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PubMed1984

Macrophage effector function in pulmonary oxygen toxicity: hyperoxia damages and stimulates alveolar macrophages to make and release chemotaxins for polymorphonuclear leukocytes.

Macrophages synthesize many secretory products in vitro but the stimuli for their production and their pathophysiologic significance in vivo are largely unknown. In the present investigation, we found that hyperoxia damaged rabbit alveolar macrophages (AM) in vitro as manifested by decreased cell numbers, increased lactate dehydrogenase (LDH) release, and the development of ultrastructural abnormalities that resembled those seen in AM in situ or lavaged from lungs of rabbits exposed to hyperoxia in vivo. Hyperoxia also stimulated cultured rabbit AM to release chemotaxins for polymorphonuclear leukocytes (PMN) that were similar in molecular weight to chemotaxins obtained from lung lavages of rabbits exposed to hyperoxia in vivo. Our results suggest that alveolar macrophage secretory products may play a physiologically relevant role in recruitment of PMN to the lungs in pulmonary oxygen toxicity.

Animals↗
PubMed1991

Intracellular localization of a lipopeptide macrophage activator: immunocytochemical investigations and EELS analysis on ultrathin cryosections of bone marrow-derived macrophages.

Synthetic lipopeptides, structurally derived from the N-terminal part of bacterial lipoprotein, constitute macrophage and B-lymphocyte activators. The molecular mechanism of macrophage activation by lipopeptides still remains unclear. The purpose of our study was to determine the route and kinetics of lipopeptide distribution in bone marrow-derived macrophages. The intracellular localization of the C-terminally biotinylated lipodipeptide Pam3Cys-Ser was investigated on ultrathin cryosections using the biotinstreptavidin-gold system. Our findings indicate that the lipopeptide penetrates the plasma membrane and can already be found within the cytoplasm, the nuclear membrane, and within the nucleus after 2 min of stimulation. The pattern of lipopeptide distribution obtained 2 min after stimulation resembles that obtained after longer incubation times (8 and 20 min). Correlating distribution patterns were observed when using the method of electron energy loss spectroscopy (EELS). These findings are a clear indication for the rapid uptake of lipopeptides into eukaryotic cells, and are of importance for further studies of the immunostimulating properties of the bacterial lipopeptides and vaccines derived therefrom.

Animals↗
PubMed2000

Enhancement of oxidised low-density lipoprotein uptake by macrophages in response to macrophage migration inhibitory factor.

We examined the expression of macrophage migration inhibitory factor (MIF) mRNA in murine macrophage cell line (RAW 264.7 cells) in response to oxidized low-density lipoprotein (oxLDL), and investigated the influence of MIF on the uptake and degradation of oxLDL by RAW 264.7 cells. MIF mRNA expression was markedly upregulated in the presence of oxLDL. Consistent with this, the MIF level of the culture medium was increased by stimulation with oxLDL in dose- and time-dependent manners. Next, we added recombinant rat MIF to the culture medium and examined its effects on the uptake of(125)I-labelled oxLDL. Pretreatment with MIF enhanced both the uptake and degradation of(125)I-oxLDL. Taken together, these results suggest that MIF released from macrophages in response to oxLDL stimulates oxLDL uptake and degradation in an autocrine and paracrine fashion, which potentially results in atherosclerosis.

Animals↗
PubMed2002

Regulation of bronchoalveolar macrophage proinflammatory cytokine production by dexamethasone and granulocyte-macrophage colony-stimulating factor after stimulation by Aspergillus conidia or lipopolysaccharide.

There is substantial evidence that local production of proinflammatory cytokines are very important in host resistance to aspergillosis. Dexamethasone (DEX) down-regulates production of these cytokines by stimulated bronchoalveolar macrophages (BAM) and constitutes a risk factor for aspergillosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonizes DEX suppression of antifungal activity by BAM. Here we investigated the possibility that GM-CSF could antagonize DEX down-regulation of interleukin (IL)-1alpha and tumour necrosis factor (TNF)-alpha production by stimulated BAM. Control BAM responded to increasing numbers of conidia of Aspergillus fumigatus with increasing production of IL-1 and TNF. DEX (10(-7)M) significantly suppressed IL-1 and TNF production by BAM+conidia. Although GM-CSF did not enhance IL-1 or TNF production by BAM+conidia, GM-CSF significantly antagonized DEX suppression of IL-1 cytokine production. For comparative purposes, lipopolysaccharide (LPS, 1 microg/ml) was used to stimulate BAM in experiments similar to the above. In contrast to the findings with conidia, GM-CSF enhanced the production of IL-1 (5-fold) and TNF (1.5-fold) by LPS treated BAM. DEX suppression of cytokine production by BAM+LPS was modestly but significantly antagonized by GM-CSF. Moreover, differences between regulation of IL-1 and TNF production by BAM+conidia or LPS and peritoneal macrophages (PM)+conidia or LPS were documented. Finally, the anti-inflammatory cytokine IL-10 was minimally produced by BAM + conidia or LPS, but IL-10 was produced by PM + conidia or LPS. In summary, these data indicate that the risk factor for aspergillosis associated with DEX could be lessened in the pulmonary compartment with GM-CSF. On the other hand, desired effects of DEX could be maintained in other compartments.

Animals↗
PubMed1986

In vitro interactions of murine peritoneal macrophages and sarcoma cells. II. Induction of DNA synthesis in macrophages.

Unstimulated peritoneal macrophages grown in vitro for 5 days do not incorporate thymidine. Sarcoma (AA) cells introduced to the culture on the fifth day die and disintegrate whereas the macrophages become markedly stimulated and autoradiography shows that they are triggered to synthesize DNA. In syngeneic cocultures up to 28% of the macrophages incorporate thymidine after 5 days of coculture.

Animals↗
PubMed2005

Tripeptide tyroserleutide enhances the antitumor effects of macrophages and stimulates macrophage secretion of IL-1beta, TNF-alpha, and NO in vitro.

Tyroserleutide (YSL) is a type of active, low molecular weight polypeptide, comprised of three amino acids, which has antitumor effects. YSL has various advantages over the other bioactive peptides such as its low molecular weight, simple construction, nonimmunogenicity, specificity, few side effects, and ease of synthesis. However, the biological activities contributing to it's antitumor effects are not yet known. We studied the effects of YSL on the in vitro cytotoxic activity of BALB/c mice peritoneal macrophages (PEMphi) against the target tumor cell lines BEL-7402 and B16-F10. We also measured the concentrations of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and nitric oxide (NO) produced by YSL-activated Mphi, and we determined the concentrations of IL-1beta and NO secreted by YSL-activated murine macrophage RAW264.7 cells. YSL activated Mphi in vitro, inhibited BEL-7402 proliferation, enhanced PEMphi antitumor effects, and stimulated IL-1beta, TNF-alpha, and NO production by RAW264.7 cells. These data suggest that YSL activates the monocyte-macrophage system, which enhances Mphi antitumor effects against BEL-7402 and B16-F10 cells and stimulates the secretion by Mphi of cytotoxic effectors such as IL-1beta, TNF-alpha, and NO.

Animals↗
PubMed2005

Down-regulation of osteoprotegerin production in bone marrow macrophages by macrophage colony-stimulating factor.

Macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL) induce the differentiation of bone marrow macrophages (BMMs) into osteoclasts. To delineate mechanisms involved, the effect of M-CSF on the production of osteoprotegerin (OPG), decoy receptor of RANKL, in BMMs was investigated. Mouse bone marrow cells were cultured with M-CSF for 4 days and adherent cells formed were used as BMMs. BMMs were cultured with or without M-CSF, and analyzed for expression of OPG and receptor activator of NF-kappaB (RANK; receptor for RANKL) mRNAs by real-time polymerase chain reaction and secretion of OPG by enzyme-linked immunosorbent assay. BMMs expressed macrophage markers, CD115 (c-fms), Mac-1 and F4/80, and showed phagocytotic activity. In addition, BMMs expressed OPG mRNA and secreted OPG into medium. M-CSF inhibited both the OPG mRNA expression and the OPG secretion dose-dependently and reversibly. The expression of RANK mRNA was not significantly affected by M-CSF. The results showed that M-CSF suppresses the OPG production in BMMs, which may increase the sensitivity of BMMs to RANKL.

Animals↗
PubMed2002

The natural resistance-associated macrophage protein 1 Slc11a1 (formerly Nramp1) and iron metabolism in macrophages.

Slc11a1 (solute carrier family 11 member 1) (formerly Nramp1) modulation of iron metabolism in macrophages plays an important role in early phase macrophage activation, and therefore host innate immunity. This review focuses on the role of Nramp1 in intramacrophage iron metabolism, with emphasis on the two prevailing mechanisms of Nramp1 modulation of iron metabolism in macrophages.

Animals↗
PubMed2001

Macrophage inflammatory protein-1alpha and C-C chemokine receptor-1 in allergen-induced skin late-phase reactions: relationship to macrophages, neutrophils, basophils, eosinophils and T lymphocytes.

BACKGROUND: Macrophage inflammatory protein (MIP)-1alpha binds to C-C chemokine receptor (CCR)-1 with high affinity. CCR-1 is expressed on neutrophils, eosinophils, monocytes, T lymphocytes and basophils; cells characteristic of atopic allergic inflammation. In vitro, MIP-1alpha is chemotactic for monocytes, T cells and basophils and is also a potent histamine-releasing factor for basophils and mast cells. Although increased levels of MIP-1alpha were shown in atopic allergic disorders, the kinetics of expression of these CC chemokines in vivo is largely unknown. OBJECTIVE: To investigate the kinetics of expression of MIP-1alpha and receptor CCR-1 and the relationships between the expression and infiltration of inflammatory cells in allergen-induced cutaneous late-phase reactions in atopic subjects. METHODS: Cryostat sections, obtained from skin biopsies from 10 human atopic subjects at 6, 24, 48, 72 h and 7 days after allergen challenge, were processed for immunohistochemistry and in situ hybridization using 35S-labelled riboprobes. RESULTS: The peak expression of allergen-induced mRNA for MIP-1alpha and CCR-1 was 6 h. This was maintained at 24 h, and gradually returned to base line at 7 days. At 6 h, the number of cells expressing MIP-1alpha mRNA significantly correlated with elastase+ neutrophils and BB-1+ basophils. At 24 h, the MIP-1alpha mRNA+ cells significantly correlated with CD68+ macrophages. There were significant inverse correlations between the numbers of MIP-1alpha mRNA cells and the numbers of Tryptase+ mast cells at 6 and 24 h after allergen challenge. CONCLUSION: Allergen-induced cutaneous late-phase reactions in humans were associated with increased expression of MIP-1alpha and CCR-1. This may be relevant to the infiltration of neutrophils, eosinophils, basophils and macrophages.

Basophils↗
PubMed2000

Effects of macrophage-colony-stimulating factor deficiency on the maturation of microglia and brain macrophages and on their expression of scavenger receptor.

Macrophage-colony-stimulating factor (M-CSF) regulates the survival, proliferation and differentiation of the mononuclear phagocyte lineage. Osteopetrotic (op/op) mice defective in producing functional M-CSF were used in order to investigate the role of M-CSF on the development of microglia and brain macrophages and the expression of scavenger receptor (SR). Adult op/op and littermate mice at 10-47 weeks of age were investigated by immunohistochemistry with a panel of monoclonal antibodies (F4/80, Mac-1, anti-major histocompatibility complex (MHC) class II and anti-SR), electron microscopy and reverse transcriptase-polymerase chain reaction (RT-PCR). Microglia were weakly immunolabeled with F4/80 and Mac-1 in op/op and littermate mice, but the number of microglia in op/op mice was reduced in the cerebrum, cerebellum and brainstem compared with that of normal littermates. The numbers of Mac-1-positive microglia in op/op mice was 39% (pons) and 30% (cerebellar cortex) lower than that in normal littermates (P<0.05). In addition, the microglia cell processes in op/op mice were often shorter than those in control mice. In op/op and littermate mice, both MHC class II and SR were present in perivascular cells and macrophages of the leptomeninx and choroid plexus. Ultrastructurally, perivascular cells appeared to be immature, since their cytoplasm was narrow and contained few inclusion bodies compared with those of control mice. Reverse transcriptase-polymerase chain reaction showed a weak expression for SR mRNA in the brains of op/op mice as well as littermate mice. These results indicate that microglia are partly dependent on M-CSF for their proliferation and differentiation and that M-CSF has no significant effect on the expression of SR in the physiological brain. The study also suggests that M-CSF affects the maturation of perivascular cells at the ultrastructural level.

Animals↗
PubMedDate not supplied

Effects of diesel exhaust on murine alveolar macrophages and a macrophage cell line.

To investigate the effects of diesel exhaust particles (DEP) and mycobacterial infection on macrophages, we examined protein and mRNA expression levels of various cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-12, and IL-18 in BALB/c mouse alveolar macrophages (AM) and a macrophage cell line (RAW264.7) after in vitro stimulation with diesel exhaust (DE), with and without Mycobacterium bovis bacillus Calmette-Guérin (BCG). The cells were exposed to DE freshly generated in an in vitro system. When AM were exposed to DE (mean DEP exposure level, 300 microg/m3), the levels of TNF-alpha and IL-12 decreased significantly (by 51% to 61% for TNF-alpha and by 69% to 78% for IL-12), whereas those of IL-1beta and IL-18 remained unchanged. When AM were exposed to DE and then treated with BCG, the level of TNF-alpha decreased by 45 % to 71%, whereas the level of IL-1beta increased by 154%, compared with AM treated with BCG alone. Similarly, RAW2264.7 cells were stimulated with DE with and without M. bovis BCG and cytokine mRNA levels examined by reverse transcriptase-polymerase chain reaction (R7-PCR). Longer exposure to DE decreased TNF-alpha and IL-12 mRNA levels in the RAW264.7 cells. When the cells were exposed to DE and subsequently treated with BCG, levels of TNF-alpha, IL-1beta, and IL12 mRNAs decreased compared with those of cells treated with BCG alone. These results show that DE exposure has complex and diverse effects on cytokine production by AM, and that longer exposure (>8 hours) may suppress cytokine production by AM in vitro. Longer exposure of DE may therefore suppress the host defense in the lung and may increase susceptibility to lung infections such as mycobacterial infection.

Air Pollutants↗
PubMed2001

Protection of bronchoalveolar macrophages by granulocyte-macrophage colony-stimulating factor against dexamethasone suppression of fungicidal activity for Aspergillus fumigatus conidia.

The objectives of this study were to: (i) see if granulocyte macrophage colony-stimulating factor (GM-CSF) could protect bronchoalveolar macrophages (BAM) against suppression by dexamethasone (DEX) and (ii) test the combined effect of GM-CSF and DEX on lymphocyte responses. Murine BAM killed Aspergillus fumigatus conidia by 33 +/- 4% (mean +/- SD) in a 2.5-h assay, unaffected by GM-CSF treatment. Killing by BAM treated with DEX (10(-7) M) for 48 h in vitro was reduced to 13 +/- 6%; however, if GM-CSF (500 U ml(-1)) was present during DEX treatment of BAM, killing of conidia (33 +/- 2%) by BAM was preserved. By contrast, DEX suppression of lymphocyte responses to concanavalin A was maintained during co-culture with GM-CSF. In sequence treatment experiments, initial treatment of BAM with GM-CSF protected against subsequent treatment with DEX. When macrophages were pretreated with DEX, GM-CSF could reverse suppression even when added subsequently, provided DEX treatment was discontinued. These data suggest that it may be possible to suppress lymphocyte responses with DEX, yet at the same time maintain BAM defenses with GM-CSF against pulmonary infections by conidia of A. fumigatus.

Animals↗
PubMed2002

Therapeutic use of cytokines to modulate phagocyte function for the treatment of infectious diseases: current status of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and interferon-gamma.

The innate immune system represents the initial arm of host defense against pathogenic bacteria, fungi, and parasites. Neutrophils, monocytes, and tissue-based macrophages are major cellular components of this system. The potential ability to augment activity of the innate immune system has increased dramatically during the past 2 decades, with the discovery and development of cytokines. Four cytokines, namely granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interferon (IFN)-gamma, have received increasing attention as potential adjunctive agents for the treatment of infectious diseases. In various animal models of infection, therapeutic administration of each of the 4 cytokines has been shown to enhance pathogen eradication and to decrease morbidity and/or mortality. However, variable therapeutic efficacy has been reported in clinical trials conducted to date. This review summarizes the current status of the use of G-CSF, GM-CSF, M-CSF, and IFN-gamma in the treatment of infectious diseases.

Animals↗
PubMed1997

Improved immunostimulatory function of bone marrow derived macrophages transduced with the granulocyte-macrophage colony stimulating factor gene.

Professional antigen presenting cells (APCs) play a prominent role in generation of antitumor immunity. Granulocyte macrophage colony stimulator factor (GM-CSF) has been shown to increase antigen presenting capacity of macrophages and dendritic cells. We examined whether retroviral mediated gene transfer of the murine GM-CSF cDNA into bone marrow precursor cells would result in generation of mature APCs with improved immunostimulatory function. We show that murine bone marrow cells can be stably transduced to produce GM-CSF (200-300 pg/mL per 10(6) cells in 24 hours). These cells proliferated in the absence of exogenous growth factor for 25 days and expressed the macrophage markers Mac-1, Mac-3 and F4/80. GM-CSF transduced bone marrow cells had enhanced stimulatory capacity in a primary mixed lymphocyte-APC reaction and improved antigen presenting function in a T helper clone proliferation assay. These data demonstrate that bone marrow cells can be genetically engineered to secrete GM-CSF resulting in expansion of effective APCs. GM-CSF transduced APCs may be used as natural adjuvants in stimulating immune responses in vivo.

Adjuvants, Immunologic↗
PubMed2006

Post-injection involutional lipoatrophy: Ultrastructural evidence for an activated macrophage phenotype and macrophage related involution of adipocytes.

We describe a 53-year-old white female with distinctive clinical and histologic changes of involutional lipoatrophy on the right elbow that developed 6 months following a steroid injection to the site. Morphologically, immunohistochemically and ultrastructurally macrophages were seen in close proximity to the altered adipocytes. The macrophages displayed an activated phenotype and were observed engulfing segments of altered adipose and stromal tissue. Other inflammatory cells were lacking and up-regulation of the intra-epidermal Langerhan cells and dermal dendrocytic populations were not observed suggesting non-immune causal mechanisms in the disease process. We believe that the progression model of involutional lipoatrophy is similar to that of glomerulonephritis in which macrophage accumulation can result from non-immune mechanisms such as trauma and lead to the production of several cytokines that induce tissue injury and subsequent fibrosis and sclerosis.

Adipocytes↗
PubMed1990

Enhancement of cytotoxicity of active macrophages by mycoplasma: role of mycoplasma-associated induction of tumor necrosis factor-alpha (TNF-alpha) in macrophages.

Tumor necrosis factor-alpha (TNF-alpha)-inducing activity of several mycoplasmas including Mycoplasma pneumoniae, a causative agent in human respiratory infectious diseases, was investigated. Purified peritoneal macrophages from BALB/c mice markedly enhanced their cytotoxic activity to Meth A cells, when cultured with either viable or non-viable mycoplasmas. The supernatants of the macrophage culture with mycoplasmas, M. pneumoniae and Acholeplasma laidlawii, showed the potent cytotoxic activity to TNF-alpha-sensitive L cells but not to TNF-alpha-insensitive L cells. Addition of anti-TNF-alpha antiserum inhibited completely the cytotoxic activity of these supernatants, indicating that a major part of the cytotoxic activity might be due to TNF-alpha. Various other mycoplasmas, either glucose- or arginine-utilizing species, as far as tested showed also the potent activity to produce TNF-alpha. These results strongly suggest the possibility that mycoplasmas possess the activity of TNF-alpha induction which might be responsible for a part of enhancement of cytotoxic activity of macrophages and resistance to infection with mycoplasmas in vivo.

Animals↗
PubMed1992

The macrophage response to bacteria. Modulation of macrophage functional activity by peptidoglycan from Moraxella (Branhamella) catarrhalis.

Moraxella (Branhamella) catarrhalis organisms have been shown to be particularly efficient in inducing in a pure population of bone marrow-derived mononuclear phagocytes secretory and cellular activities. In the present study, the ability of peptidoglycan from this Gram-negative organism to trigger a macrophage response was compared with that elicited by peptidoglycan from Staphylococcus aureus and Bacillus subtilis. The results show that the three peptidoglycans were similarly active in triggering the secretion of tumour necrosis factor and tumouricidal activity but differed considerably in their ability to induce the generation of nitrite in macrophages; in this respect, peptidoglycan from M. catarrhalis was particularly potent. The impressive capacity of M. catarrhalis peptidoglycan to induce in low concentration the secretion of tumour necrosis factor and nitrite and tumouricidal activity may, in addition to its lipopolysaccharide, contribute to the extraordinary potential of this organism to trigger the functional activities of macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages.

Mitogen-activated protein/ERK kinase kinase 3 (MEKK3) is a Ser/Thr protein kinase belonging to the MEKK/STE11 subgroup of the MAP3K family. Recently, we found that MEKK3 plays a critical role in interleukin-1 (IL-1) receptor and Toll-like receptor 4 signalling using established primary mouse embryonic fibroblast (MEF) cell lines. However, the function of MEKK3 in immune cells has not been studied because germ-line MEKK3 knockout mice are embryonically lethal between embryonic days 10 and 11. In this study, we used small interference RNA to the mouse Mekk3 gene to specifically knock down MEKK3 expression in the macrophage line Raw264.7. We found that the lipopolysaccharide-induced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production was dramatically decreased in MEKK3 knockdown cells whereas the tumour necrosis factor-alpha and IL-1beta production were not affected. We also observed that the ERK1/2, p38 and JNK MAPK induction in MEKK3 knockdown cells were moderately inhibited within the first 60 min of stimulation, while the ERK and p38 were more severely inhibited after 2-4 hr of stimulation. Degradation of IkappaBalpha was also partially blocked in MEKK3 knockdown cells. Notably, the impairment in IL-6 and GM-CSF production in the MEKK3 knockdown cells was restored by reintroducing a human Mekk3 cDNA that could not be targeted by mouse Mekk3-siRNAs. In conclusion, this study showed that MEKK3 is a crucial and specific regulator of the proinflammatory cytokines IL-6 and GM-CSF in macrophages and provided a novel method for investigating MEKK3 function in other immune cells.

Animals↗