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PubMed1995

Nitric oxide production and mycobacterial growth inhibition by murine alveolar macrophages: the sequence of rIFN-gamma stimulation and Mycobacterium bovis BCG infection determines macrophage activation.

Prestimulation with recombinant-interferon-gamma (rIFN-gamma) followed by Mycobacterium bovis BCG infection induced high nitric oxide production and potent mycobacterial growth inhibition in murine alveolar macrophages. Reversal of the sequence of treatments caused opposite effects, suggesting that a sequential 2-step process comprising first rIFN-gamma stimulation and second mycobacterial infection is operative in the activation of alveolar macrophages.

Animals↗
PubMed1991

Differential activity of granulocyte-macrophage and macrophage colony stimulating factors on bone resorption in fetal rat long bone organ cultures.

In this study, the ability of recombinant human macrophage (M) and murine granulocyte-macrophage (GM) colony stimulating factor (CSF) to affect both basal and stimulated bone resorption in fetal rat long-bone organ cultures was assessed. It was found that M-CSF does not affect basal bone resorption or bone resorption stimulated by parathyroid hormone, recombinant human interleukin 1 beta, prostaglandin E2 (PGE2), and 1,25 dihydroxy vitamin D3. Specifically, M-CSF at concentrations as high as 30 nM (1 microgram/mL) did not modulate 45Ca release from fetal rat long bones stimulated by these agents. The addition of recombinant murine GM-CSF (at equal molar concentration to M-CSF) also did not affect bone resorption stimulated by parathyroid hormone and interleukin 1 beta. On the other hand, GM-CSF stimulated basal bone resorption over a 120-h period and augmented the resorption mediated by exogenous PGE2 over a 48-h incubation. In addition, GM-CSF was shown to stimulate production of endogenous PGE2 in cultures of bone rudiments. These effects on bone resorption were blocked by the addition of prostaglandin synthesis inhibitors and specific antibodies to murine GM-CSF. These data indicate that M-CSF does not act as a regulator of bone turnover, but GM-CSF may cause bone resorption by stimulating the synthesis of PGE2 in bone.

Animals↗
PubMed2005

Ursolic acid promotes the release of macrophage migration inhibitory factor via ERK2 activation in resting mouse macrophages.

Macrophage migration inhibitory factor (MIF) plays some pivotal roles in innate immunity and inflammation. Ursolic acid (UA), an anti-inflammatory triterpene carboxylic acid, was recently reported to induce the release of pro-inflammatory mediators in resting macrophages (Mvarphi). We investigated the effects of UA on MIF protein release in resting RAW264.7 mouse Mvarphi, and found that it decreased intracellular MIF protein levels and promoted the release of MIF into the culture media in dose- and time-dependent manners, without affecting mRNA levels. Further, the triterpene strikingly induced activation of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) within 30min, whereas no phosphorylation of p38 MAPK or JNK protein was observed. In addition, UA-promoted MIF release was significantly inhibited by PD98059, a MEK1/2 inhibitor, while siRNA for ERK2, but not ERK1, significantly decreased the amount of MIF protein released. These results suggest that UA triggers the release of intracellular MIF protein through the ERK2 activation.

Animals↗
PubMed2005

Effects of voriconazole, granulocyte-macrophage colony-stimulating factor, and interferon gamma on intracellular fluconazole-resistant Candida glabrata and Candida krusei in human monocyte-derived macrophages.

Infections caused by fluconazole-resistant Candida glabrata and Candida krusei are increasingly common causes of morbidity and mortality. We investigated the intracellular killing of fluconazole-resistant C. glabrata and C. krusei by cytokine-activated human monocyte-derived macrophages (MDM) in the presence and absence of voriconazole. For C. glabrata, MDM were activated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon gamma (IFN-gamma) before infection, after infection, or both before and after infection, whereas for C. krusei MDM were activated with cytokines both before and after infection. Activated MDM were infected, treated with voriconazole, and then lysed, and viable yeast in the lysates enumerated at 0, 24, or 48 h after infection. In the presence of voriconazole (2.5 x MIC), the best activity against C. glabrata occurred when MDM were activated with GM-CSF for 24 h before infection as well as after infection or when they were activated for 24 h before infection alone. A lesser effect was observed when MDM were activated for at least 1 h before infection or when they were treated with cytokines only after infection. IFN-gamma activation had a significant but lesser effect than GM-CSF. Activity against C. krusei in the presence of voriconazole was greatest when MDM were activated with IFN-gamma rather than GM-CSF. Our results suggest that cytokines increase the intracellular anticandidal effect of voriconazole and may be useful as therapeutic adjuvants to voriconazole for treatment of infections caused by fluconazole-resistant C. glabrata and C. krusei.

Antifungal Agents↗
PubMed2006

Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase.

The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is induced by glucocorticoids (GCs), but it was not previously known if MIF regulates cellular sensitivity to GC. Here we show in GC and LPS-treated peritoneal macrophages derived from MIF-/- and wt mice that the absence of endogenous MIF is associated with increased sensitivity to GC of TNF release. This is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), concomitant decreased phosphorylation of p38 MAPK, but no effect of MIF on nuclear factor kappaB (NF-kappaB). These results demonstrate that MIF regulates GC sensitivity by phosphorylation of p38, and provides a cellular mechanism for this observation, indicating that MKP-1 is a central target of this regulation.

Animals↗
PubMed1980

Chemical characterization of macrophage cytotoxicity factor, macrophage migration inhibitory factor, T-helper cell-replacing factor and colony-stimulating factor from culture supernatants of concanavalin A-stimulated murine spleen cells.

Supernatants from Concanavalin A-stimulated murine spleen cells were subjected to hydrophobic interaction chromatography on phenyl-Sepharose. Macrophage cytotoxicity factor (MCF), macrophage migration inhibitory factor (MIF), T-helper cell-replacing factor (TRF) and colony-stimulating factor (CSF) were bound at high ionic strength and were released stepwise at low ionic strength. CSF thus could be separated from MCF, MIF and TRF and the bulk of other proteins. Chromatograhy of pools containing MCF, MIF and TRF on Sephadex did not lead to a separation of the three activities which were all found in a molecular weight range of 25.000-55.000. Isoelectric focusing of these pools in pH range from 4 to 9 gave two peaks for MCF in a single sharp peak at pH 5.3. The results demonstrate that the four biological activities can be distinguished on a chemical basis and are accessible for purification and chemical characterization.

Animals↗
PubMed1982

Phagocytosis-stimulated macrophages. Production of prostaglandins and SRS-A, and prostaglandin effects on macrophage activation.

Quiescent mouse peritoneal macrophages which phagocytose, and which respond to phagocytosis with a sudden elevation in hexose monophosphate shunt activity, immediately release into the medium oxygen metabolites, arachidonic acid oxygenation products, and lysosomal hydrolases. Such cells subsequently differentiate and acquire the properties of inflammatory macrophages. The latter process appears to be under the control of prostaglandin E2 and possibly other cyclooxygenase products which are formed as a consequence of phagocytosis and seem to act as feed-back inhibitors.

Animals↗
PubMed2002

Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.

Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.

Animals↗
PubMed2001

The effect of macrophage-colony stimulating factor and other humoral factors (interleukin-1, -3, -6, and -11, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor) on human osteoclast formation from circulating cells.

Macrophage-colony stimulating factor (M-CSF) is an essential requirement for human osteoclast formation, but its effect on the proliferation and differentiation of circulating osteoclast precursor cells is unknown. Other growth factors and cytokines are also known to support/stimulate osteoclast formation from mouse marrow precursors, but it is not certain whether these factors similarly influence human osteoclast formation. In this study, human monocytes were cocultured with osteoblast-like UMR-106 cells on coverslips and dentine slices for up to 21 days in the presence of 1,25 dihydroxyvitamin D(3) (10(-7) mol/L), dexamethasone (10(-8) mol/L), and various concentrations of either M-CSF or other humoral factors (interleukin [IL]-1beta, IL-3, IL-6, and IL-11; tumor necrosis factor-alpha [TNF-alpha]; and granulocyte macrophage [GM]-CSF). The effect on osteoclast formation was assessed by tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor staining and lacunar bone resorption. The results of time-course and proliferation studies showed that M-CSF stimulated both the proliferative and differentiation stages of human osteoclast formation from circulating osteoclast precursors in a dose-dependent manner. A high concentration of M-CSF (100 ng/mL) did not inhibit osteoclast formation. IL-3 and GM-CSF were also capable of stimulating human osteoclast formation, although these growth factors were much less potent than M-CSF. IL-3- and GM-CSF-stimulated osteoclast formation was inhibited by an antibody specific for human M-CSF. Osteoclast formation and lacunar resorption was not seen when either TNF-alpha, IL-1beta, IL-6 (+ soluble IL-6 receptor), or IL-11 was substituted for M-CSF during coculture. These results confirm that M-CSF is essential for human osteoclast formation from circulating mononuclear precursors, and also shows that IL-3 and GM-CSF may support osteoclast differentiation via the stimulation of M-CSF production by human monocytes.

Adult↗
PubMed1999

Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors can stimulate the invasive capacity of human lung cancer cells.

We and other researchers have previously found that colony-stimulating factors (CSFs), which generally include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), promote invasion by lung cancer cells. In the present study, we studied the effects of these CSFs on gelatinase production, urokinase plasminogen activator (uPA) production and their activity in human lung cancer cells. Gelatin zymographs of conditioned media derived from human lung adenocarcinoma cell lines revealed two major bands of gelatinase activity at 68 and 92 kDa, which were characterized as matrix metalloproteinase (MMP)-2 and MMP-9 respectively. Treatment with CSFs increased the 68- and 92-kDa activity and converted some of a 92-kDa proenzyme to an 82-kDa enzyme that was consistent with an active form of the MMP-9. Plasminogen activator zymographs of the conditioned media from the cancer cells showed that CSF treatment resulted in an increase in a 48-55 kDa plasminogen-dependent gelatinolytic activity that was characterized as human uPA. The conditioned medium from the cancer cells treated with CSFs stimulated the conversion of plasminogen to plasmin, providing a direct demonstration of the ability of enhanced uPA to increase plasmin-dependent proteolysis. The enhanced invasive behaviour of the cancer cells stimulated by CSFs was well correlated with the increase in MMPs and uPA activities. These data suggest that the enhanced production of extracellular matrix-degrading proteinases by the cancer cells in response to CSF treatment may represent a biochemical mechanism which promotes the invasive behaviour of the cancer cells.

Adenocarcinoma↗
PubMed1998

Effect of granulocyte-macrophage colony-stimulating factor treatment on phenotype, cytokine release and cytotoxicity of circulating blood monocytes and monocyte-derived macrophages.

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.

Adult↗
PubMed1999

Granulocyte-macrophage colony-stimulating factor modulates lipopolysaccharide (LPS)-binding and LPS-response of human macrophages: inverse regulation of tumour necrosis factor-alpha and interleukin-10.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a well-known stimulus for the activation, differentiation and survival of monocytes (MO). Up to now most investigations focused on the short-term effects of GM-CSF. In this study we investigated the effects of GM-CSF on the long-term differentiation of human MO in the presence of serum. We found that MO-derived macrophages (Mphi) cultured with serum plus GM-CSF (GM-Mphi) were different from control Mphi (SER-Mphi) in terms of lipopolysaccharide (LPS)-stimulated cytokine release: GM-Mphi showed an increased tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production, especially at lower LPS concentrations, but the secretion of IL-10 was diminished. In addition, GM-Mphi secreted TNF-alpha but not IL-6 and IL-10, spontaneously. The spontaneous TNF-alpha production was not due to LPS contamination as it could not be blocked by anti-CD14 antibody. Flow cytometry revealed, however, that the receptor for LPS, CD14, was up-regulated on GM-Mphi and those Mphi released twice as much soluble CD14 into the supernatant as compared with SER-Mphi. The higher CD14 expression also resulted in an enhanced LPS-binding capacity of GM-Mphi. Furthermore, the LPS-response of GM-Mphi could only be blocked by about fourfold higher concentration of anti-CD14 antibody compared with SER-Mphi. In summary, GM-CSF promotes the generation of a pro-inflammatory type of Mphi in two different ways: first, the down-regulation of autocrine IL-10 production increases the release of cytokines such as IL-6 and TNF-alpha and second, the up-regulation of membrane and soluble CD14 expression leads to a higher sensitivity towards LPS-stimulation.

Antibodies, Monoclonal↗
PubMed2000

Mycoplasma gallisepticum -induced release of macrophage inflammatory protein-1 beta from chicken monocytes-macrophages.

Chicken monocytes and a macrophage-like cell line were used to determine the presence of macrophage inflammatory protein-1 beta (MIP-1 beta). RNA was extracted from these cells and subjected to reverse transcription with an anti-sense primer specific for the whole length of the MIP-1 beta cDNA. After a polymerase chain reaction to amplify the cDNA, a 200 bp gene product was detected, which corresponded to the molecular weight of the MIP-1 beta. The culture supernate of these cells did not have the ability to attract heterophils. However, after infection with Mycoplasma gallisepticum, a potent chemotactic substance in the culture supernate was detected. The chemotactic activity could be neutralized by antibodies prepared against two 10-amino-acid peptides of MIP-1 beta, indicating that the substance was MIP-1 beta.

Animals↗
PubMed2002

Effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on polymorphonuclear neutrophils, monocytes or monocyte-derived macrophages combined with voriconazole against Cryptococcus neoformans.

The antifungal activity of voriconazole (VCZ) was tested against Cryptococcus neoformans (Cn) with and without the addition of polymorphonuclear neutrophils (PMN), monocytes or monocyte-derived macrophages (MDM) in vitro. Human effector cells with and without the addition of VCZ were incubated with Cn for 24 h. PMN, mono and MDM alone resulted in 61%, 34% and 23% inhibition of Cn, respectively (n = 3, P<0.01). VCZ at 0.01 and 0.05 microg ml(-1) alone resulted in 48% inhibition and 19% killing (n = 6). The addition of VCZ at 0.01 and 0.05 microg ml(-1) to human effector cells enhanced killing of Cn by 51% and 71% for the PMN, 41% and 58% for the mono, and 14% and 34% for the MDM, respectively. The addition of either granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) significantly enhanced the ability of human effector cells to kill Cn. G-CSF and GM-CSF plus PMN resulted in 47% and 46% killing, respectively; GM-CSF plus monocytes or MDM resulted in 31% or 22% killing, respectively. G-CSF and GM-CSF further enhanced the collaborative killing effect of human effector cells and VCZ. At 0.01 and 0.05 microg ml(-1) of VCZ, G-CSF or GM-CSF enhanced PMN killing to 92% and 93% or 87% and 94%, respectively. GM-CSF enhanced both mono and MDM with VCZ at 0.01 and 0.05 microg ml(-1) in killing Cn to 62% and 86%, and 61% and 84%, respectively. These results suggest that VCZ would have good efficacy in the treatment of Cn infection in humans. Furthermore, VCZ would have enhanced efficacy in clinical settings where either G-CSF or GM-CSF was being used.

Antifungal Agents↗
PubMed1982

Precursor frequency analysis of lymphokine-secreting alloreactive T lymphocytes. Dissociation of subsets producing interleukin 2, macrophage-activating factor, and granulocyte-macrophage colony-stimulating factor on the basis of Lyt-2 phenotype.

The frequencies of precursors of C57BL/6 T lymphocytes that respond to DBA/2 alloantigens by secreting the lymphokines interleukin 2 (IL-2), macrophage-activating factor (MAF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been directly compared with cytolytic T lymphocyte precursor (CTL-P) frequencies in limiting dilution microcultures established from spleen cells positively or negatively selected on the basis of Lyt-2 phenotype. A clear dichotomy was observed between CTL-P, which were contained in the Lyt-2+ fraction, and precursors of IL-2-secreting cells, which were detected almost exclusively in the Lyt-2- population. In contrast, precursors of cells secreting MAF and GM-CSF were found in both populations: almost all responding cells from the Lyt-2- fraction produced both these factors, whereas the precursor frequency of MAF-secreting and GM-CSF-secreting cells was three- to fourfold lower in the Lyt-2+ population. These frequency data were consistent with quantitative differences observed in the average production of these lymphokines by Lyt-2+ and Lyt-2- populations.

Animals↗
PubMed1997

C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells.

Human immunodeficiency virus-1 (HIV-1) expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lipopolysaccharide (LPS). However, the mechanisms are incompletely understood. We show here that HIV-1 suppression is mediated by soluble factors released by MDM stimulated with physiologically significant concentrations of LPS. LPS-conditioned supernatants from MDM inhibited HIV-1 replication in both MDM and T cells. Depletion of C-C chemokines (RANTES, MIP-1 alpha, and MIP-1 beta) neutralized the ability of LPS-conditioned supernatants to inhibit HIV-1 replication in MDM. A combination of recombinant C-C chemokines blocked HIV-1 infection as effectively as LPS. Here, we report an inhibitory effect of C-C chemokines on HIV replication in primary macrophages. Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.

Cells, Cultured↗
PubMed1998

Monocyte-macrophages, granulocyte-macrophage colony-stimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants.

Recombinant GM-CSF has been recently shown to prolong survival of elderly patients with acute myeloid leukemia (AML) by reducing the rate of induction therapy-related mortality. In a prospective, randomized, placebo-controlled, double-blind, multicenter study conducted by the Eastern Cooperative Oncology Group in the United States, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given only to those patients who had hypocellular or remission marrow on day 10 of one or two cycles of standard induction therapy. Although the administration of GM-CSF significantly reduced a wide range of adverse events, the main benefit of this cytokine seems to be mediated by a reduction in sepsis. A similarly designed study, conducted by the Southwest Oncology Group in a directly comparable AML patient population with use of granulocyte colony-stimulating factor (G-CSF) as the supportive cytokine, showed no survival benefit and no reduction in the rates of serious or lethal sepsis. In most current clinical situations, GM-CSF and G-CSF are indistinguishable both in terms of efficacy and toxicity. GM-CSF and G-CSF have very different impacts on the survival of patients with AML. The stimulation of monocyte-macrophage function and proliferation by GM-CSF may mediate the selective benefit of GM-CSF in patients with AML and stem cell transplants. GM-CSF merits further study as therapy for and/or protection against opportunistic sepsis in patients with cancer and will be included in a number of International Oncology Study Group protocols.

Adult↗
PubMed1994

Human immunodeficiency virus (HIV)-infected human blood monocytes and peritoneal macrophages have reduced anticryptococcal activity whereas HIV-infected alveolar macrophages retain normal activity.

Human immunodeficiency virus type 1 (HIV-1) infection causes immune dysfunction. Mononuclear phagocytes (MNP) are immune effector cells against some intracellular pathogens and reservoirs for HIV-1. This study determined effects of HIV-1 on MNP-mediated antifungal function. MNP from seronegative volunteers were inoculated with HIVBal or HIVIIIB. MNP were infected with an avirulent clone of Cryptococcus neoformans; 48 h later, MNP were lysed and yeasts were counted. Viral replication was determined by reverse transcriptase and by visualization of cytopathic effects. Monocytes and peritoneal macrophages exhibited reduced anticryptococcal activity 14 days after infection with HIVBal but retained normal activity when infected with HIVIIIB. Loss of anticryptococcal activity correlated with viral replication. Alveolar macrophages retained normal anticryptococcal activity whether infected with HIVBal or HIVIIIB. In vitro MNP-mediated antifungal activity may be altered by HIV-1 infection; this altered activity appears to depend on viral tropism, viral replication, and MNP tissue origin.

Cell Survival↗