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)

The Fas/APO-1 cytotoxic pathway plays an important role in the regulation of peripheral immunity. Recent evidence indicates that this regulatory function operates through deletion of activated T and B lymphocytes by CD4+ T cells expressing the Fas ligand. Because macrophages play a key role in peripheral immunity, we asked whether Fas was involved in T-cell-macrophage interactions. Two-color flow cytometry revealed that Fas receptor (FasR) was expressed on resting murine peritoneal macrophages. FasR expression was upregulated after activation of macrophages with cytokines or lipopolysaccharide, although only tumor necrosis factor-alpha rendered macrophages sensitive to anti-FasR antibody-mediated death. To determine the consequence of antigen presentation by macrophages to CD4+ T cells, macrophages were pulsed with antigen and then incubated with either Th1 or Th2 cell lines or clones. Th1, but not Th2, T cells induced lysis of 60-80% of normal macrophages, whereas macrophages obtained from mice with mutations in the FasR were totally resistant to Th1-mediated cytotoxicity. Macrophage cytotoxicity depended upon specific antigen recognition by T cells and was major histocompatibility complex restricted. These findings indicate that, in addition to deletion of activated lymphocytes, Fas plays an important role in deletion of activated macrophages after antigen presentation to Th1 CD4+ T cells. Failure to delete macrophages that constitutively present self-antigens may contribute to the expression of autoimmunity in mice deficient in FasR (lpr) or Fas ligand (gld).
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PMID:Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway. 747 70

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.
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PMID:Expression and functional significance of an additional ligand for CTLA-4. 750 92

Nitric oxide (NO) is a potent mediator involved in many biological functions including inflammation and non-specific immunity. Murine macrophages possess the prototype of high-output NO synthase which is not constitutively expressed but induced within a few hours by immunological stimuli. In this study, we explored the possibility of controlling the activity of the inducible NO synthase by interfering with the transduction signal which triggers its induction, in the RAW 264.7 macrophage cell line. We found that nicotinamide, an inhibitor of ADP-ribosylation, prevented NO synthase induction in RAW 264.7 cells after stimulation with interferon gamma (IFN-gamma) and lipopolysaccharide (LPS). Furthermore, the level of NO synthase mRNA was measured by Northern-blot analysis and we found that nicotinamide prevents expression of NO synthase mRNA in IFN-gamma- and LPS-stimulated cells. Nicotinamide was also found to inhibit other macrophage functions expressed in response to IFN-gamma, i.e. tumour necrosis factor secretion and the expression of the Ia antigen of the major histocompatibility complex. Analysis of the pattern of ADP-ribosylated proteins revealed that nicotinamide as well as cholera toxin prevented the ADP-ribosylation of a 107-117 kDa protein found constitutively ADP-ribosylated in stimulated and non-stimulated macrophage extracts. Together, our results indicate ADP-ribosylation as a crucial point of the signalling pathway which leads to NO synthase mRNA induction.
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PMID:Nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages. 750 33

The capacity of human CD4+ T cells to lyse heterologous human oligodendrocytes in an 18-hour chromium 51-release assay was compared to that of systemic blood-derived macrophages and central nervous system-derived microglia. CD4+ T cells, activated with either phytohemagglutinin, anti-CD3 antibody, or antigen (myelin basic protein), could induce lysis of the oligodendrocytes whereas macrophages and microglia, activated with interferon-gamma and lipopolysaccharide, could not. The CD4+ T-cell effect was not inhibited with an anti-tumor necrosis factor-alpha-neutralizing antibody. Both the CD4+ T cells and the macrophages could induce lysis of tumor necrosis factor-sensitive rodent cell lines, Wehi 164, and L929; these effects were inhibited with anti-tumor necrosis factor antibody. Pretreatment of the CD4+ T cells with cyclosporine or mitomycin C did not inhibit oligodendrocyte lysis. These results indicate that at least in vitro, CD4+ T cells can induce a form of oligodendrocyte injury that is not reproduced by macrophages or microglia or by tumor necrosis factor. The non-major histocompatibility complex (MHC)-restricted injury of oligodendrocytes induced by both myelin antigen-reactive and mitogen-stimulated T cells may provide a basis whereby cytotoxic CD4+ T cells could interact with a target cell that does not express MHC class II molecules. Our results suggest that immune-mediated oligodendrocyte/myelin injury, as is postulated to occur in the disease multiple sclerosis, may involve multiple effector mechanisms.
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PMID:Oligodendrocyte lysis by CD4+ T cells independent of tumor necrosis factor. 751 99

The effect of staphylococcal enterotoxin B (SEB)-elicited inducible nitric oxide synthase (iNOS) in mouse endothelial cells was investigated. Results showed that SEB stimulated the same level of NO production in gamma interferon (IFN-gamma)-primed cells as did trichloroacetic acid-extracted lipopolysaccharide. The kinetics of induced NO production and expression of mRNA for iNOS differed markedly in endothelial and macrophage cells. Induced endothelial nitrite production was transient and was 15 to 20% of that generated by macrophage cells; mRNA levels peaked by 2 h and then steadily declined, whereas macrophage message levels continually increased. The ability of endothelial cells to produce SEB-induced NO depended on priming with IFN-gamma, although detectable mRNA could be elicited by SEB alone. Induction of endothelial iNOS mRNA was inhibited by cycloheximide, which indicated a requirement for de novo protein synthesis. Niacinamide and interleukin-10 significantly reduced SEB-induced endothelial NO production. Both are reported to affect IFN-gamma-induced class II major histocompatibility complex (MHC) expression on antigen-presenting cells. Niacinamide reduced iNOS mRNA levels and markedly reduced IFN-gamma induction of endothelial class II MHC surface antigen. Interleukin-10 did not consistently reduce iNOS mRNA expression and had no effect on IFN-gamma induction of endothelial class II MHC surface antigen. These results suggest that SEB interacts with IFN-gamma-primed endothelial cells to elicit induced NO and that this induction can be effectively modulated at the receptor or transcriptional level.
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PMID:Regulation of staphylococcal enterotoxin B-elicited nitric oxide production by endothelial cells. 752 48

To investigate the regulatory effects of the prototypic Th2 lymphocyte products and potential immunotherapeutic agents interleukin-4 (IL-4) and IL-10 on macrophages differentiated in vitro under different cytokine-defined environments, blood monocytes were incubated for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor or IL-4. The effect of monocyte culture in the presence or absence of serum was also investigated. Functional responses by 7-day-cultured cells to IL-4, quantified as decreased CD14 expression and suppression of lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta production, and as a positive response, increased CD23 expression, were compared directly with the responses by monocytes from which they were derived. In response to IL-10, decreases in LPS-induced TNF-alpha and IL-1 beta production and reduction in the expression of major histocompatibility complex (MHC) class II antigens were examined. Seven-day cultured monocytes/macrophages showed (1) diminished TNF-alpha production in response to IL-10 but not IL-4 (2), diminished IL-1 beta production in response to both IL-4 and IL-10, and compared with fresh monocytes (3), diminished CD14 expression in response to IL-4, and (4) a lesser increase in CD23 expression in response to IL-4. This was the case regardless of the cytokine in the presence of which the cells had been cultured for 7 days. Monocytes cultured for 7 days in GM-CSF expressed increased levels of MHC class II and LPS-induced TNF-alpha and responded inefficiently to IL-10 for decreased MHC class II. The responses by monocytes cultured for 7 days with GM-CSF resemble the published properties of synovial fluid macrophages from patients with chronic inflammatory arthritis. The study highlights the complexity of monocyte/macrophage responses to the immunoregulatory cytokines IL-4 and IL-10 and concludes that responses to IL-4 and IL-10 by blood monocytes may not be representative of responses by their differentiated or activated counterparts.
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PMID:Monocytes cultured in cytokine-defined environments differ from freshly isolated monocytes in their responses to IL-4 and IL-10. 754 Jun 42

The tumor necrosis factor-alpha (TNF-alpha, or TNF) genes of NOD mice and NZW mice are reportedly underexpressed relative to the TNF genes of control mice in lipopolysaccharide (LPS)-induced peritoneal macrophages. These findings, as well as the well-known major histocompatibility complex (MHC) linkage of the TNF genes, have prompted speculation that mutations affecting expression of the TNF-alpha loci might represent a primary cause of autoimmune diseases. Differences in expression of the TNF genes in different strains of mice might result either from effects of cis-acting mutations or from differences in the cellular environment that operate in trans. To discriminate between these possibilities, we directly examined the relative contribution made by each of two different TNF alleles (one associated with an autoimmune-prone haplotype and the other not) to the pool of TNF mRNA within the cells of F1 hybrid mice. Reverse transcription-polymerase chain reaction (RT-PCR) was used to amplify a polymorphic fragment derived from the total pool of TNF mRNA present in LPS-induced peritoneal macrophages of hybrid animals produced by crossing BALB/c to non-obese diabetic (NOD), and New Zealand black (NZB) to New Zealand white (NZW). In both types of F1 hybrid, the two alleles were represented in nearly equal quantities at the mRNA level. It may be inferred that at all pretranslational levels, the NZW and NOD TNF alleles are functionally equivalent to the control alleles that were examined. Interstrain differences in responsiveness to LPS are therefore responsible for interstrain differences in TNF gene expression.
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PMID:Comparative expression of TNF-alpha alleles from normal and autoimmune-prone MHC haplotypes. 758 56

The induction of major histocompatibility complex (MHC) class II antigen on amoeboid microglia cells (AMC) by lipopolysaccharide (LPS) and interferon-gamma (INF-gamma) in early postnatal rat brain was studied by immunohistochemistry. In newborn rats given successive intraperitoneal injections of LPS or INF-gamma and killed at the age of 7 days, MHC class II antigen expressing AMC were consistently present in specific areas throughout the entire brain, notably in the subcortical white matter and circumventricular region. It is concluded from this study that the induction of MHC class II antigen on AMC by LPS or INF-gamma is a widespread phenomenon in the developing brain. Since MHC class II antigen is essential for the initiation of immune response, it is suggested that besides their phagocytic nature, AMC may also be involved in immunological processes in the developing brain.
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PMID:Induction of major histocompatibility complex class II antigen on amoeboid microglial cells in early postnatal rats following intraperitoneal injections of lipopolysaccharide or interferon-gamma. 760 27

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by cultured rat mesangial cells. Of particular interest was the finding that deoxyspergualin inhibited the de novo cell surface expression of MHC class II antigens after interferon-gamma stimulation. However, deoxyspergualin did not prevent the cytoplasmic accumulation of MHC class II molecules, indicating that the drug interfered with a posttranslational event in MHC class II processing and/or assembly. Deoxyspergualin was not a general inhibitor of mesangial cells, and it had no effect on constitutive or lipopolysaccharide-induced transforming growth factor beta 1 expression. In conclusion, deoxyspergualin has been shown to inhibit the mesangial cell response to glomerular injury. This novel mode of action may provide an additional therapeutic benefit in the treatment of proliferative forms of glomerulonephritis.
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PMID:Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression. 762 87

Although several murine macrophage (m phi) cell lines from different sites have previously been obtained by in vitro infection with the J2 murine retrovirus, which carries the v-raf and v-myc oncogenes, it was not possible to immortalize thioglycolate-elicited peritoneal macrophages (Pm phi s) by this in vitro procedure. A technique utilizing in vivo injection of the J2 virus has been developed to overcome this problem. The J2 virus immortalized Pm phi s in a very efficient manner in vivo because no exogenous growth factors were required for the in vitro proliferation of these cells and numerous continuous cloned cell lines were readily established. In contrast, Pm phi s obtained from uninfected mice or Pm phi s infected in vitro with the J2 virus did not proliferate. The in vivo immortalized cells had many of the morphological and functional characteristics of m phi s. Analysis of two of the clones, PMJ2-PC and PMJ2-R, demonstrated intracellular expression of the product of the v-raf gene, presence of m phi-associated cell surface antigens, interleukin-6 secretion induced by lipopolysaccharide, and biological response modifier-induced cytotoxic activity against tumor cells. In addition, one of the clones, PMJ2-PC, constitutively expressed major histocompatibility complex (MHC) class II antigens, and in the other clone, PMJ2-R, MHC class II antigens expression was induced by recombinant murine interferon-gamma. This method of utilizing the J2 virus in vivo represents a novel technique for obtaining hematopoietic cell lines from cells that are difficult to immortalize in vitro.
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PMID:In vivo immortalization of murine peritoneal macrophages: a new rapid and efficient method for obtaining macrophage cell lines. 768 28


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