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)

Glucuronoxylomannan (GXM), the major component of the capsular polysaccharide of Cryptococcus neoformans, is essential to virulence of the yeast. Previous studies found that the interaction between GXM and phagocytic cells has biological consequences that may contribute to the pathogenesis of cryptococcosis. We found that GXM binds to and is taken up by murine peritoneal macrophages. Uptake is dose and time dependent. Examination of the sites of GXM accumulation by immunofluorescence microscopy showed that the pattern was discontinuous and punctate both on the surfaces of macrophages and at intracellular depots. Although resident macrophages showed appreciable accumulation of GXM, uptake was greatest with thioglycolate-elicited macrophages. A modest stimulation of GXM binding followed treatment of resident macrophages with phorbol 12-myristate 13-acetate, but treatment with lipopolysaccharide or gamma interferon alone or in combination had no effect. Accumulation of GXM was critically dependent on cytoskeleton function; a near complete blockade of accumulation followed treatment with inhibitors of actin. GXM accumulation by elicited macrophages was blocked by treatment with inhibitors of tyrosine kinase, protein kinase C, and phospholipase C, but not by inhibitors of phosphatidylinositol 3-kinase, suggesting a critical role for one or more signaling pathways in the macrophage response to GXM. Taken together, the results demonstrate that it is possible to experimentally enhance or suppress binding of GXM to macrophages, raising the possibility for regulation of the interaction between this essential virulence factor and binding sites on cells that are central to host resistance.
 ...
PMID:Binding and internalization of glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, by murine peritoneal macrophages. 1636 67

Dendritic cells (DCs) are critical antigen presentation cells whose influence on murine immune responses to polysaccharide antigens has only recently been elucidated. Little is known about human DC-polysaccharide interactions. We set out to study the interaction between human monocyte-derived DCs and pneumococcal capsular polysaccharides (PPS) in vitro. Immature DCs were generated from peripheral blood monocytes and incubated with fluorescein isothiocyanate-labeled PPS type 9N or 14 for assessment of uptake. DCs were exposed to PPS type 1, 6B, 9N, 14, 19F, or 23F in the absence or presence of Escherichia coli lipopolysaccharide (LPS) for assessment of phenotypic DC maturation and cytokine production. PPS were taken up by immature DCs and proceeded to HLA-DR+ and lysosome-associated membrane protein-1+ late endosomal compartments. Uptake was reduced in the presence of cytochalasin D and wortmannin, suggesting that both cytoskeletal rearrangements and phosphatidylinositol 3-kinase activation may be required for internalization. None of the PPS tested induced DC phenotype changes, maturation, or interleukin-12 (IL-12)/IL-10 production. However, PPS were capable of modulating the response of the DCs to a second signal such as LPS. Exposure of DCs to PPS in the presence of LPS resulted in an altered cytokine balance with significantly increased IL-10 production and reduced IL-12 production compared to LPS alone. This effect was not seen using the control antigen tetanus toxoid. DC-pneumococcus interaction may affect subsequent immune responses to pneumococci, as an altered cytokine balance may have a profound effect on DC-driven T-cell priming.
 ...
PMID:Pneumococcal polysaccharides interact with human dendritic cells. 1649 64

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays crucial roles in inflammation and immunity. Understanding the positive and negative regulation of NF-kappaB activity is therefore of fundamental importance. A few previous studies reported that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway enhances lipopolysaccharide (LPS)-induced activation of NF-kappaB. However, many aspects of the PI3K negative regulation of NF-kappaB activation remain to be clarified. The present study was conducted to shed light on cell-type specificity, stimulus specificity, and upstream mechanisms of the enhanced NF-kappaB activation by PI3K inhibitors. Gel shift assays showed that LY294002 (LY29) potently increased interleukin (IL)-1-induced NF-kappaB DNA binding in human monocytic THP-1 cells. Moreover, another PI3K inhibitor 3-methyladenine also strongly enhanced IL-1-induced NF-kappaB DNA binding, while LY303511, an inactive analogue of LY29, did not increase the NF-kappaB DNA binding. Compared with LY29, wortmannin (WM) effected only a marginal enhancement of NF-kappaB DNA binding. LY29 treatment also augmented tumor necrosis factor (TNF)-mediated NF-kappaB DNA binding. Furthermore, LY29, but not WM, increased cyclooxygenase (COX)-2 mRNA expression by IL-1 or TNF in THP-1 cells. Likewise, prostaglandin E2 production by IL-1 was increased by LY29, but not by WM. Western blot analysis demonstrated that IkappaB kinase (IKK) activation as well as IkappaB-alpha degradation and NF-kappaB nuclear translocation was elevated by LY29 and WM. Among the tested cell lines (HL-60, ECV304, Hep-2, and Molt-4), only HL-60, a promyelocytic cell line, showed enhanced NF-kappaB DNA binding by LY29. These results suggest that pharmacological inhibition of PI3K enhances the NF-kappaB-activating pathways by IL-1 through augmentation of IKK activation in myeloid/monocytic cells and the NF-kappaB enhancement is more robustly achieved by LY29 than by WM.
 ...
PMID:Enhancement of cytokine-mediated NF-kappaB activation by phosphatidylinositol 3-kinase inhibitors in monocytic cells. 1664 76

The synthesis of nitric oxide by inducible nitric-oxide synthase (iNOS) plays an important role in the innate immune response by promoting microbial killing and cell damage. In response to inflammatory cytokines and bacterial products, the human iNOS (hiNOS) gene undergoes rapid transcriptional activation via binding of stimulatory transcription factors (e.g. AP-1 and NF-kappaB) to its 5'-flanking region. However, maximal hiNOS promoter induction was suppressed via an unknown phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. We hypothesized that inhibition of the transcription factor FKHRL1 by the PI3K/protein kinase B pathway attenuates hiNOS promoter induction by bacterial lipopolysaccharide and interferon-gamma (LPS/IFN-gamma). Human lung epithelial adenocarcinoma (A549) cells were transiently transfected with an 8.3-kb hiNOS promoter luciferase reporter construct. Co-expression of dominant-negative protein kinase B potentiated LPS/IFN-gamma-stimulated hiNOS promoter activity. In response to LPS/IFN-gamma, FKHRL1 was phosphorylated in a PI3K- and time-dependent fashion. Co-expression of constitutively active FKHRL1 increased hiNOS promoter activity and mRNA levels. Dominant-negative siRNA expression showed that FKHRL1 was necessary for the inhibitory effects of PI3K on hiNOS induction. The same effect was observed upon mutation of a consensus FKHRL1-binding site in the hiNOS promoter. By gel-shift analysis, the corresponding oligonucleotide probe bound endogenous FKHRL1 in an LPS/IFN-gamma- and PI3K-sensitive fashion. Regulation of the hiNOS promoter by FKHRL1 represents a potentially important molecular mechanism by which the PI3K pathway might suppress pro-inflammatory and proapoptotic responses to cytokines and bacterial products.
 ...
PMID:Phosphatidylinositol 3-kinase-dependent suppression of the human inducible nitric-oxide synthase promoter is mediated by FKHRL1. 1668 94

Antipsychotic drugs are widely used to alleviate a number of psychic disorders and have been found to modulate some immune parameters, but the molecular mechanism of their action on the proliferative activity has been poorly recognized. In the present study, we investigated effects of various antipsychotics on the proliferative activity of lymphocytes stimulated by concanavalin A (Con A) and lipopolysaccharide (LPS). Chlorpromazine (3 x 10(-6)-10(-4) M) showed the most potent effect in inhibiting 3H-thymidine incorporation into C57BL/6 mouse spleen cells stimulated by Con A and LPS. Treatment of the cells with thioridazine (10(-5)-10(-4) M), promazine (10(-5)-10(-4) M), haloperidol (10(-5)-10(-4) M), risperidone (10(-5)-10(-4) M), raclopride (3 x 10(-5) - 10(-4) M), remoxipride (3 x 10(-5)-10(-4) M) and clozapine ( 3 x 10(-5)-10(-4) M), but not with sulpiride (10(-7)-10(-4) M), suppressed proliferative activity of splenocytes after Con A stimulation. On the other hand, LPS-induced proliferation of splenocytes was inhibited by clozapine, promazine, thioridazine and haloperidol, but not by risperidone, remoxipride, sulpiride and raclopride. In the next part of the study, the influence of some kinase modulators on chlorpromazine- and clozapine-evoked inhibition of the proliferative activity of splenocytes was determined. Wortmannin, a selective phosphatidylinositol 3-kinase (PI3-K) inhibitor, blocked chlorpromazine and clozapine inhibitory effect on the mitogen-stimulated splenocyte proliferation. The involvement of PI 3-K /protein kinase B (PKB, Akt) pathway was confirmed by the results of the Western blot study, which showed that both drugs increased the level of active phospho-Ser-473 Akt, without changing the total Akt level, and decreased the level of active, nonphosphorylated glycogen synthase kinase-3 (GSK-3beta). Additionally, we have found that chlorpromazine action was also attenuated by a selective p-38-MAPK inhibitor, while clozapine effect was suppressed by a protein kinase C (PKC) activator. The obtained results indicated that atypical antipsychotic drugs markedly inhibited the proliferative activity of splenocytes only after ConA stimulation. Inhibition of the proliferative capability of splenocytes by chlorpromazine and clozapine resulted mainly from the activation of PI3-K/Akt pathway.
 ...
PMID:Inhibitory effect of antipsychotic drugs on the Con A- and LPS-induced proliferative activity of mouse splenocytes: a possible mechanism of action. 1684 29

Endothelial dysfunction plays a crucial role in the pathophysiology of sepsis. Alterations in endothelial nitric-oxide synthase (eNOS) may contribute to the impaired endothelial function. We investigated whether the regulatory mechanism for eNOS phosphorylation and activation is altered in a rabbit lipopolysaccharide-induced septic model. Following induction of sepsis, a time-dependent marked reduction in eNOS phosphorylation was observed in mesenteric arteries, with a significant decrease in eNOS expression. Likewise, Akt phosphorylation was progressively and profoundly reduced, although total Akt remained unchanged. Furthermore, the amounts of the two subunits of phosphatidylinositol 3-kinase (PI3-K) in the membranous pool were diminished without changes in the total amount of the PI3-K heterodimer, indicating a decrease in translocation to the membranes. In vivo treatment with fluvastatin restored the decrease in eNOS phosphorylation in septic mesenteric vessels. This was possibly the result of the recovery of Akt phosphorylation. Treatment with the PI3-K inhibitor wortmannin partially inhibited the fluvastatin-induced increases in phosphorylation of Akt and eNOS, and the decrease in translocation of PI3-K heterodimer to the membranes during sepsis was slightly improved by fluvastatin. Sepsis-induced impairment of eNOS expression was also nearly normalized by fluvastatin. It is noteworthy that rabbits treated with fluvastatin exhibited a dramatic improvement in sepsis survival. The present results showed vascular abnormalities of the PI3-K/Akt pathway involved in the impairment of eNOS phosphorylation and activation in sepsis. We also suggest that fluvastatin would ameliorate vascular endothelial dysfunction, in part, presumably via its recovery effect on Akt-dependent eNOS phosphorylation. It may be potentially useful for therapy of sepsis.
 ...
PMID:Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway: reversal effect of fluvastatin therapy. 1700 32

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.
 ...
PMID:ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. 1713 26

In this study, we cloned the cDNAs encoding porcine RP105 (poRP105) and porcine MD-1 (poMD-1) from Peyer's patches of adult swine. The complete open reading frames of poRP105 and poMD-1 contain 1986 and 480bp and encode 661 and 159 amino acid residues, respectively. These two proteins were more similar to the human (77.6% and 76.5% amino acid identity) than the mouse counterparts (70.0% and 71.1% amino acid identity). The results of several experiments in cells cotransfected with poRP105 and poMD-1 indicated both lipopolysaccharide and extracellular phosphopolysaccharide from Lactococcus lactis subsp. cremoris (Lc.cremoris) strongly activate nuclear factor-kappaB and induce the expression of various cytokines via RP105. These effects were mediated by phosphatidylinositol 3-kinase and Bruton's tyrosine kinase. Thus, we identified extracellular polysaccharide from Lc.cremoris as an active substance that can induce immune activation via RP105 and MD-1.
 ...
PMID:Molecular cloning of porcine RP105/MD-1 involved in recognition of extracellular phosphopolysaccharides from Lactococcus lactis ssp. cremoris. 1725 34

In the present study, we report the inhibitory effect of equol on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) gene expression in murine macrophages. In vivo administration of equol (i.p.) attenuated NO production by peritoneal adherent cells isolated from lipopolysaccharide (LPS)-treated mice. Equol dose-dependently inhibited the LPS-induced production of NO in isolated peritoneal adherent cells and RAW 264.7 cells. The mRNA expression of iNOS was also blocked by equol in LPS-stimulated RAW 264.7 cells. Further study demonstrated that the LPS-induced activation of Akt was suppressed by equol in RAW 264.7 cells while the activation of ERK, SAPK/JNK and p38 MAP kinase was not affected. Equol also blocked LPS-induced NF-kappaB activation. Moreover, the LPS-induced NO production and NF-kappaB activation was inhibited by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase/Akt pathway, in RAW 264.7 cells. These results suggest that equol might inhibit NO production and iNOS gene expression, at least in part, by blocking Akt activation and subsequent down-regulation of NF-kappaB activity.
 ...
PMID:Equol inhibits nitric oxide production and inducible nitric oxide synthase gene expression through down-regulating the activation of Akt. 1732 72

Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the zeta isoform of the DGK family (DGKzeta) is expressed in macrophages (Mphi) and dendritic cells. DGKzeta deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor alpha production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKzeta negatively controls the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKzeta-deficient Mphi. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKzeta promotes TLR responses via a pathway involving inhibition of PI3K.
 ...
PMID:Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii. 1737 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>