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)

Previous studies showed that activation of CD4+ T cells with mouse mammary tumor virus-encoded Mls(a) superantigens induces strong proliferative responses and interleukin-2 production but fails to elicit typical early T cell receptor (TCR)-mediated signal transduction events, such as hydrolysis of polyphosphoinositides (PI) or an increase in intracellular calcium. Here we show that the failure of Mls(a) antigen to activate PI hydrolysis applies when resting B cells are used as antigen-presenting cells (APC). By contrast, when Mls(a)-bearing B cells are activated for 24 h by exposure to lipopolysaccharide or, more importantly, to Mls(a)-reactive T cells or anti-CD40 antibodies the cells develop the capacity to elicit easily detectable PI turnover. These studies demonstrate that, for B cells as APC, the initiation of certain TCR-associated signal transduction pathways can depend on activation of the APC. The data suggest that cross talk between T cells and resting B cells can suffice to generate competent B APC and lead to the delayed initiation of signaling pathways important in T cell responses.
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PMID:Cross talk between T and B cells generates B antigen-presenting cells able to induce inositol phosphate production in T cells responding to Mls(a) superantigens. 946 13

L-carnitine is an essential nutrient with a major role in cellular energy production. There is evidence that, at high doses, L-carnitine might mimic some of the biological activities of glucocorticoids, especially immunomodulation. To explore the molecular basis of this effect, we tested the influence of L-carnitine on glucocorticoid receptor-alpha (GRalpha) functions. Millimolar concentrations of L-carnitine, which were not cytotoxic in vitro, significantly reduced the whole cell binding of [3H]dexamethasone to GRalpha by decreasing the affinity of this receptor for its steroid ligand. At the same concentrations, L-carnitine was able to trigger nuclear translocation of green fluorescent protein (GFP)-fused human GRalpha and transactivate the glucocorticoid-responsive mouse mammary tumor virus (MMTV) and TAT3 promoters in a dose-dependent fashion. This effect was solely dependent on the presence of glucocorticoid-responsive elements on the promoter and on the expression of functional GRalpha by the cell. Finally, similarly to glucocorticoids, L-carnitine suppressed tumor necrosis factor-alpha (TNFalpha) and interleukin-12 release by human primary monocytes stimulated with lipopolysaccharide ex vivo. Both GRalpha transactivation and cytokine suppression by L-carnitine were abrogated by the GRalpha-antagonist RU 486. Taken together, our results suggest that pharmacological doses of L-carnitine can activate GRalpha and, through this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.
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PMID:L-carnitine: A nutritional modulator of glucocorticoid receptor functions. 1282 92

Previously, we have found that some antipsychotic drugs are able to inhibit glucocorticoid receptor (GR)-mediated gene transcription. Since these drugs are known not only to inhibit hypothalamic-pituitary-adrenal (HPA) axis activity, but also to modulate the immunological system, the aim of the present study was to compare the effect of sulpiride and clozapine on GR function under basal culture conditions and during activation by lipopolysaccharide (LPS). The effect of clozapine and sulpiride alone and with LPS, the immune system activator, on glucocorticoid-mediated gene transcription was investigated in fibroblast cells, stably transfected with a mouse mammary tumor virus--chloramphenicol acetyltransferase plasmid (LMCAT cells). Treatment of the cells with clozapine (3-10 microM) for 2 days significantly and in concentration-dependent manner decreased the chloramphenicol acetyltransferase (CAT) activity, while sulpiride (1, 3, 5 and 10 microM) was without any effect. LPS (1 microg/ml) given alone inhibited the corticosterone-induced gene transcription by ca. 35%. Clozapine (3, 5 and 10 microM) inhibited the effect of LPS (1 microM), while sulpiride, which alone had no effect on GR function, enhanced LPS (1 microM) action. The obtained results indicate that inhibition of GR-mediated gene transcription by LPS and clozapine can be a mechanism by which these compounds blocked some effects induced by glucocorticoids. Opposite effect of clozapine and sulpiride on LPS action may result from their distinct effect on activity of some kinases involved in regulation of GR transcriptional function and may determine their utility in the treatment of schizophrenia with or without immune system activation.
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PMID:Opposite effects of clozapine and sulpiride on the lipopolysaccharide-induced inhibition of the GR-mediated gene transcription in fibroblast cells. 1473 Jan 15

It has been hypothesized that dysregulations of the immune system and glucocorticoid receptor (GR) function are involved in the pathogenesis of schizophrenic disorders. Previously, we found that among antipsychotics, chlorpromazine most potently inhibited GR function under in vitro conditions. In order to study a role of the some immune system mediators in this process, we investigated the effect of lipopolysaccharide (LPS) on chlorpromazine-induced changes in GR-mediated gene transcription in fibroblast cells, stably transfected with mouse mammary tumor virus promoter (LMCAT cells). Two days of incubation of the cells with LPS (1 and 5 microg/ml) and chlorpromazine (3-30 microM) inhibited the corticosterone-induced gene transcription in a concentration-dependent manner. Concomitant incubation of the cells with LPS (1 microg/ml) and chlorpromazine had stronger inhibitory effect than that evoked by each compound alone. The effect of LPS, but not that of chlorpromazine, on GR function was dependent on p38 mitogen-activated protein kinase (MAPK). Moreover, LPS-stimulated proliferative activity was also p38-MAP kinase dependent, but this effect was suppressed by chlorpromazine.
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PMID:Effects of lipopolysaccharide and chlorpromazine on glucocorticoid receptor-mediated gene transcription and immunoreactivity: a possible involvement of p38-MAP kinase. 1558 93

It has been hypothesized that pro-inflammatory response and hyperactivity of hypothalamic-pituitary-adrenocortical axis (HPA) are involved in the pathogenesis of depression. Hyperactivity of HPA axis results probably from deregulation of glucocorticoid receptor function and impairment of the control mechanism of glucocorticoid secretion. Previously, we found that antidepressants inhibited glucocorticoid receptor (GR) function under the in vitro condition. In order to study a role of some mediators of pro-inflammatory response in this process, presently, we investigated the effect of lipopolysaccharide (LPS) on imipramine- or fluoxetine-induced inhibition of GR-mediated gene transcription in fibroblast cells, stably transfected with mouse mammary tumor virus promoter (LMCAT cells). Two days of incubation of the cells with imipramine (3-10 microM), fluoxetine (10 microM) or LPS (1 microg/ml) inhibited the corticosterone-induced gene transcription. Concomitant incubation of the cells with LPS and fluoxetine or imipramine had stronger inhibitory effect than that evoked by each compound alone. Moreover, we found that fluoxetine (10 microM) but not imipramine (3-10 microM) significantly inhibited the LPS-stimulated interleukin-6 (IL-6) production in these cells. These data suggest that pro-inflammatory agents facilitate antidepressant-induced inhibition of glucocorticoid receptor function.
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PMID:Effect of lipopolysaccharide and antidepressant drugs on glucocorticoid receptor-mediated gene transcription. 1612 23

Interactions between malignant tumors and the host immune system shape the course of cancer progression. The molecular basis of such interactions is the subject of immense interest. Proinflammatory cytokines produced by macrophages are critical mediators of immune responses that contribute to the control of the advancement of neoplasia. We have shown that the expressions of interleukin 12 (IL-12) and inducible nitric oxide synthase (iNOS) are decreased in macrophages from mammary tumor-bearing mice. In this study, we investigated the causes of IL-12 dysregulation and found deficient nuclear factor kappaB (NFkappaB) and CCAAT/enhancer binding protein (C/EBP) expression and function in tumor bearers' peritoneal macrophages. The constitutive expressions of NFkappaB p50, c-rel, p65, and C/EBPalpha and beta, as well as the lipopolysaccharide-induced nuclear translocation and DNA binding of NFkappaB components and C/EBPalpha and beta, are profoundly impaired in macrophages from mice bearing D1-DMBA-3 tumors. Because similar findings occur with the iNOS gene, it seems that it represents a novel mechanism by which tumor-derived factors interfere with the host immune defenses.
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PMID:Diminished expression of transcription factors nuclear factor kappaB and CCAAT/enhancer binding protein underlies a novel tumor evasion mechanism affecting macrophages of mammary tumor-bearing mice. 1628 51

Nitric oxide (NO) is one of the main cytotoxic effector molecules involved in the killing of tumor cells by macrophages. In macrophages, lipopolysaccharide (LPS) alone or in combination with IFN-gamma causes the generation of NO by an inducible form of NO synthase (iNOS). We have previously reported that macrophages from mammary tumor bearers have a downregulation of their NO production leading to a diminished cytotoxic activity. Further studies lead to the isolation and characterization of phosphatidyl serine (PS) as a NO inhibitory factor produced by mammary tumor cells. Pretreatment of macrophages with PS was shown to downregulate their cytotoxic potential and NO production upon stimulation with LPS. Activation of PS-pretreated macrophages with LPS and IFN-gamma resulted in higher levels of NO than those observed with LPS alone, but lower than those of untreated macrophages activated with LPS and IFN-gamma. These results correlated with the levels of iNOS RNA as detected by Northern blot analyses. A study of the expression and binding activity of the transcription factor NF kappa B in macrophages pretreated with PS revealed no differences with untreated macrophages. Investigation of the possible signaling pathways leading to the induction of iNOS revealed that in LPS-stimulated macrophages, increases in internal calcium concentration [Ca2+]i were not observed, while NO was normally produced even under calcium-deprived conditions. In contrast, an effective synergism of IFN-gamma with LPS in the production of NO by macrophages required an optimal increase in [Ca2+]i stimulated by IFN-gamma. This increment in [Ca2+]i was significantly reduced in PS-pretreated macrophages. Further experiments demonstrated that pretreatment of macrophages with PS did not change the normal pattern of tyrosine phosphorylation stimulated by LPS but strikingly inhibited PKC activity. Combinations of LPS and IFN-gamma did not alter the latter result, suggesting that IFN-gamma enhances LPS-induction of iNOS through a pathway other than activation of PKC. Importantly, expression of PKC isozymes in both untreated and PS-pretreated macrophages stimulated with LPS remained constant. Out data suggest that, in tumor bearers, PKC and not NF kappa B is the main target for PS to exert its NO inhibitory action on LPS-activated macrophages. An excess of PS in PS-PKC interaction may be responsible, at least in part, for this type of PKC inhibition. Furthermore, PS also appears to downregulate the rise in [Ca2+]i promoted by IFN-gamma in macrophages, reducing the synergism of this cytokine with LPS and leading to a less effective production of NO.
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PMID:Involvement of protein kinase C and not of NF kappa B in the modulation of macrophage nitric oxide synthase by tumor-derived phosphatidyl serine. 1829 49

APOBEC3 proteins are important cellular factors that restrict infection by a number of viruses, including human immunodeficiency virus type 1 (HIV-1). Previously, we found that the mouse APOBEC3 (mA3) restricts infection by mouse mammary tumor virus (MMTV) in its natural host. Dendritic cells (DCs) are the first in vivo targets of MMTV infection. In this study, we demonstrate that mA3 expressed in target cells restricts MMTV infection in DCs ex vivo and in vivo. By comparing infection of DCs from mA3(+/+) and mA3(-/-) mice with one-hit viruses, we show that mA3 expression in target cells blocked MMTV infection at a postentry step and acted together with virion-packaged mA3 to inhibit infection. Similar results were obtained upon infection of mouse DCs with HIV-1 cores pseudotyped with vesicular stomatitis virus G protein. In addition, treatment of cells or mice with lipopolysaccharide (LPS) caused increased levels of mA3 expression and rendered them resistant to MMTV infection. Alpha interferon treatment had a similar effect. This LPS-induced resistance to infection was seen only in mA3(+/+) mice and not in mA3(-/-) mice, arguing that mA3 is the major anti-MMTV restriction factor that is induced upon DC maturation. Thus, increasing the levels of this intrinsic antiretroviral factor in vivo can lead to increased levels of restriction because of higher levels of both cell-intrinsic as well as virion-packaged APOBEC3.
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PMID:Induction of APOBEC3 in vivo causes increased restriction of retrovirus infection. 1915 38

The growth of the DI-DMBA-3 mammary adenocarcinoma in BALB/c mice results in a profound deficit in the tumoricidal function of their peritoneal elicited macrophages (PEM) after stimulation with lipopolysaccharide (LPS). The capacity of these macrophages to respond to stronger signals, such as a combination of LPS and low levels (5 U/ml) of interferon-gamma (IFN-gamma) is also impaired. Importantly, a combination of high levels (50 U/ml) of IFN-gamma with 10 mug/ml of LPS, is able to trigger a cytolytic response in macrophages from tumor bearing mice against mammary tumor target cells, indicating that their lytic machinery is intact. However, IFN-gamma production is severely diminished in T lymphocytes from tumor bearing mice as detected by ELISA, moreover, Northern blots revealed that the levels of IFN-gamma RNA are also decreased in T cells from tumor bearers. The cooperation between T cells and macrophages is mediated, at least in part, by IFN-gamma. Thus, mammary tumors have die potential to overcome host defenses, either by affecting the capacity of macrophages to respond adequately to activating agents, and/or by impairing the production of T-cell derived lymphokines important in macrophage activation for tumor killing.
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PMID:Impaired activation of tumoricidal function in macrophages from mammary-tumor bearers - the role of IFN-gamma. 2157 24

To establish chronic infections, viruses must develop strategies to evade the host's immune responses. Many retroviruses, including mouse mammary tumor virus (MMTV), are transmitted most efficiently through mucosal surfaces rich in microbiota. We found that MMTV, when ingested by newborn mice, stimulates a state of unresponsiveness toward viral antigens. This process required the intestinal microbiota, as antibiotic-treated mice or germ-free mice did not transmit infectious virus to their offspring. MMTV-bound bacterial lipopolysaccharide triggered Toll-like receptor 4 and subsequent interleukin-6 (IL-6)-dependent induction of the inhibitory cytokine IL-10. Thus, MMTV has evolved to rely on the interaction with the microbiota to induce an immune evasion pathway. Together, these findings reveal the fundamental importance of commensal microbiota in viral infections.
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PMID:Successful transmission of a retrovirus depends on the commensal microbiota. 2204 39


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