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)

Modulations of maternal immune cell function are critical for successful growth and development of an antigenically distinct fetus. It has been proposed that pregnancy is associated both with suppression of the adaptive immune system and a generalised maternal inflammatory response with changes in immune function resembling those associated with septicemia, and these changes are more exaggerated when pregnancies are complicated with pre-eclampsia. The nuclear factor (NF)-kappaB family of transcription factors play a significant role in immune regulation. We hypothesised therefore that if pregnancy is associated with activation of the maternal immune system, this would be supported by the activation of NF-kappaB and degradation of IkappaBalpha and beta in peripheral blood mononuclear cells (PBMCs). We demonstrate the contrary: NF-kappaB activity is suppressed in PBMCs from pregnant females and more in pre-eclampsia. The inhibition of NF-kappaB activation in pregnancy is not attributed to over-expression of IkappaBalpha or beta. In contrast, levels of IkappaBalpha and beta in cytoplasmic extracts from PBMCs in pregnancy are decreased compared with non-pregnant controls, and IkappaBalpha levels are decreased more so in pre-eclampsia. We have shown that activation of NF-kappaB in PBMCs from patients with septicemia follows the classical pathway. This pathway is differentially regulated in pregnancy. Alterations in NF-kappaB nuclear binding and IkappaBalpha levels were reproducible by culturing PBMCs in pooled pregnant serum. Taken together, these data indicate that pregnancy-specific factors exist to regulate expression of NF-kappaB/IkappaB in a pregnancy-specific manner, and may underlie one mechanism by which the fetus avoids maternal rejection throughout pregnancy.
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PMID:Pregnancy is associated with suppression of the nuclear factor kappaB/IkappaB activation pathway in peripheral blood mononuclear cells. 1260 23

Macrophage inflammatory protein-2 (MIP-2) is a mouse C-X-C chemokine that plays an important role in the recruitment of neutrophils. The unregulated production of MIP-2 has been associated with inflammatory diseases such as arthritis, glomerulonephritis, and sepsis. We have shown that the MIP-2 gene expression is transcriptionally activated by synthetic oligodeoxynucleotide (ODN) containing unmethylated CpG dinucleotides in the context of particular base sequences (CpG-ODN) in a CpG sequence-dependent manner. Inhibition of NF-kappaB nuclear localization by coexpression of a mutant IkappaBalpha protein blocked CpG-ODN-induced transcription from a MIP-2 promoter-reporter construct, showing that NF-kappaB activation is required for MIP-2 gene expression in the CpG-ODN-signaling pathway. We also provided evidence that NF-kappaB and c-Jun contributes to the expression of MIP-2 gene in response to CpG-ODN, since ectopical expression of NF-kappaB and c-Jun in RAW 246.7 cells leads to dramatically increase the ability of CpG-ODN 1826(S) in MIP-2 promoter activity. These results perhaps give more insights into understanding of the mechanisms involved in transient inflammatory arthritis induction by CpG-ODN treatment.
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PMID:Regulation of macrophage inflammatory protein-2 gene expression in response to oligodeoxynucleotide containing CpG motifs in RAW 264.7 cells. 1291 94

Tissue factor (TF) is an important regulator and effector molecule of coagulation in various inflammatory states. In sepsis, expression of TF by activated endothelial cells leads to disseminated intravascular coagulation. Scoparone is extracted from the traditional Chinese herb ARTEMISIA SCOPARIA and is known to have potent anti-inflammatory properties. In the current studies, we examined the effects of scoparone on inhibiting lipopolysaccharide (LPS)-induced TF expression in cultured human umbilical vein endothelial cells (HUVECs). Flow-cytometric analysis revealed LPS (10 micro g/ml)-activated surface TF induction was concentration-dependently inhibited by scoparone (10-400 micro M). The concentrations of scoparone used in this study did not affect cell viability. The elevation of the procoagulant activity of TF by LPS was suppressed by scoparone. The LPS-induced superoxide formation was markedly decreased by scoparone. Messenger RNA expression of TF in LPS-activated HUVECs was also reduced by scoparone. Furthermore, scoparone did not significantly affect the IkappaBalpha degradation. Our results demonstrate that the inhibition of scoparone on LPS-induced TF expression in HUVECs may mediate by the mechanisms suppressing superoxide anion formation and TF transcription.
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PMID:Scoparone inhibits tissue factor expression in lipopolysaccharide-activated human umbilical vein endothelial cells. 1292 92

In sepsis, there is evidence that excessive C5a generation leads to compromised innate immune functions, being associated with poor outcome. We now report that in vitro exposure of neutrophils to C5a causes increased levels of IkappaBalpha, decreased NF-kappaB-dependent gene transcription of TNFalpha, and decreased lipopolysaccharide (LPS)-induced TNFalpha production. Similar findings were obtained with neutrophils from cecal ligation/puncture (CLP)-induced septic rats. Such changes were reversed by antibody-induced in vivo blockade of C5a. In contrast, in vitro exposure of alveolar macrophages to C5a and LPS resulted in enhanced production of TNFalpha and no increase in IkappaBalpha. These data suggest that CLP-induced sepsis causes a C5a-dependent dysfunction of neutrophils, which is characterized by altered signaling associated with NF-kappaB activation.
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PMID:Regulation by C5a of neutrophil activation during sepsis. 1293 53

While moderate hypothermia is protective against ischemic cardiac and brain injury, it is associated with much higher mortality in patients with sepsis. We previously showed that in vitro exposure to moderate hypothermia (32 degrees C) delays the induction and prolongs the duration of TNF-alpha and IL-1beta secretion by lipopolysaccharide (LPS)-stimulated human mononuclear phagocytes. In the present study, we extended these observations by showing that moderate hypothermia exerts effects on TNF-alpha and IL-1beta generation in the human THP-1 monocyte cell line that are similar to those that we previously found in primary cultured monocytes; that hypothermia causes comparable changes in cytokine generation stimulated by zymosan, toxic shock syndrome toxin-1, and LPS; and that hypothermia causes similar changes in TNF-alpha and IL-1beta mRNA accumulation. TNF-alpha mRNA half-life, determined after transcriptional arrest with actinomycin D, was not significantly prolonged by lowering incubation temperature from 37 to 32 degrees C, suggesting that hypothermia modifies TNF-alpha gene transcription. This finding was further supported by reporter gene studies showing a threefold increase in activity of the human TNF-alpha promoter at 32 vs. 37 degrees C. Electrophoretic mobility shift assay revealed that hypothermia prolonged NF-kappaBeta activation, identifying a potential role for this transcription factor in mediating the effects of hypothermia on TNF-alpha and IL-1beta production. Delayed reexpression of the inhibitor IkappaBalpha, shown by Northern blotting and immunoblotting, may account in part for the prolonged NF-kappaBeta activation at 32 degrees C. Augmentation of NF-kappaBeta-dependent gene expression during prolonged exposure to hypothermia may be a common mechanism leading to increased lethality in sepsis, late-onset systemic inflammatory response syndrome after accidental hypothermia, and neuroprotection after ischemia.
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PMID:Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. 1507 Aug 15

Toll-like receptor 4 (TLR4) has become a new target for combating Gram-negative bacterium-induced sepsis. In this study, we screened peptides that can interact with TLR4 from a random 16-peptide library using yeast two-hybrid system and performed functional identification for the obtained peptides. We got two positive clones out of 1.28x10(7) transformants. The peptides were sequenced and synthesized. Protein sequence comparison confirmed that the two peptides had no homologous proteins. The two peptides were found to significantly inhibit LPS-induced NF-kappaB activation in HEK-293 cells that were transfected with TLR4 cDNA, LPS-induced IkappaBalpha (IkappaB alpha) phosphorylation and NF-kappaB activation in monocytes, and release of IL-1, IL-6, and TNF-alpha by monocytes. We further confirmed that the No. 9 peptide could bind to TLR4 extracellular domain, but the No. 24 peptide could not, suggesting that two novel peptides were identified as the antagonists of TLR4, which significantly inhibited the effects of endotoxin in vitro. The No. 9 peptide may function through binding to TLR4 extracellular domain. Our findings suggest a promising countermeasure against Gram-negative bacterium-induced sepsis.
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PMID:Novel TLR4-antagonizing peptides inhibit LPS-induced release of inflammatory mediators by monocytes. 1575 33

Macrophage prostaglandin E2 (PGE2) production is important in cellular immune suppression and in affecting the potential development of sepsis after trauma. We hypothesized that macrophage PGE2 production after trauma is regulated by mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB). Mice were subjected to trauma and splenic macrophages isolated 7 days later. Macrophages from traumatized mice showed increased cyclooxygenase-2 (COX-2) mRNA, protein expression, and PGE2 production compared with controls. Increased phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 kinase was observed in macrophages from traumatized mice. Pharmacologic inhibition of MAPK blocked trauma-induced COX-2 expression, and PGE2 production. Trauma macrophages showed increased IkappaBalpha phosphorylation and NF-kappaB binding to DNA. Inhibiting IkappaBalpha blocked trauma-induced NF-kappaB activity, COX-2 expression and PGE2 production. This suggests that trauma-induced PGE2 production is mediated through MAPK and NF-kappaB activation and offers potential for modifying the macrophages' responses following injury.
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PMID:Enhanced expression of cyclooxygenase-2 and prostaglandin E2 in response to endotoxin after trauma is dependent on MAPK and NF-kappaB mechanisms. 1589 Mar 24

Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1beta, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and IkappaBalpha expression in the IkappaB kinase-NF-kappaB pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.
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PMID:Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades. 1610 45

Liver plays an important role in the pathogenesis of sepsis by releasing various cytokines and producing acute phase proteins. Heat shock preconditioning is reported to be effective in protection of lung and liver from injury in sepsis and in endotoxemia models, but the exact mechanism is still not fully understood. We report here on the effects of the heat shock response (HSR) induced by sodium arsenite on endotoxemia-induced liver injury as well as hepatic NF-kappaB activation and proinflammatory cytokine expression. Prior induction of HSR significantly attenuated endotoxemia-induced histological changes, inhibited hepatic NF-kappaB activation and IkappaBalpha degradation and decreased mortality. Expression of mRNA coding for TNF-alpha and IL-6 in liver was significantly lower in arsenite-pretreated animals. We conclude that attenuation of endotoxin-induced hepatic NF-kappaB activation and subsequent proinflammatory cytokine production may be one of the mechanisms of the beneficial effect of the heat shock response.
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PMID:Induction of the heat shock response in vivo inhibits NF-kappaB activity and protects murine liver from endotoxemia-induced injury. 1616 Sep 14

The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IkappaBalpha. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-kappaB signaling by selectively removing K63-linked polyubiquitin chains that activate IkappaB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IkappaBalpha. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ.
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PMID:Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation. 1630 42


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