction in HMGB1, were the latter associated with lethality in BLP-related sepsis. In testing this hypothesis, it was noted that neutralization of HMGB1, using anti-HMGB1 antibodies, abrogated BLP-associated lethality almost completely. To conclude, tolerization with BLP leads to a down-regulation of HMGB1, thus offering a novel means of targeting the latter. HMGB1 is also a mediator of lethality in BLP-related sepsis.
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PMID:Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality. 1762 48

Recent studies indicate that the High Mobility Group Box-1 protein (HMGB1) acts as a potent proinflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. The proinflammatory cytokine activity of HMGB1 has become a therapeutic target. In this study, we cloned the cDNA encoding human HMGB1 and constructed HMGB1 mutants using a one-step opposite direction PCR. The binding of the HMGB1 mutants to THP-1 cell and the cytokine activities of these HMGB1 mutants were observed. Results showed that the HMGB1 Mut (102-105), one of the HMGB1 mutants, in which amino acids 102-105 (FFLF) were replaced with two Glys, significantly decreased the full-length HMGB1 protein induced TNF-alpha release in human monocyte cultures. The results indicate that we have developed a novel recombinant HMGB1 mutant that competitively antagonizes the proinflammatory activity of HMGB1. This may be of significant importance in providing a new anti-inflammatory strategy for the treatment of severe sepsis and other inflammatory disorders.
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PMID:Construction and characterization of the HMGB1 mutant as a competitive antagonist to HMGB1 induced cytokines release. 1851 78

Staphylococcus aureus is a common etiologic agent for Gram-positive sepsis, and its lipoteichoic acid (LTA) may be important in causing Gram-positive bacterial septic shock. Here, we demonstrate that highly purified LTA (pLTA) isolated from Lactobacillus plantarum inhibited aureus LTA (aLTA)-induced TNF-alpha production in THP- cells. Whereas pLTA scarcely induced TNF-alpha production, aLTA induced excessive TNF-alpha production. Interestingly, aLTA-induced TNF-alpha production was inhibited by pLTA pretreatment. Compared with pLTA, aLTA induced strong signal transduction through the MyD88, NF-kappaB, and MAP kinases. This signaling, however, was reduced by a pLTA pretreatment, and resulted in the inhibition of aLTA-induced TNF-alpha production. Whereas dealanylated LTAs, as well as native LTAs, contributed to TNF- induction or TNF-alpha reduction, deacylated LTAs did not, indicating that the acyl chain of LTA played an important role in the LTA-mediated immune regulation. These results suggest that pLTA may act as an antagonist for aLTA, and that an antagonistic pLTA may be a useful agent for suppressing the septic shock caused by Gram-positive bacteria.
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PMID:Inhibitory effects of Lactobacillus plantarum lipoteichoic acid (LTA) on Staphylococcus aureus LTA-induced tumor necrosis factor-alpha production. 1860 67

Tissue factor (TF), which is expressed on the surface of activated monocytes, is the major procoagulant that initiates thrombus formation in sepsis. Two endogenous neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), are attractive candidates for the development of therapies against septic shock. The purpose of this study was to examine whether VIP or PACAP inhibit the LPS-induced TF expression in monocytes. Treatment of freshly isolated human monocytes or cultured monocytic THP-1 cells with VIP or PACAP leads to reduced LPS-induced TF protein, mRNA expression and activity, as demonstrated by Western blot, real-time polymerase chain reaction, and TF activity assay, respectively. In an endotoxemic model, VIP blunts the increase of LPS-induced TF expression in blood cells at the transcriptional level, as demonstrated by real-time polymerase chain reaction. However, neither neuropeptide affects the expression of TF pathway inhibitor in monocytes. In vitro, LPS increases the migration of c-Rel/p65 into the nucleus and the phosphorylation of p38 and JNK, all of which are essential for LPS-induced TF expression. In addition, interestingly, VIP and PACAP block both the migration of c-Rel/p65 and the phosphorylation of p38 and JNK, as demonstrated by Western blot analysis. These data indicate that VIP and PACAP inhibit LPS-induced TF expression in monocytes in vitro and in vivo, confirming these peptides as candidates for the multitarget therapy of septic shock.
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PMID:Vasoactive Intestinal Peptide and pituary adenylate cyclase-activating polypeptide inhibit tissue factor expression in monocyte in vitro and in vivo. 1865 Jul 85

Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria. It is a ligand for Toll-like receptor 4 (TLR4), which plays an essential role in innate immunity. Macrophages and dendritic cells exposed to LPS overproduce proinflammatory mediators, leading to septic shock. In this study, we screened for peptides that associate with TLR4 with a yeast two-hybrid screen using the human TLR4 extracellular domain as bait. A peptide (STM28) isolated from the screen inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activation in human and mouse macrophage cells and interacted with TLR4 in yeast and mammalian cells. STM28 showed no inhibitory effects against NF-kappaB activation induced by TLR1/2, TLR3 and TLR9 ligands in a mouse macrophage cell line, RAW 264. In addition, STM28 suppressed LPS-induced tumor necrosis factor-alpha production by differentiated THP-1 cells. Moreover, LPS-induced lethality in d-galactosamine-sensitized mice was significantly repressed by STM28 in a dose-dependent manner. These results demonstrate that STM28 selectivity inhibits TLR4-induced macrophage activation, and suggest that STM28 may have utility as a novel therapeutic agent for Gram-negative bacterial sepsis.
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PMID:A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-kappaB and in vivo toxicity. 1870 Jan 40


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