Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00035 (CSF)
 30,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular killing is regarded as one of the main functions of eosinophils. Therefore, a cytotoxicity assay against antibody-coated Daudi-lymphoma cells was established to measure cytokine effects on peripheral blood eosinophils from healthy volunteers. Optimal time of exposure to cytokines and half optimal concentrations (EC50) were determined and the capability of various cytokines to enhance cytotoxicity of eosinophils was compared. Thus, after 24 h with cytokine, the highest activation of eosinophils was observed with recombinant human rhIFN-gamma (EC50 = 0.2 U/ml), followed by the known activators of eosinophils recombinant human granulocyte/macrophage CSF (rhGM-CSF), rhIL-3, and murine IL-5 (mIL-5). rhIFN-alpha and natural human IFN-beta (nhIFN-beta) enhanced cytotoxicity as well. On the other hand, in short term assays, eosinophils were not stimulated by IFN and the strongest stimulator was rhGM-CSF (EC50 = 0.2 U/ml), followed by rhIL-3, mIL-5, rhTNF, and rhIL-4. With rhTNF-alpha enhancement was more pronounced on freshly isolated eosinophils (EC50 = 0.6 U/ml) and declined with time. No significant stimulation was detected with rhG-CSF, rhIL-1 beta, rhIL-2, rhIL-6, and rhIL-8. On neutrophils, rhIL-8 enhanced cytotoxicity, but the stimulation was weak in relation to other neutrophil activators. Studies on the mechanism of cytotoxic activity revealed that cytotoxicity required opsonization of targets with specific antibody. FMF analysis was performed demonstrating that freshly isolated eosinophils express Fc-gamma RII (CD32), small amounts of Fc-gamma RIII (CD16), but not Fc-gamma RI (CD64). In experiments with blocking antibodies to Fc-gamma R cytotoxicity was restricted to Fc-gamma RII. Expression of Fc-gamma RII was not enhanced by rhGM-CSF, rhTNF-alpha, and mIL-5, but a significant increase in the number of positive cells was observed after incubation with rhIFN-gamma for 24 h (p less than 0.05). In addition, enhanced viability of eosinophils was observed when cultured in the presence of rhIFN-gamma, rhIFN-alpha, rhGM-CSF, and rhTNF-alpha, but not of rhG-CSF and rhIL-2. Thus, IFN appear to be another class of activators of eosinophils, characterized by their delayed type of action.
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PMID:Effects of IFN on human eosinophils in comparison with other cytokines. A novel class of eosinophil activators with delayed onset of action. 169 67

We have previously shown that the antiviral state of explanted mouse peritoneal macrophages (PM) decays during in vitro culture and that this decay is much more rapid in Lpsd PM than it is in Lpsn PM. Moreover, Lpsn PM can transfer the antiviral state to other cells, whereas Lpsd PM cannot. In vitro treatment of Lpsn PM with different agents [i.e., bacterial lipopolysaccharide (LPS), interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, macrophage colony-stimulating factor (M-CSF) and antibody to Mac-1 antigen] induced an antiviral state to vesicular stomatitis virus (VSV) which was inhibited by antibodies to IFN-beta. Treatment of Lpsn PM with LPS or IFN-gamma resulted in greater accumulation of IFN-beta mRNA, whereas no change in the barely detectable levels of IFN-alpha mRNA was observed. Marked accumulation of IFN-beta mRNA was also observed in PM after TNF-alpha treatment. M-CSF and IFN-gamma (but not LPS) also induced an IFN-mediated antiviral state in Lpsd PM. Low levels of spontaneous transcription of IFN-beta mRNA were detected in nuclei from Lpsd PM. Treatment of Lpsd PM with IFN-gamma for 3 h resulted in the accumulation of IFN-beta mRNA without any concomitant increase in the transcription of the IFN-beta gene, as determined by run-on transcription assays with isolated nuclei. The addition of as little as I international unit/ml of IFN-gamma to PM resulted in a 100-fold inhibition of VSV yield. As antibodies to IFN-alpha/beta inhibited only a portion of the IFN-gamma-induced antiviral state, such an antiviral state might reflect the synergism between IFN-gamma and endogenous IFN-beta. In fact, the addition of low doses of both IFN-gamma and IFN-beta to either Lpsn or Lpsd PM resulted in synergistic antiviral effects. In vivo treatment of Lpsd mice with granulocyte-macrophage (GM)-CSF, M-CSF, IFN-gamma or Newcastle disease virus rendered peritoneal cells capable of transferring an antiviral state. These results indicate that (i) various stimuli can induce IFN-beta production by PM, (ii) Lpsd PM spontaneously transcribe low levels of IFN-beta mRNA, even though they cannot transfer an antiviral state, (iii) different stimuli, but not LPS, induce a normal IFN response in Lpsd PM, (iv) IFN-gamma increases the accumulation of IFN-beta mRNA in Lpsd PM by post-transcriptional mechanisms and (v) IFN-gamma may act synergistically with endogenous IFN-beta in inducing a potent antiviral state to VSV in PM.
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PMID:Effects of different biological response modifiers on interferon expression in bacterial lipopolysaccharide (LPS)-responsive and LPS-hyporesponsive mouse peritoneal macrophages. 170 75

In macrophages from inbred mice the magnitude of the interferon (IFN) response to Newcastle disease virus (NDV) infection is under genetic control of the locus If-1, with C57BL/6 carrying the 'high-producer' allele If-1h whereas BALB/c have the 'low-producer' allele If-1l. The IFN produced consists of 90% IFN-beta and there are 10-fold differences between macrophages from If-1h and If-1l mice. Recently, we observed that interleukin-6 (IL-6) is coinduced by NDV in macrophages and seems to be under the same genetic control. Noninduced macrophages have been shown to secrete low amounts of antiviral activity endogenously when cultured in the presence of the macrophage-colony-stimulating factor (M-CSF). Here, we report that the amount of this endogenous IFN varies between macrophages from different mouse strains. Macrophages from BALB/c were found to secrete 5-10 times more endogenous IFN compared to C57BL/6. The antiviral activity could be identified as IFN-beta. Interestingly, we observed that endogenous IFN specifically down-regulates NDV-induced IFN and IL-6 production. Preculture of BALB/c macrophages in M-CSF plus anti-IFN-beta to neutralize the biological effects of the endogenous IFN provoked a 30- to 50-fold increase in NDV-induced cytokine production, resulting in a nearly complete abrogation of the genetically determined difference since the same treatment only caused a 6-fold increase in C57BL/6 macrophages following NDV infection. This increase in cytokine gene expression was specific for NDV and marked by a strong additional activation of IFN-alpha genes. Addition of mouse recombinant IFN-alpha 4 to anti-IFN-beta-treated macrophages for 18 h prior to NDV infection down-regulated again IFN gene expression and reestablished the genetic differences between macrophages from If-1h and If-1l mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation by endogenous interferon of virus-induced cytokine gene expression in mouse macrophages. 171 14

Macrophage CSF (M-CSF, CSF-1) and IL-4 are two cytokines known to have effects on mature monocytic phagocytes in vitro. In this report we show that M-CSF and IL-4 activate resident mouse peritoneal macrophages to ingest particles via their C3b and C3bi receptors, which are not capable of mediating ingestion in resting cells. IgG-mediated ingestion was also increased by IL-4 and M-CSF. IL-1, IL-2, TNF-alpha, and IFN-gamma were not able to stimulate C receptor-mediated ingestion. Stimulation by IL-4 and M-CSF is dependent upon high cell density and greater than 24-h exposure to the cytokine. Interestingly, antibody to IFN-alpha/beta and mAb to IFN-beta inhibited the enhanced ingestion caused by both M-CSF and IL-4. However, neither IFN-alpha nor IFN-beta alone stimulated C receptor-mediated ingestion. M-CSF did not affect the ligand-independent distribution of CR3 on the macrophage surface. We conclude that two apparently unrelated cytokines, M-CSF and IL-4, both enhance macrophage phagocytosis of C and IgG-coated targets via a common pathway in which autocrine stimulation with IFN-alpha/beta is necessary but not sufficient.
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PMID:Cytokine regulation of complement receptor-mediated ingestion by mouse peritoneal macrophages. M-CSF and IL-4 activate phagocytosis by a common mechanism requiring autostimulation by IFN-beta. 198 89

Ia expression is an important marker of macrophage functional capacity. IFN-gamma induces Ia expression on perhaps all murine macrophages, whereas IL-4, granulocyte-macrophage CSF, and CSF-1 induce Ia on restricted sets of macrophages. Inhibitors of expression include PGE2, glucocorticoids, and IFN-beta. TNF has been found to augment Ia expression on several macrophage lineage cell lines but to inhibit expression on murine peritoneal macrophages. Our study shows that TNF can have opposite effects on Ia expression (induced by IFN-gamma) on thioglycollate-elicited peritoneal macrophages, depending on the length of time cells are treated and on the presence of other modulators. In particular, TNF augmented early expression induced by IFN-gamma but inhibited later expression. And although TNF synergized with PGE2 to markedly inhibit Ia induction on these cells, it partially antagonized the inhibition by corticosterone and IFN-beta. TNF and PGE2 also synergized to inhibit Ia expression induced on bone marrow-derived and splenic macrophages by either IFN-gamma or IL-4. In contrast to their effect on Ia expression, TNF and PGE2 had opposite effects on expression of gamma 2a FcR in macrophages. TNF blocked the increase in FcR expression due to any combination of PGE2, IFN-gamma, and IFN-beta. However, TNF and PGE2 both increased expression of gamma 2a FcR on WEHI-3 cells. If the different effects of TNF reflect the differentiation states of macrophages, its effects on Ia and FcR expression may vary with the progression of an immune response.
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PMID:Combined effects of tumor necrosis factor-alpha, prostaglandin E2, and corticosterone on induced Ia expression on murine macrophages. 211 76

We investigated whether various recombinant cytokines induce vascular hyperpermeability when intradermally injected into rats. Only TNF did so. Of the other cytokines examined (IL-1, IL-2, granulocyte-CSF, IFN-alpha, IFN-beta, IFN-gamma) none had this effect. The increase in vascular permeability was dose dependent, and the peak response was observed at 90 min after TNF injection. When mixtures of TNF and various other cytokines (IL-1, IL-2, granulocyte-CSF, IFN-alpha, IFN-beta, IFN-gamma) were injected, only IL-1 and IFN-gamma augmented TNF-induced vascular hyperpermeability, the increase occurring in a dose-dependent manner. The induction of vascular hyperpermeability by TNF and its enhancement by IL-1 and IFN-gamma were inhibited by selective depletion of peripheral blood neutrophils with i.p. administration of an anti-rat neutrophil mAb, RP-3. Reconstitution of neutrophils to the depleted rats by in situ injection of these cells, restored TNF increased vascular permeability.
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PMID:Vascular hyperpermeability induced by tumor necrosis factor and its augmentation by IL-1 and IFN-gamma is inhibited by selective depletion of neutrophils with a monoclonal antibody. 212 Mar 40

In response to antigenic stimulation, T cells and macrophages secrete a set of glycoproteins termed lymphokines and monokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, GM-CSF, G-CSF, IFN-alpha, IFN-gamma, TNF-alpha, and lymphotoxin. These glycoproteins mediate immune and inflammatory responses by regulating proliferation, differentiation and maturation of lymphocytes, hemopoietic cells and endothelial cells. Along with factors such as M-CSF, IL-7, LIF, IFN-beta and TGF-beta produced by stromal cells, all these molecules are collectively called cytokines. Most cytokines are pleiotropic and have multiple biological activities. Accordingly, regulatory network is formed between lymphoid cells, hemopoietic cells and endothelial cells. All or a part of this network can be activated in different ways by unique combinations of cytokines. IL-3, IL-4 and IL-5 produced by TH2 cells enhance whereas IFN-gamma produced by TH1 cells suppresses IgE mediated allergic response. Through production of a spectrum of cytokines, T cells and macrophages play a vital role in coordinating the function of different body compartments in immune and inflammatory responses. The activation of cytokines genes in T cells and macrophages is transient. Therefore, an inflammatory response that involves proliferation and maturation of hemopoietic progenitor cells may be restricted to the site of cytokine production. The inducible nature of the hemopoiesis associated with inflammatory response is in contrast to the constitutive, steady state hemopoiesis that occurs in the bone marrow microenvironment in the absence of immunological stimuli.
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PMID:[Coordinate regulation of immune and inflammatory responses by cytokines]. 219 88

Receptors for IgE (Fc epsilon R) on rat bone marrow-derived macrophages (BMDM phi) were demonstrated by a rosette assay employing trinitrophenyl-coated ox erythrocytes (EoTNP) sensitized with mouse IgE anti-dinitrophenyl monoclonal antibody (EoTNP-IgE). Virtually all BMDM phi emerging from bone marrow cells cultured for 1 week in the presence of mouse L929 cell supernatant, with partially purified murine CSF-1 or recombinant murine GM-CSF, formed IgE rosettes. To study the effect of interferons (IFNs) on Fc epsilon R expression, 1-week-old rat BMDM phi were incubated with murine recombinant IFN-gamma, purified IFN-alpha or IFN-beta, and were tested for their capacity to bind and ingest EoTNP sensitized suboptimally with IgE. A marked increase in the percentage of cells forming IgE rosettes or phagocytosing EoTNP-IgE was noted after 8-72 hr incubation of BMDM phi with 0.1-1000 U/ml of IFNs. At similar concentrations IFN-gamma and IFN-beta triggered EoTNP-IgE binding or ingestion more efficiently than IFN-alpha. The enhancing effect was blocked by the respective anti-IFN antibodies, cycloheximide or actinomycin D but not by mitomycin C. The IgE rosette formation and IgE-mediated phagocytosis were dose-dependently inhibited by native rat IgE but not by heat-denaturated IgE myeloma protein IR162 or monomeric rabbit IgG. Our results demonstrate that rat BMDM phi express constitutively Fc epsilon R, and that murine IFNs augment Fc epsilon R-mediated binding and ingestion in a time- and dose-dependent manner. This effect probably reflects an increase in the number of Fc epsilon R per cell, as a result of de novo synthesis of Fc epsilon R.
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PMID:Augmentation of IgE receptor expression and IgE receptor-mediated phagocytosis of rat bone marrow-derived macrophages by murine interferons. 245 Aug 38

Macrophage colony-stimulating factor (M-CSF) was investigated as a stimulator of ADCC to the murine R1.1 thymoma target by murine peritoneal exudate macrophages which were elicited by proteose peptone. Both an 125IUdR release and a viable cell count assay were used. The latter assay avoids radiation damage, and the fate of the targets can be determined over a long period. Pretreatment of macrophages for several days in culture with lymphokine (LK) from concanavalin A-induced mouse spleen cells moderately stimulated ADCC. Preincubation of macrophages with conventional or recombinant human M-CSF or immunoaffinity-purified mouse M-CSF alone had little effect. However, M-CSF greatly enhanced ADCC to the tumor target when used as a costimulant with LK, IFN-gamma, IFN-alpha, IFN-beta, or IL-2 to pretreat macrophages. Incubation of macrophages with LK or LK plus M-CSF for 2 days generated stronger ADCC than 1- or 3-day incubations. Enhancement of LK-stimulated ADCC by M-CSF appeared to plateau at about 1000 U/ml. The enhancement of macrophage cytotoxicity when stimulated with IFNs or IL-2 was most effective at the lowest active concentration of these LKs. At 1 U/ml IFN-gamma or IL-2, or 5 U/ml IFN-alpha or IFN-beta, M-CSF boosted ADCC activity to that using 10-fold of the LK alone. IL-1, IL-4, and TNF had little or no stimulating activity for ADCC alone or with M-CSF, and the other hemopoietic growth factors IL-3 and GM-CSF did not promote this effector function alone or with IFN-gamma. We previously showed that M-CSF boosted macrophage antibody-independent killing of TU5 sarcoma targets with or without LK (Cell. Immunol. 105, 270, 1987). These studies thus show that M-CSF is a positive regulator of both macrophage-nonspecific tumor lysis and ADCC.
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PMID:Stimulation of macrophage antibody-dependent killing of tumor targets by recombinant lymphokine factors and M-CSF. 246 Feb 49

To determine the effects of immunomodulatory agents upon HIV replication in macrophages, cultured monocyte-derived macrophages were treated with various substances and then infected with a macrophage-tropic strain of HIV-1. Pretreatment with rIFN-alpha, IFN-beta, and IFN-gamma, or bacterial LPS prevented viral replication in macrophages. In treated cultures, little or no infectious HIV or p24 core antigen was released into the supernatant, no virions were seen by electron microscopy, no viral RNA or DNA was detectable in the cell lysates, and no cytopathology (as determined by multinucleated giant cell formation) occurred. In contrast, pretreatment with a wide dose range of recombinant IL-1 beta, IL-2, IL-4, IL-6, M-CSF, TNF, or lymphotoxin failed to protect macrophages from productive infection by HIV. A consistent effect of granulocyte/macrophage-CSF on HIV replication in macrophages was not observed. In dose response studies, pretreatment with approximately 100 U/ml of IFN-alpha, approximately 10 U/ml of IFN-beta, or approximately 100 U/ml of IFN-gamma was sufficient to prevent virion release maximally and to prevent cytopathology completely. In kinetic studies, IFN-alpha, IFN-gamma, or LPS were added to the macrophage cultures either before or after infection with HIV. Even when added 3 d after infection with a multiplicity of 1 50% tissue-culture infectious dose per cell, all three treatments markedly reduced virion release, suggesting that these agents act at a point in the viral life cycle beyond the early events of virus binding, penetration, and uncoating. These data indicate that HIV replication in previously uninfected macrophages may be regulated by an inducible host cell mechanism. These findings may explain the restricted replication of HIV in macrophages in vivo and suggest an antiviral role for interferons in the therapy of HIV infection.
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PMID:Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro. 246 37


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