Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ehrlichia chaffeensis, an obligately intracellular bacterium, resides within a cytoplasmic vacuole in macrophages, establishes persistent infection in natural hosts such as white-tailed deer and canids, and is transmitted transstadially and during feeding by ticks, particularly Amblyomma americanum. Ehrlichial cell walls contain glycoproteins and a family of divergent 28 kDa proteins, but no peptidoglycan or lipopolysaccharide. The dense-cored ultrastructural form preferentially expresses certain glycoproteins, including a multiple repeat unit-containing adhesin. Ehrlichiae attach to L-selectin and E-selectin, inhibit phagolysosomal fusion, apoptosis, and JAK/STAT activation, and downregulate IL-12, IL-15, IL-18, TLR2 and 3, and CD14. Mouse models implicate overproduction of TNF-alpha by antigen-specific CD8 T lymphocytes in pathogenesis and strong type 1 CD4 and CD8 T lymphocyte responses, synergistic activities of IFN-gamma and TNF-alpha, and IgG2a antibodies in immunity. Human monocytotropic ehrlichiosis (HME) manifests as a flu-like illness that progresses in severity to resemble toxic shock-like syndrome, with meningoencephalitis or adult respiratory distress syndrome in some patients, and requires hospitalization in half. In immunocompromised patients, HME acts as an overwhelming opportunistic infection. In one family physician's practice, active surveillance for three years revealed an incidence of 1000 cases per million population. Diagnosis employs serology or polymerase chain reaction, which are not utilized sufficiently to establish the true impact of this emerging virus-like illness.
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PMID:Ehrlichia under our noses and no one notices. 1635 25

Interleukin (IL)-18 is considered to induce exclusively the Th1 immune response but not the Th2 response in the presence of adequate IL-12 stimulation in bacterial infections. However, we demonstrate herein that multiple IL-18 injections to the mice not only enhance the early Th1 response but also stimulate the Th2 response later after viable Escherichia coli infection. Multiple IL-18 injections (three alternate-day injections) raised the serum interferon (IFN)-gamma level at 6 h and serum Th2 cytokine levels, such as IL-4, IL-10 and IL-13, at 48 h after infection, while a single IL-18 injection increased only the serum IFN-gamma level. Depletion of mouse CD4+ cells suppressed the IL-18-induced Th2 cytokines, IL-4, IL-10 and IL-13. In contrast, depletion of natural killer (NK)1.1+ cells reduced the IFN-gamma and IL-13 levels. Moreover, multiple IL-18 injections up-regulated the serum IgM level at 72 h after infection while a single IL-18 injection did not. Interestingly, neutralization of IL-4 but not IFN-gamma partially suppressed the increased serum IgM. Liver mononuclear cells (MNCs) from the mice treated with multiple IL-18 injections significantly increased more production of not only IFN-gamma but also Th2 cytokines and IgM by in vitro lipopolysaccharide (LPS) stimulation than those from the phosphate-buffered saline (PBS)-treated mice, while liver MNCs from the single IL-18-injected mice also increased IFN-gamma production but significantly suppressed IL-4 and IgM production compared to those from the PBS-treated mice. Our findings suggest that multiple injections of IL-18 up-regulate both the cellular and humoral innate immunities, thereby enhancing host defence against bacterial infections.
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PMID:Multiple interleukin-18 injections promote both mouse Th1 and Th2 responses after sublethal Escherichia coli infection. 1636 32

Innate immunity assures the first line of defense against pathogenic microorganisms. Innate immune responses induced by bacteria, fungi, or viral replication are triggered by granulocytes, monocytes, macrophages, dentritic cells, and natural killer cells. Neonatal deficiency of innate cellular immunity includes a decreased production of interferons, IL-12/IL-23, and IL-18, and other proinflammatory cytokines, an impaired type-1 response of macrophages to IFN-gamma, the most potent macrophage-activating agent in vivo, and to lipopolysaccharide, the primary constituent of the outer membrane of Gram-negative bacteria. An increasing body of evidence suggests impaired responses of neonatal monocytes and macrophages to multiple TLR ligands. This review will discuss recent advances in understanding innate cellular immunity in human neonates, with respect to selected aspects of immune functions that may be related to increased susceptibility to infections. Components of TLR signaling and the immune consequence that may result from neonatal deficiencies will be highlighted. A better understanding of innate immunity can make the development of techniques possible by which physicians more accurately tailor prevention and treatment of neonatal infections.
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PMID:Innate cellular immune responses in newborns. 1637 52

Proinflammatory cytokines, such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha), are suggested to have an important role in the process of atherosclerosis. Patients with heterozygous familial hypercholesterolemia (FH) have a marked elevation in the plasma level of low-density lipoproteins (LDL), and they show early development of atherosclerosis. The aim of the present study was to test with a whole blood culture system if hyperlipoproteinemia is associated with increased cytokine production capacity in these patients and if treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors influences this production capacity of blood cells, at both the protein and mRNA levels. The capacity of blood cells in a whole blood culture to produce IL-1beta, IL-6, TNF-alpha, IL-12, IL-18, and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS) appeared to be similar for heterozygous FH patients and healthy volunteers. Furthermore, the capacity to produce IL-1beta, IL-6, and TNF-alpha in response to LPS was not modified by cholesterol synthesis inhibitors at the level of mRNA expression or at the level of release. On the other hand, the release of IL-1Ra was significantly increased after treatment with HMG-CoA reductase inhibitors, although only at the protein level. This suggests a possible beneficial anti-inflammatory role for this therapy.
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PMID:LPS-induced release of IL-1 beta, IL-1Ra, IL-6, and TNF-alpha in whole blood from patients with familial hypercholesterolemia: no effect of cholesterol-lowering treatment. 1648 30

Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1alpha, IL-1beta, and IL-18. IL-1beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway.
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PMID:Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. 1654 91

We studied inhibition of histone deacetylases (HDACs), which results in the unraveling of chromatin, facilitating increased gene expression. ITF2357, an orally active, synthetic inhibitor of HDACs, was evaluated as an anti-inflammatory agent. In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduced by 50% the release of tumor necrosis factor-alpha (TNFalpha) at 10 to 22 nM, the release of intracellular interleukin (IL)-1alpha at 12 nM, the secretion of IL-1beta at 12.5 to 25 nM, and the production of interferon-gamma (IFNgamma) at 25 nM. There was no reduction in IL-8 in these same cultures. Using the combination of IL-12 plus IL-18, IFNgamma and IL-6 production was reduced by 50% at 12.5 to 25 nM, independent of decreased IL-1 or TNFalpha. There was no evidence of cell death in LPS-stimulated PBMCs at 100 nM ITF2357, using assays for DNA degradation, annexin V, and caspase-3/7. By Northern blotting of PBMCs, there was a 50% to 90% reduction in LPS-induced steady-state levels of TNFalpha and IFNgamma mRNA but no effect on IL-1beta or IL-8 levels. Real-time PCR confirmed the reduction in TNFalpha RNA by ITF2357. Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNFalpha and IFNgamma by more than 50%. Anti-CD3-induced cytokines were not suppressed by ITF2357 in PBMCs either in vitro or in the circulation in mice. In concanavalin-A-induced hepatitis, 1 or 5 mg/kg of oral ITF2357 significantly reduced liver damage. Thus, low, nonapoptotic concentrations of the HDAC inhibitor ITF2357 reduce pro-inflammatory cytokine production in primary cells in vitro and exhibit anti-inflammatory effects in vivo.
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PMID:The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. 1655 34

Preterm birth is a major contributor of adverse perinatal outcome. Clinical data suggest that an inflammatory response is important in the process leading to preterm labor. By using a recently introduced mouse model of localized intrauterine lipopolysaccharide-induced inflammation, the effect of interleukin (IL)-18 gene disruption and/or IL-18 neutralization as well as combined IL-1alpha/beta gene disruption on inflammation-induced fetal loss was investigated. The frequency of preterm fetal loss was significantly higher in IL-18 knockout mice (58.9%) and in mice administered IL-18-binding protein (59.7%) compared to wild-type controls (34.7%). The rate of fetal loss was not affected by IL-1alpha/beta gene deficiency (38.7%). Decreased IL-18 protein expression combined with elevated IL-12 protein expression in uterine tissue of IL-18 knockout mice and IL-18-binding protein-treated animals was noticed. These data demonstrate that preterm pregnancy loss in response to intrauterine inflammation was enhanced by disruption of the IL-18 gene and/or IL-18 neutralization, events that may relate to exaggerated Th1 responses because of an increased IL-12/IL-18 ratio.
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PMID:Disruption of interleukin-18, but not interleukin-1, increases vulnerability to preterm delivery and fetal mortality after intrauterine inflammation. 1693 70

Bone marrow (BM) cells fractioned in Percoll gradients yield a low-density fraction (Fr3) highly enriched in suppressor activity. Previously, it has been demonstrated that BM associated suppressor activity was mediated by early myeloid cells, through a mechanism dependent on endogenous IFNgamma and nitric oxide production after bacterial stimuli, e.g. lipopolysaccharide (LPS). However, the mechanism(s) through which the IFNgamma is produced in BM has not yet been fully elucidated. Therefore, in the present study we investigated the involvement of IL-12, IL-18 and IFNbeta on the production of IFNgamma and nitric oxide in cultures of BM Fr3 cells, and characterized the IFNgamma-producing cells, in response to LPS. The results show that both IL-12 and IFNbeta, but not IL-18, are involved on IFNgamma production. However, only IFNbeta appears to be critical on nitric oxide production. Furthermore, we found that cells of the Thy1.2+CD3+ phenotype produce IFNgamma and are tightly involved on nitric oxide production by BM Fr3 cells. In conclusion, IFNbeta appears to be critical on IFNgamma- and nitric oxide production by BM cells in response to LPS, through a mechanism that is dependent on Thy1.2+CD3+ IFNgamma-producing cells.
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PMID:Involvement of IFNbeta on IFNgamma and nitric oxide (NO) production by bone marrow (BM) cells in response to lipopolysaccharide. 1697 28

Secretion of the proinflammatory cytokines, interleukin (IL)-1beta and IL-18, usually requires two signals. The first, due to microbial products such as lipopolysaccharide, initiates transcription of the cytokine genes and accumulation of the precursor proteins. Cleavage and secretion of the cytokines is mediated by caspase-1, in association with an inflammasome containing Nalp3, which can be activated by binding of extracellular ATP to purinergic receptors. We show that treatment of macrophages with ATP results in production of reactive oxygen species (ROS), which stimulate the phosphatidylinositol 3-kinase (PI3K) pathway and subsequent Akt and ERK1/2 activation. ROS exerts its effect through glutathionylation of PTEN (phosphatase and tensin homologue deleted from chromosome 10), whose inactivation would shift the equilibrium in favor of PI3K. ATP-dependent ROS production and PI3K activation also stimulate transcription of genes required for an oxidative stress response. In parallel, ATP-mediated ROS-dependent PI3K is required for activation of caspase-1 and secretion of IL-1beta and IL-18. Thus, an increase in ROS levels in ATP-treated macrophages results in activation of a single pathway that promotes both adaptation to subsequent exposure to oxidants or inflammation, and processing and secretion of proinflammatory cytokines.
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PMID:ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. 1713 26

Pentoxifylline (PTX) is a drug used for the treatment of vascular disorders, but it also has a positive therapeutic effect in experimental models of some autoimmune diseases. In this work, we studied the effect of PTX on human monocyte-derived dendritic cells (MDDCs). Immature MDDCs were generated in vitro from monocytes in the presence of recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and recombinant human interleukin-4 (rhIL-4), while mature MDDCs were obtained by cultivation of immature MDDCs with lipopolysaccharide (LPS). PTX (200 micro g/ml) was added at the beginning of cell cultivation. We found that PTX significantly impaired differentiation and function of immature MDDCs, as judged by the reduced allostimulatory activity of these cells on allogeneic T cells and down-regulation of costimulatory and adhesion molecules, such as CD86, CD40 and CD54. The maturation of MDDCs in the presence of PTX and LPS was characterized by the decreased expression of maturation marker CD83 and costimulatory molecule CD86, as well as lower stimulation of alloreactive T cells compared to the control MDDCs cultivated with LPS alone. PTX-treated MDDCs which were induced to mature with LPS produced lower levels of TNF-alpha, IL-12 and IL-18 and higher levels of IL-10 than corresponding control MDDCs. PTX did not significantly alter endocytosis of dextran by both immature and mature MDDCs. Cumulatively, our results show for the first time that PTX might impair differentiation, maturation and function of human MDDCs in vitro, suggesting an additional mechanism of its immunomodulatory activity.
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PMID:Effect of pentoxifylline on differentiation and maturation of human monocyte-derived dendritic cells in vitro. 1717 83


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