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)

We studied phenotype, function and differentiation of mononuclear phagocytes in 11 cancer patients treated subcutaneously with 10O microg/kg recombinant human (rhu) GM-CSF for 7 d. The rhuGM-CSF treatment induced (1) a 5.9-fold increase in the number of blood monocytes (MO), (2) a decrease of CD14bright/CD16bright cells with a diminution of the mean fluorescence intensity (MFI) of CD14, and (3) a decrease of MO cellular cytotoxicity. In patients' sera, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-12, neopterin, macrophage-colony-stimulating factor (M-CSF), and IL-1 receptor antagonist (IL-1RA) increased, whereas GM-CSF and granulocyte-colony-stimulating factor (G-CSF) decreased after an initial peak. In whole blood samples the lipopolysaccharide (LPS)-stimulated release of TNF-alpha, IL-6 and IL-1RA increased initially, whereas IL-1beta, IL-10 and IL-12 decreased. During differentiation from MO to macrophages (MAC), interferon (IFN)-gamma-stimulated tumour cytotoxicity increased, but both MO and MAC were less cytotoxic upon rhuGM-CSF treatment. The differentiation-associated increase of LPS-induced TNF-alpha, IL-1RA and IL-10 secretion was reduced by the rhuGM-CSF treatment, and the expression of CD14 on MAC as well as the proportion of CD14+/CD16+, CD14+/MAX.1+ and CD14+/CD71+ cells in 7-d cultured MAC declined. We interpret these findings as (1) an increase of immature MO upon rhuGM-CSF therapy, (2) a priming effect on the LPS-induced proinflammatory cytokine repertoire of MO, and (3) an impact of rhuGM-CSF on the capacity of MO to differentiate to MAC in vitro.
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PMID:Effect of granulocyte-macrophage colony-stimulating factor treatment on phenotype, cytokine release and cytotoxicity of circulating blood monocytes and monocyte-derived macrophages. 975 45

Certain cytokines are believed to play a key role in the development of autoimmune demyelinating diseases. Little is known, however, about the effects of these cytokines in the regulation of the key event in myelin destruction, the phagocytosis of myelin by phagocytic cells. We investigated the effects of certain cytokines and growth factors on cultured peritoneal macrophages and microglia in respect to their various functions, phagocytosis, secreted proteolytic activity, and oxidative activity. Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccharide (LPS), all proinflammatory factors, actually decreased (IFN-gamma and LPS), or had no effect (TNF-alpha) on myelin phagocytosis by macrophages, but substantially increased phagocytic activity by microglia. Surprisingly, interleukins 4 and 10 (IL-4 and IL-10), considered to be downregulating cytokines, increased phagocytic activity by macrophages, while with microglia, IL-4 had no effect, but IL-10 almost doubled myelin phagocytosis. Transforming growth factor-beta (TGF-beta) had no significant effect on either cell. These cytokines did not affect proteolytic secretion in microglia, while IFN-gamma and LPS induced a doubling of the secreted proteases. This proteolytic activity was almost completely suppressed by calpain inhibitors, although some gelatinase appeared to be present. Microglia exerted much more oxidative activity on the membranes than macrophages, and granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 1beta (IL-1beta) significantly increased microglial oxidative activity. The pattern of responses of macrophages and microglia to the cytokine types indicate that in cytokine-driven autoimmune demyelinating disease, microglia may be the more aggressive cell in causing tissue injury by phagocytosis and oxidative injury, while infiltrating macrophages may produce most of the proteolytic activity thought to contribute to myelin destruction.
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PMID:Macrophage and microglial responses to cytokines in vitro: phagocytic activity, proteolytic enzyme release, and free radical production. 977 51

Leustroducsin B (LSN-B), a novel colony-stimulating factor (CSF) inducer, has been shown to have various biologic activities in vivo. To compare the CSF-inducing activity of LSN-B in vitro with that of the well-known cytokine inducer, interleukin-1beta (IL-1beta), bacterial lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA), we measured granulocyte (G)-CSF and granulocyte-macrophage (GM)-CSF levels that were induced with the stimuli in several mesenchymal cells. The results indicated that each stimulant displayed a different profile in the induction of G-CSF and GM-CSF. Next, to investigate if LSN-B induces cytokines other than G-CSF and GM-CSF, we characterized cytokines that were induced with LSN-B from bone marrow stromal cells (BMSCs). The results showed that a variety of cytokines, including G-CSF and GM-CSF, were induced in both clonal and primary BMSCs. From these results, we speculate that LSN-B induces cytokine production via a regulatory pathway distinct from that of IL-1beta, LPS, or PMA and that this signaling of LSN-B might lead to the production of a variety of cytokines in BMSCs. In addition, from our in vitro and in vivo results, we speculate that the biologic activities of LSN-B in vivo might be based on its own cytokine-inducing activity even though the target cell type of LSN-B in vivo remains to be determined.
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PMID:The effect of leustroducsin B on the production of cytokines by human mesenchymal cells. 980 22

We test the hypothesis that the monocyte-macrophage colony-stimulating factor (CSF-1 or M-CSF) plays a major role in the inflammatory responses of Mphi by acting as a priming agent that heightens their responsiveness to secondary stimulation by other mediators. We previously reported that CSF-1 induced peritoneal Mphi (PMphi) to transcribe several genes including interleukin-6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm). It was reported that the Il6 and Csfgm genes were individually regulated by different pathways but it was not clear to what extent the two genes interacted during Mphi-mediated inflammatory responses. We now show that CSF-1 induces the release of bioactive GM-CSF from mouse resident PMphi. GM-CSF induces Il6 gene expression and synergizes with CSF-1 to induce the release of large amounts of IL-6. PMphi from C57BL/6J-Csfgm(null) mice were shown to release minimal IL-6 in response to CSF-1 and to express a much reduced response to the highly stimulatory combination of CSF-1 and lipopolysaccharide (LPS). Exogenous recombinant GM-CSF restored the IL-6 response of GM-CSF null PMphi to a great extent but not completely. As controls, three other recombinant proteins were tested but of these only tumor necrosis factor alpha (TNF-alpha) was shown to synergize with both CSF-1 and GM-CSF. Using PMphi from mice deficient in the expression of the Il6 gene, it was shown that they released two- to threefold more GM-CSF in response to CSF-1 than their control counterparts. However, an exogenous supply of recombinant IL-6 had no effect on GM-CSF release. The data indicate that the pathways regulating Il6 gene expression are under the control of a complex network of cytokine interactions involving at least CSF-1, GM-CSF, and TNF-alpha, with the added possibility that IL-6 may exert modulatory activity within this network.
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PMID:CSF-1 regulation of Il6 gene expression by murine macrophages: a pivotal role for GM-CSF. 985 Jan 65

We examined whether priming monocytes (MO) with lipopolysaccharide (LPS) influenced their further differentiation into either macrophages (Mphi) or dendritic cells (DC). LPS-primed MO differentiated into Mphi when cultured further with Mphi colony-stimulating factor (M-CSF) but, if cultured then with granulocyte/Mphi (GM)-CSF and IL-4 (interleukin-4), only about 30% of the cells differentiated into CD1a+ CD14- DC and half became CD1a- CD14+ Mphi. Cytokines present during LPS priming could affect subsequent MO differentiation. Relative to priming with LPS alone, adding M-CSF to LPS did not modify differentiation of MO to Mphi in further culture with M-CSF, nor did it change the way of differentiation of MO into DC was altered if culture was later switched to GM-CSF/IL-4. Using GM-CSF/IL-4 plus LPS upon priming did not modify differentiation of MO to Mphi in further culture with M-CSF, as compared to priming with GM-CSF/IL-4 alone, but it counteracted the effect of LPS on the differentiation of MO to DC in further culture with GM-CSF/IL-4: about 75% of cells then became DC. Alternatively, despite activation by LPS, mature M-CSF-induced Mphi preserved the potential to differentiate into DC on subsequent culture with GM-CSF/IL-4. Thus, LPS, a bacterial product known to sustain maturation of MO/Mphi as well as of DC, may block the differentiation of MO into DC, except if signal triggering DC differentiation is delivered concomitantly, and modulate in this manner the induction of adaptive immune responses to infection.
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PMID:Lipopolysaccharide can block the potential of monocytes to differentiate into dendritic cells. 1008 6

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

Leptomeningeal (LM) neoplastic metastases are painful, debilitating and inevitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic potential. We evaluated 3F8, an anti-G(D2) murine IgG(3) monoclonal antibody (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NMB7) xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in the presence of rat neutrophils or rat complement. Antibody-dependent cellular cytotoxicity (ADCC) was not augmented by recombinant human GM-CSF (rhGM-CSF), rhG-CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysaccharide (LPS). In vivo, continuous intraventricular administration of 3F8 and LPS prevented tumor engraftment, retarded tumor growth and eradicated 3-day-old established xenografts whereas 3F8 alone, LPS alone or F(ab)'(2) plus LPS had no or only marginal effects. Tumor establishment in brain was completely prevented in 36% of animals implanted with SKMEL-1 and 65% of animals implanted with NMB7. Twenty percent of established xenografts around the brain were eradicated but all animals had persistent tumor in the lumbosacral meninges despite treatment. Continuous intraventricular infusion of LPS produced a variable polymorphonuclear (PMN) pleocytosis that was dose-dependent. Continuous intraventricular infusion of 3F8 produced immunohistochemically detectable attachment to 86% of persistent brain deposits of tumor but <1% of spinal lumbosacral deposits. We conclude that regional therapy with anti-G(D2) MAb could target neutrophils to inhibit LM tumor growth. However, optimal activation and mobilization of neutrophils into the cerebrospinal fluid (CSF) and improved penetration of MAb to tumor sites remain critical variables.
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PMID:Treatment of neoplastic meningeal xenografts by intraventricular administration of an antiganglioside monoclonal antibody, 3F8. 1040 68

A human THP-1 monocyte cell line culture system has been utilized to evaluate the morphological changes in THP-1 cells and to measure expression of activation antigens (CD-11b, CD-11c, CD-14, CD-35, CD-68, CD-71 and HLA-DR) as evidence of maturation of THP-1 cells in response to stimulation by lipopolysaccharide (LPS) from the oral microorganisms, Fusobacterium nucleatum and Porphyromonas gingivalis, and granulocyte-macrophage colony-stimulating factor. THP-1 cells were stimulated with LPS (1 microgram/ml) of P. gingivalis or F. nucleatum for different time periods (1, 2, 4 and 7 d). Detection of different activation antigens on THP-1 cells was performed by indirect immunohistochemical staining followed by light microscopy. Confirmational studies were performed in parallel using indirect immunofluorescence and immunogold electron microscopy for detection of the corresponding activation antigens. Expression of different activation antigens by resting THP-1 cells revealed HLA-DR to be on 3% of the cells; CD-11b, 9%; CD-11c, 8%; CD-14, 22%; CD-35, 9% and CD-68, 7%. The CD-71 activation antigen was not expressed in untreated THP-1 cells. LPS stimulation increased expression of all activation antigens. A significant (p < 0.05) increase in expression of CD-11b, CD-11c, CD-14, CD-35, CD-68 and CD-71 was observed when GM-CSF (50 IU/ml) was supplemented during the treatment of THP-1 cells with LPS of F. nucleatum or P. gingivalis. Activation and differentiation of THP-1 cells by LPS from oral microorganisms in the presence of GM-CSF supports a role for human macrophages in acute and chronic periodontal diseases and may explain the clinically observable periodontal exacerbations in some patients after GM-CSF therapy.
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PMID:Antigen activation of THP-1 human monocytic cells after stimulation with lipopolysaccharide from oral microorganisms and granulocyte-macrophage colony-stimulating factor. 1044 44

The aim of this study was to investigate the effects of pentoxifylline (PTX) on the production of TNF-alpha, IL-1 beta, IL-6 and GM-CSF by lipopolysaccharide (LPS)-stimulated alveolar macrophages (AM). AM and peripheral blood monocytes (PBM) from 10 patients were cultured for 24 h in the presence of LPS (10 micrograms ml-1) and PTX at concentrations of 2.0 mM, 1.0 mM, 0.5 mM, 0.1 mM and 0.01 mM. TNF-alpha and GM-CSF were measured from the culture supernatants of both the AM and PBM from all 10 patients and IL-1 beta and IL-6 from the culture supernatants of the AM from five patients. The TNF-alpha production by AM was significantly suppressed in the presence of PTX at concentrations of 2.0 and 1.0 mM, while production of IL-1 beta, IL-6 and GM-CSF remained unaffected. In PBM cultures, PTX significantly suppressed the production of TNF-alpha and GM-CSF, at all tested concentrations. The present study provides evidence that PTX selectively suppresses the production of TNF-alpha by LPS-stimulated AM and may have a role in the treatment of lung diseases where TNF-alpha is involved. The mode of administration of PTX should take into account the suppressive effect of this drug on GM-CSF production by PBM.
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PMID:The differential effect of pentoxifylline on cytokine production by alveolar macrophages and its clinical implications. 1046 49

Oncostatin M (OSM), an IL-6 subfamily cytokine, inhibits proliferation and causes morphological changes in many tumor cell lines. GM-CSF, phorbol-12-myristate-13-acetate (PMA), and lipopolysaccharide (LPS) induce OSM expression. To investigate the mechanisms governing OSM promoter activity, we have cloned and partially sequenced an 8.5 kb fragment of human genomic DNA immediately 5' of the OSM coding region and mapped the transcription start site. Transient transfection assays with a series of 5' deletion plasmids demonstrated maximal reporter activity in U937 cells with a minimum 304 bp construct. The 5'-proximal region of the human OSM gene contains a C/EBP consensus element around -45 bp and several GC-rich regions around -60, each of which is responsible for basal promoter activity. Electrophoretic mobility shift assay coupled with supershift analysis confirmed the presence of a cis -acting binding site for activated STAT5 complexes following GM-CSF treatment. Furthermore, transient transfection studies demonstrated a loss of GM-CSF responsiveness in reporter constructs containing mutations within this STAT element. Our results establish that C/EBP and an as yet unidentified GC-rich binding transcription factor are responsible for basal OSM promoter activity, while GM-CSF-stimulated OSM expression is driven by activated STAT5 complexes binding to a cis -acting STAT element on the OSM promoter.
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PMID:Cloning and characterization of human oncostatin M promoter. 1055 23


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