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)

Activated macrophages mediate cytotoxicity against tumor targets and thus may modulate development and growth of metastatic tumor cells. Macrophage colony stimulating factor (M-CSF) has a potential role in activating mature macrophages to a cytotoxic state. We employed a murine Kupffer cell (KC) model of cytotoxicity against a tumor necrosis factor (TNF) - sensitive murine colon adenocarcinoma cell line (MCA26) to evaluate the ability of recombinant human M-CSF (rhM-CSF) 1) to act alone as a KC-activating agent and 2) to enhance KC cytotoxicity against MCA26 cells in association with known macrophage activating compounds. rhM-CSF produced a dose-dependent increase in TNF release by KC in vitro with a parallel increase in MCA26 killing. KC activated by rhM-CSF produced less TNF and concomitantly demonstrated a lower cytotoxicity against MCA26 cells when compared with KC activated by gamma interferon (gamma IFN) with or without lipopolysaccharide (LPS). M-CSF did not act in a synergistic fashion with gamma IFN and LPS to increase TNF secretion or cytotoxicity against MCA26 cells. rhM-CSF thus acts as a single agent capable of activating murine KC to a cytotoxic state but does not cooperate with classical priming/triggering signals to achieve KC activation.
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PMID:Human recombinant macrophage colony stimulating factor activates murine Kupffer cells to a cytotoxic state. 211 71

Peripheral blood-derived human polymorphonuclear leukocytes (PMNL) can be induced to synthesize prostaglandin E2 (PGE2) from endogenous and exogenous arachidonic acid (AA) when exposed to agents such as human recombinant (hr) granulocyte-macrophage (GM) colony-stimulating factor (CSF), hr tumor necrosis factor-alpha, hr granulocyte (G)-CSF, lipopolysaccharide and the chemoattractant N-formyl-methionyl-leucyl-phenylalanine. Treatment of PMNL with hr macrophage (M)-CSF and interleukin 3, however, did not result in detectable PGE2 synthesis. Cytokines stimulated PGE2 production during two distinct time intervals, an early peak of PGE2 that was detectable at 20 min and a late one detectable after 4 h. Inhibition of protein synthesis by cycloheximide (CHX) had virtually no effect on the early increase of PGE2 but prevented the late increase. Late addition of CHX to cultures after stimulation with hr GM-CSF at 4 h resulted in decline of PGE2 synthesis from exogenous arachidonic acid. Treatment of PMNL with GM-CSF had direct effects on cyclooxygenase (COx). PMNL depleted from COx by acetyl salicylic acid (ASA) recovered to synthesize PGE2 following exposure to GM-CSF. Recovery from COx inhibition by ASA could be prevented by CHX.
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PMID:Cytokine-stimulation of prostaglandin synthesis from endogenous and exogenous arachidonic acids in polymorphonuclear leukocytes involving activation and new synthesis of cyclooxygenase. 212 94

Human T cell hybridomas were constructed by somatic cell fusion in order to dissect molecular heterogeneity of human macrophage activating-factors (MAF). Two stable human hybridoma supernatants contained MAF activity capable of inducing human monocytes tumoricidal without the help of bacterial lipopolysaccharide (LPS). These supernatants in the presence of LPS could also render mouse macrophages tumoricidal. In contrast, recombinant and natural human interferon-gamma (Hu-IFN-gamma) activated human monocytes, but not mouse peritoneal macrophages. The supernatants from the two clones could neither support the growth of human-granulocyte-macrophage colony stimulating factor/human-interleukin-4-dependent (Hu-GM-CSF/Hu-IL-4) cell lines, such as AML 193 and TALL-101, nor stimulate the proliferation of human-interleukin-2-dependent human cell line and lectin-stimulated lymphoblast, which are responsive to human-interleukin-2 and human-interleukin-4. Rabbit or murine antibodies against human-interferon-gamma (Hu-IFN), human-granulocyte-macrophage colony stimulating factor, human interleukin-1 alpha, human-interleukin-1 beta, human-interleukin-6, human-tumour necrosis factor (Hu-TNF), human-lymphotoxin and human-macrophage migration inhibitory factor (Hu-MIF) could not absorb MAF activity. MAF activity in the hybridoma supernatants is associated with the two polypeptides of molecular weights of 70,000-80,000 and 20,000-30,000 daltons, as determined by gel filtration. These results indicate decisively that novel MAF molecule(s) is secreted by human T cell hybridomas.
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PMID:Constitutive production of novel macrophage-activating factor(s) by human T cell hybridomas. 212 37

To clarify which cytokines could potentially be produced by astrocytes, we have assessed the presence of mRNA for a number of cytokines in astrocyte-enriched brain cultures. The cultures were derived from neonatal murine brain and were treated with either interferon-gamma, lipopolysaccharide or tumor necrosis factor-alpha, or infected with murine cytomegalovirus. RNA was extracted at 0, 4, 24 and 48 hours post treatment. A DNA copy of total cytoplasmic RNA was synthesised and specific cDNA amplified using the polymerase chain reaction and detected by hybridization with specific probes. The following cytokines were studied: IL3, IL4, IL6, TNF alpha, TGF beta, LIF, G-CSF, M-CSF and GM-CSF. Transcripts for TGF beta, IL6, LIF and M-CSF were present constitutively but increased with stimulation, whereas transcripts for TNF alpha, IL6, GM-CSF, G-CSF and LIF were detected only after stimulation. Messenger RNA for IL3 and IL4 was not detected. The magnitude and kinetics of the induction varied according to the cytokine and the stimulus. These results indicate the possibility of intra-cerebral production of a number of cytokines that may play a role in the clearance of viral or bacterial pathogens and in the generation of neuropathology.
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PMID:Detection of cytokine mRNA in astrocyte cultures using the polymerase chain reaction. 216 30

We examined the role of augmented formation of intracellular cyclic AMP (cAMP) in the mediation of stromal cell growth factor production that occurs constitutively or upon cytokine stimulation. Clonal murine marrow adherent cell lines were stimulated under serum-free conditions by interleukin-1 (IL-1) or lipopolysaccharide (LPS) and one (+/+ -1.LDA11) was found to produce low quantities of granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF identity was confirmed by the ability of supernatants from stromal cells to promote proliferation of the factor-dependent cell line FDC-P1, neutralization of this activity by antiserum to GM-CSF, and by Northern blot analysis. However, optimal concentrations of IL-1 and tumor necrosis factor-alpha (TNF-alpha), in combination, led to synergistic (greater than 5-fold higher quantity) GM-CSF production compared with either stimulus alone in the +/+ -1. LDA11 cell line, capable of GM-CSF production after only single stimulation with IL-1 or LPS. In addition, synergistic stimulation by IL-1 and TNF-alpha led to equivalent high amounts of GM-CSF in another cell line incapable of GM-CSF production after induction with only IL-1 or LPS. Any of several means to raise intracellular cAMP levels, including addition of 8-bromo-cyclic AMP (8Br cAMP) (0.25-1mM), pertussis toxin (20-100 ng/ml), or addition of prostaglandin E1 (PGE1) (1 microM), failed to stimulate GM-CSF production alone and strongly inhibited GM-CSF production in stromal cells stimulated by IL-1, LPS, or the synergistic combination of IL-1 and TNF-alpha. In addition, PGE1 and pertussis intoxication were agonists of adenylate cyclase in membranes of marrow adherent cells, whereas IL-1 and LPS were not. The role for regulators of intracellular cAMP was specific because any of the cAMP agonists alone, or in the presence of cytokine stimulators of stromal cells, strongly enhanced IL-6 production, an event known to be cAMP-responsive. Thus, acute formation of intracellular cAMP is a negative regulator of stromal cell GM-CSF production mediated by cytokines, but positively regulates IL-6 production and may be an important determinant of cytokine-directed marrow microenvironmental function. These findings on the requirement for augmentation versus inhibition of cytokine-mediated production of hemopoietic growth factors might be applied to an analysis of marrow stromal cell heterogeneity.
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PMID:Role for cyclic AMP in the postreceptor control of cytokine-stimulated stromal cell growth factor production. 216 2

We investigated the production of interleukin-3 (IL-3)-like factor by murine astrocytes. Supernatants from lipopolysaccharide (LPS)-stimulated astrocytes induced proliferation of IC-2, an IL-3- and granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent cell line. This activity was completely neutralized by the antibody against GM-CSF but not by the anti-IL-3 monoclonal antibody. Northern blot analysis revealed the expression of GM-CSF mRNA, but not of IL-3 mRNA, in cultured astrocytes. These results indicate that with proper stimuli murine astrocytes produce GM-CSF.
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PMID:Production of granulocyte/macrophage colony-stimulating factor by cultured astrocytes. 219 11

We have investigated the expression of macrophage-colony stimulating factor (M-CSF) gene in mouse brain during development. Northern blot analysis of cerebral RNA evidenced a 4.5-kb M-CSF transcript from day 14 of gestation until 2 weeks after birth. The cell type responsible for this transcription was studied using in vitro cell cultures. The 4.5-kb M-CSF transcript was found both in astrocyte primary cultures and in immortalized astrocytic cell lines. M-CSF mRNA was also detected in lipopolysaccharide-stimulated brain macrophage cultures. These results suggest that M-CSF is involved in the outgrowth of microglia during ontogenesis.
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PMID:Expression of macrophage colony-stimulating factor gene in the mouse brain during development. 219 67

The viability of normal bone marrow myeloid precursor cells induced by interleukin-6 (IL-6) or IL-1 alpha and the ability of IL-6 and IL-1 alpha to induce the formation of colonies of granulocytes, macrophages, or megakaryocytes in densely seeded bone marrow cultures was suppressed by transforming growth factor-beta 1 (TGF-beta 1). Induction of normal bone marrow colony formation by IL-3 was much less sensitive to TGF-beta 1, and there was little or no effect of TGF-beta 1 on colony formation induced by macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF). In different clones of myeloid leukemic cells, TGF-beta 1 suppressed differentiation induced with IL-6, IL-1 alpha, or lipopolysaccharide (LPS), but did not suppress differentiation induced with IL-3 or GM-CSF. The effect of TGF-beta 1 on differentiation of the leukemic cells can be dissociated from its effect on cell growth. TGF-beta 1 suppressed the production of IL-6 in normal bone marrow cells cultured with IL-1 alpha and the production of IL-6 and GM-CSF in leukemic cells cultured with IL-1 alpha or LPS. The suppression of IL-6 production can explain the suppression by TGF-beta 1 of the effects of IL-1 alpha and LPS that are mediated by IL-6. TGF-beta 1 also suppressed differentiation in clones of myeloid leukemic cells induced with differentiation factor/leukemia inhibitory factor and tumor necrosis factor. In different leukemic clones TGF-beta 1 suppressed or enhanced induction of differentiation with dexamethasone. The results show that TGF-beta 1 can selectively control the activity of different molecular regulators of normal and leukemic hematopoiesis.
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PMID:Selective regulation of the activity of different hematopoietic regulatory proteins by transforming growth factor beta 1 in normal and leukemic myeloid cells. 220 8

The effects of macrophage colony-stimulating factor (M-CSF or CSF-1) on the survival, proliferation, maturation and activation of human blood monocytes were examined. M-CSF (100-1,000 U/ml) doubled the number of monocytes surviving after eight days in culture and accelerated the usual increase in cell volume. Antiserum to M-CSF abolished both of these effects. There was no sizable increase in 3H-thymidine incorporation in monocytes over this time period. Of various factors tested, including gamma-interferon (gamma-IFN), interleukin (IL) 1 alpha, granulocyte CSF (G-CSF), platelet-derived growth factor (PDGF), and lipopolysaccharide (LPS), only granulocyte-macrophage CSF (GM-CSF) could also enhance survival and augment cell volume. While antiserum to human M-CSF eliminated the increase in survival induced by GM-CSF, it could not ablate the GM-CSF-stimulated increase in monocyte cell volume. Monocyte cell surface markers that increase with maturation (i.e., Fc gamma RIII) or with activation (i.e., Fc gamma RI) were unaffected by incubation with M-CSF.
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PMID:Examination of survival, proliferation and cell surface antigen expression of human monocytes exposed to macrophage colony-stimulating factor (M-CSF). 223 Feb 85

We have previously reported that lipopolysaccharide (LPS) could induce the production of interleukin-3 (IL-3) by mouse spleen cells. In the present study, we show that recombinant human interleukin-1, in the absence of other stimuli, is able to induce the production of IL-3. IL-3 was detected in the supernatants of adult, although neither in young nor in nude mouse splenocytes and was assessed by its capacity to support the growth of the IL-3-dependent FDC-P2 cell line. The presence of IL-3 was antigenically confirmed with a monoclonal anti-IL-3 antibody. Both recombinant IL-1 alpha and IL-1 beta had similar potential for inducing IL-3 production. IL-3 activity was detected in the supernatants of cells cultured in the presence of 100 pg/ml IL-1; maximal IL-3 levels were obtained with 10-30 ng/ml IL-1. Kinetic studies of IL-1-induced IL-3 production indicated that 4-6 days of culture were required for optimal production, whereas 1-2 days were sufficient in cultures stimulated with concanavalin A. Recombinant IL-6 failed to induce significant amounts of IL-3, and TNF alpha induced only weak IL-3 production. GM-CSF but not M-CSF could lead to the appearance of IL-3 in spleen cell culture supernatants. Removal of macrophages decreased the production of IL-3 induced by LPS and GMF-CSF though did not affect the IL-3 production induced by IL-1. This observation suggests that IL-1 production might be an intermediate event in IL-3 production induced by LPS and GM-CSF through the activation of macrophages. IL-3 was detected in culture supernatants of B-cell-depleted splenocytes indicating that T-cells were the source of IL-3. Surprisingly T-cell-depleted populations could also produce IL-3 upon IL-1 stimulation. Preliminary experiments with an autoreactive CD4- CD8- V beta 8+ clone suggested that these cells might also be involved in the described IL-3 production.
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PMID:Induction of interleukin-3 by interleukin-1 in the absence of other exogenous stimuli. 236 39


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