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)

Bacterial lipopolysaccharide (LPS) plays a central role in the pathogenesis of gram-negative sepsis and shock. The glycosylphoshatidyl inositol (GPI) anchored glycoprotein CD14 on mononuclear cells binds LPS, especially in the presence of an LPS binding serum protein, activating the production of pro-inflammatory cytokines, i.e. TNF-alpha. However, since GPI anchorage to the cell membrane lacks the intracellular signalling capacity, the existence of at least a second receptor has been postulated. In attempt to identify additional LPS receptors, we used the human myelomonocytic cell line THP-1. This undifferentiated cell line did not respond to LPS in terms of TNF-alpha release, but when induced with 250 U/ml of IFN-gamma for 48 h, the cells released TNF-alpha (174 +/- 58.6 U/ml. L929 cell bioassay) in response to 10 vg/ml of E. coli 0111 LPS, in the absence of serum. Blockade of either HLA-DR or CD14 receptors with specific MAbs did not reduce the amount of cytokine released. However, when both the receptors were sequentially blocked involved on the effector cells a remarkable inhibition of TNF-alpha release was observed (8.6 +/- 1.4). It seems therefore, that HLA-DR receptor may be with CD14 in triggering TNF-alpha release by IFN-gamma, induced THP-1 cells.
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PMID:The release of tumor necrosis factor alpha (TNF-alpha) by interferon gamma (IFN-gamma) induced THP-1 cells stimulated with smooth lipopolysaccharide is inhibited by MAbs against HLA-DR and CD14 receptors on the effector cell. 903 62

AS-101 is a tellurium-based compound with known immunomodulating properties. The ability of AS-101 to potentiate the effects of chemotherapeutic drugs and augment cytokine production in vivo has led to clinical trials on AS-101 which are currently being carried out in cancer patients. In the present study we show that AS-101 selectively augments the release of TNF alpha and IL-1 alpha and inhibits the release of IL-10 by lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages and human monocytes. It does not significantly affect the release of IL-6 or leukemia inhibitory factor (LIF). By itself AS-101 does not induce the release of any of these cytokines. Analysis of IL-10 and TNF alpha RNA levels using semiquantitative PCR reveals that AS-101 blocks the transcription of IL-10 mRNA, but does not significantly affect TNF alpha mRNA. Although both AS-101 and interferon (IFN)-gamma inhibit IL-10, AS-101, unlike IFN-gamma, does not prime macrophages for LPS-induced nitric oxide release and does not appear to significantly affect monocyte HLA-DR expression. Our data suggest that AS-101 is a partial IFN-gamma agonist and may explain the shift toward the release of Th-1 type cytokines observed in AS-101-treated patients.
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PMID:The immunomodulator AS-101 inhibits IL-10 release and augments TNF alpha and IL-1 alpha release by mouse and human mononuclear phagocytes. 907 92

Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.
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PMID:Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. 917 97

We report a 70-year-old Japanese man who had splenic lymphoma with villous lymphocytes and a complex chromosomal abnormality. No monoclonal gammopathy was present. The peripheral blood film showed lymphocytes with thin and short villi arising from one or two poles of the cells. These cells were negative for tartrate-resistant acid phosphatase stain. Immunophenotyping of peripheral blood lymphocytes showed moderate to strong expression of surface membrane IgM, IgD, IgA, and lambda as well as CD19, CD20, CD21, CD24, and HLA-DR. In addition, there was weak CD5, CD22, and CD25 expression, but no CD10, CD11c, CD23, CD38, or B-ly-7 expression. All 20 metaphases obtained from peripheral blood cells cultured for 5 days with lipopolysaccharide showed an abnormal karyotype: 47, XY, +der(3) t(3; 13) (q26; q12) inv(3) (?), t(7; 14), (q21; q11), der(13) t(3; 13) (q26; q12). Our patient followed a relatively benign clinical course and splenectomy was not performed.
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PMID:[Splenic lymphoma with villous lymphocytes and complex chromosomal abnormality]. 924 32

Infections are frequent complications in end-stage renal failure patients undergoing hemodialysis (HD), and peripheral blood monocytes are important cells in host defense against infections. The majority of circulating monocytes express high levels of lipopolysaccharide receptor antigen CD14 and are negative for the immunoglobulin Fcgamma receptor type III (CD16). We studied the occurrence of a minor subpopulation coexpressing low levels of CD14 together with CD16 in HD patients. In healthy controls CD14+ CD16+ monocytes account for 8% +/- 4% of CD14+ monocytes, with an absolute number of 29 +/- 14 cells/microl. In stable HD patients the CD14+ CD16+ subpopulation was significantly elevated (14% +/- 3%, or 66 +/- 28 cells/microl), while the number of CD14(++) monocytes (monocytes strongly positive for CD14) remained constant. In HD patients suffering from chronic infections a further rise in CD14+ CD16+ monocytes was observed (128 +/- 71 cells/microl; P < 0.01) such that this subpopulation constituted 24% of all blood monocytes. In contrast, numbers of CD14++ cells did not change compared to those for stable HD patients, indicating that the CD14+ CD16+ monocyte subpopulation was selectively expanded. During acute infections the CD14+ CD16+ cell subpopulation always expanded. A whole-blood assay revealed that CD14+ CD16+ monocytes exhibited a higher phagocytosis rate for Escherichia coli bacteria than CD14++ monocytes, underlining their role during host defense. In addition, CD14+ CD16+ monocytes expressed higher levels of major histocompatibility complex (MHC) class II antigens (HLA-DR, -DP, and -DQ) and equal amounts of MHC class I antigens (HLA-ABC). Thus, CD14+ CD16+ cells constitute a potent phagocytosing and antigen-presenting monocyte subpopulation, which is expanded during acute and chronic infections commonly observed in chronic HD patients.
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PMID:Expanded CD14+ CD16+ monocyte subpopulation in patients with acute and chronic infections undergoing hemodialysis. 959 48

Macrophages play an important role in the intestinal mucosal immune system. However, they are a poorly defined cell population. We therefore determined their phenotype in normal colonic mucosa. Macrophages were isolated from colonic biopsies and surgical specimens by collagenase digestion. Colonic macrophages were positively sorted by anti-CD33 magnetic beads. Flow cytometric triple fluorescence analysis was applied to study CD14, CD16, CD33, CD44, CD11b, CD11c, CD64, HLA-DR, CD80, CD86 and CD3/CD19 expression. CD33 was evaluated as a positive marker for intestinal macrophages. CD33+ cells isolated from normal colonic mucosa showed co-expression of the established intracellular macrophage marker CD68 in FACS analysis. CD33+ cells were capable of phagocytosis. Isolation of this cell population by magnetic anti-CD33 beads and culture resulted in a 4.2-40-fold increase in IL-1beta and 4.5-44-fold increase in tumour necrosis factor-alpha (TNF-alpha) secretion compared with unsorted lamina propria mononuclear cells (LPMC). Of the CD33+ cells, 90.9 +/- 6.9% (mean +/- s.d.) were CD44+. However, macrophages from colonic mucosa showed only a low expression of CD14 (10.5 +/- 3.8%), CD16 (10.1 +/- 3.9%), HLA-DR (27.3 +/- 9.2%), CD11b (17.4 +/- 6.8%), CD11c (17.8 +/- 10.4%). Furthermore, expression of CD80 (9.2 +/- 4.2%) and CD86 (15.1 +/- 7.3%) was low, suggesting a low ability of normal intestinal macrophages to activate T cells and T cell-mediated immune responses. We conclude that CD33 is useful for the isolation and flow cytometric characterization of colonic macrophages. These cells exhibit a single phenotype in normal mucosa (CD33++, CD44++, CD14-, CD16-, CD11b-, CD11c-, HLA-DRlow, CD80-, CD86-) lacking lipopolysaccharide (LPS) receptor and costimulatory molecules.
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PMID:Isolation and phenotypic characterization of colonic macrophages. 964 82

The effects of priming monocytes from septic patients with granulocyte-macrophage colony-stimulating factor (GM-CSF) ex vivo were investigated. Monocytes from septic patients had depressed plasma GM-CSF and dysregulated levels of other cytokines compared with normal subjects. Membrane expression of CD71 and HLA-DR were depressed, and monocytes were anergic to lipopolysaccharide (LPS) stimulation in vitro, which was associated with spontaneous and accelerated activation-induced apoptosis by LPS. Priming monocytes with GM-CSF ex vivo augmented membrane cytokine expression, CD71, and HLA-DR. GM-CSF priming augmented cytokine secretion in response to LPS stimulation, restored cytokine secretion in monocytes from septic patients, and reversed their predilection to undergo apoptosis. Thus, monocyte dysfunction in septic shock is associated with depressed plasma levels of GM-CSF and enhanced apoptosis; however, GM-CSF stimulation ex vivo restored normal monocyte function and cytokine secretion by a mechanism that may depend on abrogating apoptosis.
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PMID:Monocyte anergy in septic shock is associated with a predilection to apoptosis and is reversed by granulocyte-macrophage colony-stimulating factor ex vivo. 978 Feb 64

Cytokines play a pivotal role in the pathogenesis of septic shock. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) stimulate the progression of septic shock whereas the anti-inflammatory cytokine IL-10 has counterregulative potency. The amino acid glycine (GLY) has been shown to protect against endotoxin shock in the rat by inhibiting TNF-alpha production. In the current study we investigated the role of GLY on lipopolysaccharide (LPS) -induced cell surface marker expression, phagocytosis, and cytokine production on purified monocytes from healthy donors. GLY did not modulate the expression of HLA-DR and CD64 on monocytes, whereas CD11b/CD18 expression (P<0.05) and E. coli phagocytosis (P<0.05) decreased significantly. GLY decreased LPS-induced TNF-alpha production (P<0.01) and increased IL-10 expression of purified monocytes. Similarly, in a whole blood assay, GLY reduced TNF-alpha (P<0.0001) and IL-1beta (P<0.0001) synthesis and increased IL-10 expression (P<0.05) in a dose-dependent manner. The inhibitory effects of GLY were neutralized by strychnine, and the production of IL-10 and TNF-alpha was augmented by anti-IL-10 antibodies. Furthermore, GLY decreased the amount of IL-1beta and TNF-alpha-specific mRNA. Our data indicate that GLY has a potential to be used as an additional immunomodulatory tool in the early phase of sepsis and in different pathophysiological situations related to hypoxia and reperfusion.
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PMID:Immunomodulatory effects of glycine on LPS-treated monocytes: reduced TNF-alpha production and accelerated IL-10 expression. 1006 24

Recombinant adenoviral vectors have promise for human gene therapy because of efficient transgene expression in nondividing primary cell types. Dendritic cells (DC) have potential as adjuvants for immune therapy, since they are specialized to capture antigens to form MHC-peptide complexes, migrate to T cell areas in the lymph node, and activate T cells including CD4+ helpers and CD8+ cytotoxic T lymphocytes (CTL). We show that several current chemical and physical transfection methods allow < 2 % of DC to express reporter genes but that recombinant adenoviruses, encoding the reporter genes green fluorescent protein and LacZ, efficiently transfect monocyte-derived human DC. Immature DC, generated with IL-4 and GM-CSF, are transfected to 95% efficiency, while mature DC show reduced transfection (50%) and gene expression. Adenovirus-transfected, immature DC exhibit several critical functions. The DC can differentiate in the presence of lipopolysaccharide or a monocyte-conditioned medium to express the surface markers of mature, T cell stimulatory DC including CD25, CD83, and high levels of CD86 and HLA-DR. Transfected DC can also secrete high levels of IL-12 and are potent inducers of T cell growth. Transgene expression in DC is stable for at least 6 days in the presence of the DC survival factor, TRANCE. Therefore adenoviral infection does not perturb the maturation and function of DC. The efficiency of adenoviral-mediated gene transfer prompts the evaluation of this vector in studies of DC biology, including the expression of antigens for active immune therapy.
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PMID:Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells. 1009 1

The Ob gene product, leptin, is an adipocyte-secreted hormone that centrally regulates weight control. However, leptin receptor is expressed not only in the central nervous system, but also in other systems such as reproductive and hematopoietic tissues. Human leptin has previously been shown to enhance cytokine production by murine peritoneal macrophages. In this paper we show that human leptin stimulates proliferation in a dose-dependent manner and functionally activates human circulating monocytes in vitro, by inducing the production of cytokines such as TNF-alpha and IL-6. Proliferation was assessed both by [3H]thymidine and bromodeoxyuridine incorporation at 48 h. We also checked the leptin stimulated monocyte expression of activation markers by flow cytometry: CD25, HLA-DR, CD38, CD71, CD11b, and CD11c expression increased after 72 h. Moreover, leptin increases the expression of the early activation marker CD69 in monocytes but not in lymphocytes. The stimulation produced by leptin is comparable to that produced by endotoxin [lipopolysaccharide (LPS)]. In addition, leptin can potentiate the stimulatory effect of LPS or PMA. Furthermore, we studied cytokine production (TNF-alpha and IL-6) simultaneously by flow cytometric detection of intracellular cytokines in the activated monocytes. Leptin produced a dose-dependent increase in the number of activated monocytes producing cytokines. These data indicate that leptin is a potent stimulatory hormone on human peripheral blood monocytes and suggest that it may have a role as a proinflammatory cytokine.
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PMID:Human leptin stimulates proliferation and activation of human circulating monocytes. 1035 75


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