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

2',3'-Dideoxyinosine (ddI) is a purine nucleoside analog currently being used for the treatment of HIV-positive individuals and patients with AIDS. Preliminary immunotoxicity studies have shown that a consequence of ddI treatment in female B6C3F1 mice is the inhibition of the humoral immune response. This effect was dose dependent in a range of 100 to 1000 mg/kg with a no observed adverse effect level of less than 100 mg/kg for a 28-day treatment period. These studies were undertaken to investigate the immune cell target of ddI and to determine the mechanism of this toxicity. B6C3F1 mice were treated with 1000 mg/kg/day by oral gavage for 28 days. The B lymphocyte was identified as the cellular target of ddI through separation-reconstitution experiments of the adherent and nonadherent cell populations and of the T and B lymphocyte populations. These studies revealed a deficit in the ability of the nonadherent cells from ddI-treated mice to mount a normal antibody response to sRBC. A further separation of the nonadherent cells into T and B cells revealed a decreased ability of ddI-treated B cells to develop specific humoral immunity. Additional studies were undertaken to determine the mechanism by which ddI is affecting the B cell. Surface marker analysis of splenocytes revealed no difference in the cell populations between vehicle- and ddI-treated mice. B cell proliferation was also unaffected as shown by incubation with either a polyclonal stimulator, lipopolysaccharide, or anti-IgM plus IL-4. These results indicate that the primary cellular target of ddI is the B lymphocyte.
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PMID:2'3'-Dideoxyinosine inhibits the humoral immune response in female B6C3F1 mice by targeting the B lymphocyte. 926 98

Caprine arthritis encephalitis virus (CAEV) is a lentivirus of goats that leads to chronic mononuclear infiltration of various tissues, in particular, the radiocarpal joints. Cells of the monocyte/macrophage lineage are the major host cells of CAEV in vivo. We have shown that infection of cultured goat macrophages with CAEV results in an alteration of cytokine expression in vitro. Constitutive expression of interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) was increased in infected macrophages, whereas transforming growth factor beta1 (TGF-beta1) mRNA was down-regulated. When macrophages were infected with a CAEV clone lacking the trans-acting nuclear regulatory gene tat, IL-8 and MCP-1 were also increased. No significant differences from cells infected with the wild-type clone were observed, suggesting that Tat is not required for the increased expression of IL-8 and MCP-1 in infected macrophages. Furthermore, infection with CAEV led to an altered pattern of cytokine expression in response to lipopolysaccharide (LPS), heat-killed Listeria monocytogenes plus gamma interferon, or fixed cells of Staphylococcus aureus Cowan I. In infected macrophages, tumor necrosis factor alpha, IL-1beta, IL-6, and IL-12 p40 mRNA expression was reduced in response to all stimuli tested whereas changes in expression of granulocyte-macrophage colony-stimulating factor depended on the stimulating agent. Electrophoretic mobility shift assays demonstrated that, in contrast to effects of human immunodeficiency virus infection of macrophages, CAEV infection had no effect on the level of constitutive nuclear factor-kappaB (NF-kappaB) activity or on the level of LPS-stimulated NF-kappaB activity, suggesting that NF-kappaB is not involved in altered regulation of cytokine expression in CAEV-infected cells. In contrast, activator protein 1 (AP-1) binding activity was decreased in infected macrophages. These data show that CAEV infection may result in a dysregulation of expression of cytokines in macrophages. This finding suggests that CAEV may modulate the accessory functions of infected macrophages and the antiviral immune response in vivo.
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PMID:Caprine arthritis encephalitis virus dysregulates the expression of cytokines in macrophages. 931 28

The effect of a single bolus injection (0.4 g/kg) of intravenous immunoglobulin (IVIG) on the tumor necrosis factor (TNF) system in human immunodeficiency virus type 1 (HIV-1)-infected patients was investigated. At 140 h after infusion, there was a significant decrease in levels of TNF-alpha and a significant increase in levels of soluble TNF receptors (sTNFR) in both plasma and lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC). A rapid (within 1 h) decline in expression of membrane-bound TNF-alpha and p55-TNFR on PBMC persisted throughout the study. In contrast, there was an increased expression of membrane-bound p75-TNFR after 140 h. IVIG administration also resulted in significantly increased numbers of circulating CD4 lymphocytes, correlated with down-regulation of TNF-alpha activity in PBMC supernatants. Thus, down-regulation of the abnormally increased TNF-alpha activity may be achieved by IVIG administration. Studies evaluating the possible therapeutic role of long-term TNF-alpha suppression by IVIG may be warranted in HIV-1-infected patients.
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PMID:Effects of intravenous immunoglobulin in vivo on abnormally increased tumor necrosis factor-alpha activity in human immunodeficiency virus type 1 infection. 933 49

Chemokines play an important role in the regulation of endothelial cell (EC) function, including proliferation, migration and differentiation during angiogenesis, and re-endothelialization after injury. In this study, reverse transcriptase-polymerase chain reaction was used to reveal expression of various CXC and CC chemokine receptors in human umbilical vein EC. Northern analysis showed that CXCR4 was selectively expressed in vascular EC, but not in smooth muscle cells. Compared with other chemokines, stromal cell-derived factor-1alpha (SDF-1alpha), the known CXCR4 ligand, was an efficacious chemoattractant for EC, causing the migration of approximately 40% input cells with an EC50 of 10-20 nM. Of the chemokines tested, only SDF-1alpha induced a rapid, though variable mobilization of intracellular Ca2+ in EC. Experiments with actinomycin D demonstrated that CXCR4 transcripts were short-lived, indicating a rapid mRNA turnover. Interferon-gamma (IFN-gamma) caused a pronounced down-regulation of CXCR4 mRNA in a concentration- and time-dependent manner. In a striking functional correlation, IFN-gamma treatment also attenuated the chemotactic response of EC to SDF-1alpha. IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide produced a time course-dependent biphasic effect on CXCR4 transcription. Expression of CXCR4 in EC is significant, more so as it and several CC chemokine receptors have been shown to serve as fusion co-receptors along with CD4 during human immunodeficiency virus infection. Taken together, these findings provide evidence of chemokine receptor expression in EC and offer an explanation for the action of chemokines like SDF-1alpha on the vascular endothelium.
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PMID:Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines. 946 27

To characterize the effect of human immunodeficiency virus-1 (HIV-1) nef expression in human monocytes/macrophage (HMO) and U937 on the levels of FcgammaRs, HLA antigens, and monokines, elutriated HMOs and U937 cells were transfected with an adenovirus-mediated Nef expression system. Nef-expressing cells downmodulated FcgammaRI, FcgammaRII, and upregulated HLA class I molecules. Nef-expressing HMOs, treated with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA), overexpressed tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-10. However, IL-6 was induced by LPS and inhibited by PMA. Additionally, a subpopulation of Nef-expressing HMOs underwent apoptosis. Our data suggest that HIV-1 nef downmodulated FcgammaRs in myeloid cells in a manner similar to that previously reported for its effect on CD4+ in T cells.
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PMID:Adenovirus-mediated human immunodeficiency virus-1 Nef expression in human monocytes/macrophages and effect of Nef on downmodulation of Fcgamma receptors and expression of monokines. 949 Jun 97

Chronic use of morphine affects the immune system and predisposes an individual to opportunistic infections. Macrophages play an important role in conferring a first line of defense against invading pathogens. Understanding the mechanisms by which morphine affects the functioning of macrophages would have significant therapeutic benefit in treatment against infections such as HIV and AIDS related syndromes. Two of the major cytokines secreted by activated macrophages are Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). Our studies show that morphine differentially modulates lipopolysaccharide (LPS) induced expression of IL-6 and TNF-alpha. Nanomolar concentrations of morphine synergize with LPS and augment the secretion of both IL-6 and TNF-alpha. However, at micromolar concentrations morphine inhibits LPS induced synthesis of IL-6 and TNF-alpha. Expression of both these cytokine genes is dependent on the activation of a transcription factor, NF kappa B. Interestingly, morphine treatment also modulated the activation of NF kappa B by LPS. Pretreatment with a low dose of morphine (nanomolar) resulted in an increase in NF kappa B activation. In contrast pretreatment with a high dose of morphine (micromolar) led to a significant decrease in NF kappa B activation. Furthermore unlike the augmentation which was naloxone reversible, the inhibition of NF kappa B by morphine was not reversed by naloxone, suggesting the involvement of a nonclassical opioid receptor.
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PMID:Morphine modulates NF kappa B activation in macrophages. 957 Nov 61

The Nef protein of HIV-1 binds to and induces apoptotic cytolysis of a broad spectrum of uninfected blood cells of humans and mice independently of CD95 (Fas). A 24-kDa glycoprotein responsible for Nef binding and the Nef-induced apoptosis has been identified on the surface of human CD4+ T cells. Using mouse monoclonal antibodies (mAbs) against the human Nef-binding protein and flow cytometry, we analyzed the expression of a corresponding protein on murine cells. The mAbs were shown to bind to the surface of various murine cell lines including T and B lymphocytes and macrophages, in a fashion similar to the binding by soluble Nef protein. The mAbs competed with the Nef protein in binding to the cell surfaces. Immunoprecipitation of cell membranes revealed a 25-kDa protein recognized by the mAbs. Treatment of the soluble Nef protein with anti-Nef (C terminus) mAb, but not anti-Nef (N terminus) mAb, deprived the Nef of the cell binding activity, indicating that binding site is located in the C-terminal domain. Cross-linking of the cell-bound mAbs with secondary antibodies induced apoptotic cytolysis, which occurred independently of CD95 (Fas). On the other hand, neither the mAbs nor the soluble Nef protein reacted with primary lymphocytes in a resting stage obtained from lymph nodes, thymus and spleen of 5-week-old mice. However, some of the cells, predominantly comprising CD4+ T cells, became positive for the both reactions after mitogenic stimulation with phytohemagglutinin, concanavalin A or lipopolysaccharide of Escherichia coli. These results suggest that the 25-kDa protein on murine cell surfaces corresponds to the human Nef binding protein and is responsible for the Nef-induced apoptosis, and that its expression on the cell surface depends on cellular activation.
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PMID:HIV-1 Nef binding protein expressed on the surface of murine blood cells. 957 3

Increased mortality has been observed when HIV-infected patients were treated with pyrimethamine (Pyr) as prophylaxis for toxoplasmic encephalitis, suggesting that Pyr might possess immunosuppressive activity. To analyze this in an animal model, immune function was assessed in BALB/c mice using a battery of in vivo and ex vivo assays and an in vivo model of host resistance to Listeria monocytogenes infection. Treatment for 30 days with 60 mg/kg Pyr decreased circulating white blood cell and lymphocyte counts but not neutrophil, red blood cell, or platelet counts or hemoglobin levels. Splenic B cell percentages and lipopolysaccharide-induced B cell proliferation decreased significantly after treatment with 60 mg/kg Pyr, as did levels of anti-keyhole limpet hemocyanin (KLH) IgM in serum 7 days after immunization with KLH. Anti-KLH IgG levels 14 days after immunization were not affected. Percentages of splenic T cells and macrophages and T cell proliferation in the presence of concanavalin A or allogeneic cells were not decreased by Pyr treatment. An ex vivo assay of T-cell-mediated cytotoxicity was also unaffected. When host resistance to L. monocytogenes infection was assessed, dramatic increases in mortality were observed in Pyr-treated compared to control mice. Increased numbers of L. monocytogenes organisms were observed in liver and spleen of Pyr-treated mice, compared to controls. The reduction in Listeria resistance, which is T cell mediated, contrasts with the fact that no significant changes in T-cell-mediated immunity were observed. It is possible that Pyr affects parameters of innate immunity, which were not monitored in this study.
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PMID:Pyrimethamine impairs host resistance to infection with Listeria monocytogenes in BALB/c mice. 957 21

Activation of brain glial cells with the bacterial endotoxin lipopolysaccharide (LPS), the HIV-1 coat protein gp120, or beta-amyloid-derived peptides, stimulates the expression of several cytokines, including tumor necrosis factor-alpha (TNFalpha), interleukin-1 (IL-1) and IL-6. and nitric oxide (NO) which have been proposed as causes of neurodegeneration in the brain. In the present study, the neurotoxic effects of several cytokines, alone or in various combinations, and the correlations of the release of lactate dehydrogenase, the loss of neurons, and the secretion of NO in brain neuronal cell injury were investigated in murine primary mixed neuronal/glial cell cultures. A specific combination of cytokines, i.e., IL-1 (1 ng/ml)+ TNFalpha (10 ng/ml)/interferon-gamma (IFNgamma) (200 u/ml), induced a dramatic neuronal cell injury in the neuron/glia cultures, and its cytotoxic profile was very similar to that seen with the LPS/IFNgamma-induced neuron injury. This indicates that among the many toxic immune mediators secreted in response to LPS, IL-1 and TNFalpha can mimic LPS as the triggering signals and primary mediators for glia-mediated neuron injury in the presence of IFNgamma. This study provides new insights about the cytotoxic mechanism(s) for cytokine-mediated neuron injury.
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PMID:Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures. 962 92

Soluble (s) CD14, a marker for monocyte/macrophage activation and a mediator of bacterial lipopolysaccharide (LPS) action, was elevated in serum from human immunodeficiency virus type 1 (HIV- 1)-infected individuals (n = 92) compared with seronegative controls. The highest levels were found in patients with advanced clinical and immunological disease. Patients with ongoing clinical events had significantly higher sCD14 levels than symptomatic HIV-1-infected individuals without clinical events, with especially elevated levels in patients infected with Mycobacterium avium complex (MAC). On longitudinal testing of patients (n = 26) with less than 100 x 10(6) CD4 lymphocytes/L at baseline, we found that increasing sCD14 serum concentrations per time unit were associated with death, whereas no differences in CD4 cell number decrease were found between survivors and nonsurvivors. In vitro studies showed that HIV-1 glycoprotein 120 and purified protein derivative (PPD) from M avium (MAC-PPD) stimulated normal monocytes to release sCD14. Furthermore, MAC-PPD induced tumor necrosis factor (TNF) release from monocytes through interactions with CD14 and, importantly, the addition of sCD14 enhanced this MAC-PPD stimulatory effect. Our findings suggest that the CD14 molecule may be involved in the immunopathogenesis of HIV-1 infection, and it is conceivable that serial determination of sCD14 may give useful predictive information concerning disease progression and survival in HIV-1-infected patients.
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PMID:Elevated levels of serum-soluble CD14 in human immunodeficiency virus type 1 (HIV-1) infection: correlation to disease progression and clinical events. 973 Oct 66


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