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PubMed1982

Inhibition of cellular division of a murine macrophage tumor by macrophage-activating agents.

Although the murine reticulum cell sarcoma M5076 is highly malignant in vivo, in vitro it displays many of the functional characteristics of an activated macrophage, such as phagocytosis and tumor cytotoxicity. This study was designed to determine what effect macrophage-activating agents would have on the function and growth of M5076 cells. Exposure of M5076 tumor cells to substances that activate normal macrophages to the tumoricidal state rapidly and irreversibly induced cessation of cellular division. The treated tumor cells, however, retained the same characteristics as those of untreated M5076 cells in vitro with respect to viability and the activated macrophage functions of phagocytosis and tumor cytotoxicity. Even after a short exposure to lipopolysaccharide, the ability of M5076 cells, injected i.v. into syngeneic mice, to form tumor nodules was greatly reduced. These results indicate that a highly malignant tumor of macrophage origin, M5076, can be induced to cease cellular division while retaining the functional attributes of an activated macrophage. We speculate that the exposure of M5076 to macrophage-activating agents results in the induction of terminal differentiation of this tumor.

Animals↗
PubMed1980

Augmentation of macrophage complement receptor function in vitro. II. Characterization of the effects of a unique lymphokine upon the phagocytic capabilities of macrophages.

The means by which a unique lymphokine imparts to macrophages the capacity to ingest complement- (C) coated particles was explored. In contrast to other previously described lymphokines that influence macrophage behavior, the T cell product that enhances macrophage C receptor function was found to act immediately upon contact with macrophages and to be of substantially lower apparent m.w. than either MIF, MAF, lymphotoxin, or interferon. Evidence is presented that indicates that the lymphokine does not act by causing a generalized increase in plasma membrane phagocytic activity or by enhancing phagocytosis mediated by other immunologic receptors. Nor does the lymphokine act by inducing the synthesis of new protein receptors. Our findings suggest that the more likely possibilities by which the lymphokine acts include induction of an increased rate of insertion of C receptors into the macrophage plasma membrane, induction of a rearrangement of C receptors within the macrophage plasma membrane, or a qualitative alteration of the function of existing macrophage C receptors in their relationship with the intracellular machinery involved in phagocytosis.

Animals↗
PubMed1993

Macrophage colony-stimulating factor gene transfer into tumor cells induces macrophage infiltration but not tumor suppression.

In order to analyze the effect of a high local concentration of macrophage colony-stimulating factor (M-CSF; CSF-1) on tumor growth, the plasmacytoma cell line J558L was transfected with the human M-CSF gene and injected into syngeneic BALB/c mice. In contrast to the parental tumors, M-CSF transfectants were heavily infiltrated by macrophages as evidenced by immunohistochemistry with antibodies to Mac-1 and Mac-3 and by isolation of the macrophages from the tumor. Nevertheless, tumor growth was only slightly affected by M-CSF and M-CSF-producing cells grew as tumor in all cases. The growth retardation of M-CSF-producing cells varied depending on the experiment and seemed to be due to an indirect effect because the growth rate of the cells in vitro had not changed upon gene transfer. Attempts to activate the tumor-infiltrating macrophages for tumor suppression by systemic application of interferon-gamma and/or lipopolysaccharide were not successful. Altogether, our results suggest that M-CSF is a potent chemoattractant for macrophages in vivo but alone is not sufficient to activate these macrophages for tumoricidal activity.

Animals↗
PubMed1990

Recombinant granulocyte-macrophage colony-stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex.

Organisms belonging to the Mycobacterium avium complex (MAC) are associated with life-threatening bacteremia in patients with the acquired immunodeficiency syndrome (AIDS). As these organisms survive within macrophages, we examined the ability of recombinant human granulocyte-monocyte colony-stimulating factor (GM-CSF) to activate human monocyte-derived macrophages to inhibit the intracellular growth or kill the most mouse-virulent MAC strain in our collection that belongs to serotype 1. While unstimulated cells did not inhibit intracellular growth of MAC, macrophages activated by GM-CSF (10-10(4) U/ml) inhibited or killed up to 58 +/- 5% of the initial inoculum. This activation was dose-dependent, with maximal change occurring with a dose of 100 U/ml after 72 hr exposure. Inhibition or killing was demonstrated if GM-CSF was given both before or after establishment of infection. The combination of GM-CSF (10(2) U/ml) plus TNF (10(2) U/ml) augmented macrophage killing (range, 31 +/- 4%) compared with GM-CSF (10(2) U/ml) alone, but the combination of recombinant human interferon-gamma (IFN gamma) plus GM-CSF resulted in a significant decrease in intracellular inhibition of growth or killing (13.3 +/- 2%) compared with 57.7 +/- 5% obtained with GM-CSF alone. These results indicate that: 1) GM-CSF can activate macrophages to inhibit intracellular growth or kill MAC; 2) killing may be augmented by TNF; and 3) IFN gamma may impair GM-CSF-dependent macrophage activation.

Cell Survival↗
PubMed2004

Differentiation of human monocytes in vitro with granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor produces distinct changes in cGMP phosphodiesterase expression.

The cytokines macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) promote differentiation of monocytes into macrophages with distinct phenotypes and unique functional abilities. In this report, we characterize how monocytes and macrophages differentiated from monocytes with M-CSF and GM-CSF regulate their cGMP levels by controlling which phosphodiesterases (PDEs) and guanylyl cyclases (GCs) are expressed. We find that PDE1B and PDE2A are expressed at low levels in monocytes, but are the major cGMP PDEs expressed in macrophages. M-CSF differentiation triggers increased expression of PDE1B and PDE2A, while GM-CSF causes a large increase only in PDE1B. Based on PDE expression, we identified THP-1 and U937 cell lines as possible models for studying the roles of PDE1B and PDE2A in macrophage function. We additionally characterized changes in expression of GCs upon differentiation. We found that GM-CSF differentiation triggers a small decrease in soluble guanylyl cyclase (sGC) and a large increase in GC-A, while M-CSF significantly decreases sGC.

Cell Culture Techniques↗
PubMed2006

Macrophage scavenger receptor down-regulates mycobacterial cord factor-induced proinflammatory cytokine production by alveolar and hepatic macrophages.

We aimed to reveal the regulatory function of macrophage scavenger receptor-A (MSR-A) in proinflammatory cytokine production by macrophages stimulated with mycobacterial cord factor (CF). By the culture with CF, MSR-A (+/+) alveolar macrophages and Kupffer cells produced TNF-alpha/MIP-1alpha in a time- and dose-dependent manner. However, the amounts of cytokines produced by them were much less compared to those produced by MSR-A (-/-) macrophages. Consistent with this, treatment of MSR-A (+/+) macrophages with anti-MSR-A antibody increased TNF-alpha production. Binding of CF to MSR-A was demonstrated by measuring the binding affinity. These results indicate that CF binds MSR-A, and MSR-A down-regulates TNF-alpha/MIP-1alpha production by activated macrophages, suggesting the role of this receptor in suppression of excessive inflammatory responses during mycobacterial infection.

Animals↗
PubMed1996

Immunomodulation of peritoneal macrophages by granulocyte-macrophage colony-stimulating factor in humans.

Colony-stimulating factors are growth factors which induce differentiation of the hematopoietic stem cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates proliferation and improves functions of neutrophils and monocyte/macrophages. A macrophage submesothelial stratum has been suggested to constitute the first line of peritoneal defense. We have tested whether intraperitoneally administered GM-CSF could increase the number and activation of peritoneal macrophages in peritoneal dialysis patients. Eight stable patients injected 17 micrograms of GM-CSF in each of their four daily CAPD bags over three days. The clinical status, the peritoneal effluent and peripheral blood cell count, membrane receptor expression, phagocytosis activity and cytokine levels were monitored at days 0, 1, 3, 10 and 28. GM-CSF administration caused a large increase in peritoneal macrophage number (89-fold mean increase after 72 hr), returning to baseline seven days after withdrawal. GM-CSF triggered an increase in the expression of CD11b/CD18 (CR3) and its counterreceptor CD54, indicating the cellular progression into a more activated state. Both the number of phagocytic cells (55 +/- 15% to 83 +/- 10%, P < 0.05) and the phagocytic index (137 +/- 29 to 255 +/- 61, P < 0.01) were also augmented. Peritoneal effluent cytokine-chemokine levels demonstrated an increase in IL-6 and MCP-1 levels while TNF-alpha, IL-1, IL-8, MIP-1 alpha and RANTES were not significantly altered. GM-CSF administration did not affect the peritoneal transport of water or solutes. Minor side-effects were registered in two patients. In conclusion, intraperitoneal GM-CSF causes a marked and transient recruitment of primed macrophages into the peritoneum without inducing inflammatory parameters. GM-CSF should improve the peritoneal defensive capacity through potentiation of the effector functions of resident and newly-recruited macrophages.

Adult↗
PubMed2006

Differential regulation of colony stimulating factor 1 and macrophage migration inhibitory factor expression by inflammatory cytokines in term human decidua: implications for macrophage trafficking at the fetal-maternal interface.

Macrophages are a major component of the leukocyte population of human pregnant endometrium. Although several crucial functions have been ascribed to these cells, the mechanisms underlying macrophage trafficking in the placental bed are poorly understood. The aim of this study was to evaluate the in vivo expression of two potentially antagonistic macrophage-targeting chemokines, colony stimulating factor 1 (CSF1, also known as M-CSF) and macrophage migration inhibitory factor (MIF), in term decidua, and to examine the effects of the inflammatory cytokines tumor necrosis factor (TNF, also known as TNF alpha) and interleukin 1beta (IL1B) on CSF1 and MIF expression in cultured decidual cells. The expression of CSF1 and MIF in term decidua was evaluated by immunohistochemistry. Cultured decidual cells were primed with estradiol (E2) or with E2+medroxyprogesterone acetate (MPA), and then incubated with corresponding steroid(s) with or without TNF or IL1B. The levels of CSF1 and MIF protein and mRNA were assessed by ELISA and quantitative RT-PCR, respectively. Immunostaining for CSF1 and MIF was observed in term decidua. The levels of secreted CSF1 and MIF were similarly unchanged whether the decidual cells were incubated with E2 or with E2+MPA. The CSF1 levels significantly increased in cultures exposed to E2 or E2+MPA plus TNF or IL1B. In contrast, the MIF levels in TNF- and IL1B-treated cells were not changed significantly from the control cultures. The ELISA data were confirmed by quantitative RT-PCR analysis. These results indicate that CSF1 and MIF are involved in regulating macrophage trafficking at the fetal-maternal interface, and suggest a mechanism by which inflammatory cytokines influence pregnancy by regulating decidual macrophage infiltration.

Cell Movement↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor is not involved in production of reactive nitrogen intermediates by or toxoplasmastatic activity of gamma interferon-activated murine macrophages.

The induction of reactive nitrogen intermediates (RNI) and toxoplasmastatic activity of murine macrophages by recombinant gamma interferon (rIFN-gamma) is mediated by an autocrine pathway involving tumor necrosis factor alpha (TNF-alpha). To investigate whether cytokines other than TNF-alpha play a role in the activation of these effector functions, granulocyte-macrophage colony-stimulating factor (GM-CSF) was studied. Recombinant GM-CSF (rGM-CSF) could stimulate peritoneal macrophages, since this cytokine stimulated the production of prostaglandin E2 by these cells. However, rGM-CSF did not induce either the release of RNI by or the toxoplasmastatic activity of macrophages. rGM-CSF in combination with various concentrations of rIFN-gamma did not enhance these effector functions more than rIFN-gamma alone. Furthermore, neutralization of endogenously produced GM-CSF by monoclonal antibodies did not affect the release of RNI by or the toxoplasmastatic activity of rIFN-gamma-activated macrophages. Together these results indicate that GM-CSF is not involved in RNI production by and toxoplasmastatic activity of IFN-gamma-activated murine macrophages.

Animals↗
PubMed2003

Human immunodeficiency virus type 1 infection inhibits granulocyte-macrophage colony-stimulating factor-induced activation of STAT5A in human monocyte-derived macrophages.

Human immunodeficiency virus type 1 (HIV-1) infects cells of the monocyte/macrophage lineage. While infection of macrophages by HIV-1 is generally not cytopathic, it does impair macrophage function. In this study, we examined the effect of HIV-1 infection on intracellular signaling in human monocyte-derived macrophages (MDM) stimulated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important growth factor for cells of both the macrophage and granulocyte lineages and enhances effector functions of these cells via the heterodimeric GM-CSF receptor (GM-CSFR). A major pathway which mediates the effects of GM-CSF on macrophages involves activation of the latent transcription factor STAT5A via a Janus kinase 2 (JAK2)-dependent pathway. We demonstrate that GM-CSF-induced activation of STAT5A is inhibited in MDM after infection in vitro with the laboratory-adapted R5 strain of HIV-1, HIV-1(Ba-L), but not after infection with adenovirus. HIV-1 infection of MDM did not decrease the STAT5A or JAK2 mRNA level or STAT5A protein level or result in increased constitutive activation of STAT5A. Surface expression of either the alpha-chain or common beta(c)-chain of GM-CSFR was also unaffected. We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway. These data provide further evidence of disruption of cellular signaling pathways after HIV-1 infection, which may contribute to immune dysfunction and HIV-1 pathogenesis.

Base Sequence↗
PubMed1992

Endotoxin induces the expression of macrophage inflammatory protein 1 alpha mRNA by rat alveolar and bone marrow-derived macrophages.

Macrophage inflammatory protein 1 alpha (MIP-1 alpha) is a newly described cytokine that is present in large amounts in the culture supernatant of an endotoxin-stimulated murine macrophage-like cell line (RAW 264.7). There is increasing information that suggests that this cytokine mediates acute neutrophilic inflammation, although the mechanism of mediation is unknown. Data examining the production and regulation of MIP-1 alpha by primary rat macrophages are lacking, and MIP-1 alpha has not been studied previously in an animal model of endotoxin-induced neutrophilic alveolitis. In this study, we performed Northern analysis of steady-state rat MIP-1 alpha mRNA using an oligonucleotide probe complementary to amino acids 4-13 of murine MIP-1 alpha. Our data demonstrate that rat alveolar and bone marrow-derived macrophages can be induced by in vitro endotoxin treatment to express a 1.1-kb MIP-1 alpha mRNA. Expression of the mRNA could be elicited by treatment with 0.1 to 10.0 micrograms/ml of endotoxin in vitro with peak steady-state levels detectable up to 9 h after adding endotoxin to the media. Alveolar macrophages recovered by whole lung lavage from endotoxin-treated rats expressed increased amounts of the mRNA homologous to MIP-1 alpha mRNA when treated in vitro with endotoxin. We also found that rat neutrophils could be induced by endotoxin in vitro to express the MIP-1 alpha mRNA. We were able to identify MIP-1 alpha in culture supernatant from endotoxin-stimulated rat alveolar and bone marrow-derived macrophages by immunoprecipitation with a specific goat anti-murine MIP-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Expression of macrophage colony-stimulating factor, scavenger receptors, and macrophage proliferation in the pregnant mouse uterus.

During pregnancy, mouse uterine epithelial cells produce and secrete a large amount of macrophage colony-stimulating factor (M-CSF/CSF-1). Macrophages accumulate and proliferate in the undecidualized endometrium of the pregnant uterus. Observations showed that macrophages expressed scavenger receptor class A (type I and type II) and class C (macrosialin). Scavenger receptors appeared to be involved in the removal of apoptotic cells in the degenerated decidual tissue. The expression of class A and class C scavenger receptor mRNAs in the uterus of pregnant mice was elevated but the expression of class B scavenger receptor (CD36) mRNA was similar to that of non-pregnant mice. The expression of various cytokines and chemokines, including M-CSF, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein 1-alpha (MIP1-alpha), was enhanced in the uterus of pregnant mice, suggesting that these molecules regulate macrophage chemotaxis and immunological function in the uterus. These findings imply that the pregnant uterus provides a microenvironment for the recruitment, differentiation, and proliferation of macrophages and the regulation of scavenger receptor and cytokine expression for a successful pregnancy.

Animals↗
PubMed2006

Macrophage-colony-stimulating factor-induced proliferation and lipopolysaccharide-dependent activation of macrophages requires Raf-1 phosphorylation to induce mitogen kinase phosphatase-1 expression.

Macrophages are key regulators of immune responses. In the absence of an activating signal, murine bone marrow-derived macrophages undergo proliferation in response to their specific growth factor, namely M-CSF. The addition of bacterial LPS results in macrophage growth arrest and their engagement in a proinflammatory response. Although participation of ERKs is required for both macrophage proliferation and activation, ERK phosphorylation follows a more delayed pattern in response to activating agents. In primary macrophages, mitogen kinase phosphatase-1 (MKP-1) is a key regulator of the time course of MAPK activity. Here we showed that MKP-1 expression is dependent on Raf-1 activation. The time course of Raf-1 activation correlated with that of ERK-1/2. However, whereas ERK phosphorylation in response to M-CSF is Raf-1 dependent, in response to LPS, an alternative pathway directs the activation of these kinases. Inhibition of Raf-1 activity increased the expression of cyclin-dependent kinase inhibitors and growth arrest. In contrast, no effect was observed in the expression of proinflammatory cytokines and inducible NO synthase following LPS stimulation. The data reported here reveal new insights into how signaling determines opposing macrophage functions.

Animals↗
PubMed1984

Macrophage activation to kill Leishmania tropica: kinetics of macrophage response to lymphokines that induce antimicrobial activities against amastigotes.

Lymphokine (LK) treatment of resident peritoneal macrophages from C3H/HeN mice induced two antimicrobial activities against Leishmania tropica: increased resistance of activated macrophages to infection with amastigotes and intracellular destruction of those parasites that entered activated cells. The onset and duration of these two antimicrobial activities were quite different. Resistance to infection was observed as early as 4 hr after the addition of LK, became maximal at 8 hr, and persisted in a subpopulation of treated cells for as long as 72 hr. In contrast, intracellular killing occurred with as little as 4 hr of LK treatment after infection, and maximal killing was observed in cultures exposed to LK 24 hr. Intracellular killing capacity of lymphokine-treated cells was progressively lost in macrophages treated longer than 12 hr before exposure to parasites. This decay in ability to destroy intracellular L. tropica was also seen in macrophages cultured longer than 12 hr before LK treatment, and may reflect loss of macrophage responsiveness to LK with increasing time in vitro. Thus, treatment of macrophages with lymphokines induced both a stable change in cell-parasite interactions, resistance to infection, and a short-lived capacity to destroy intracellular amastigotes.

Animals↗
PubMed2002

Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors.

Endothelins (ET-1, ET-2 and ET-3) are 21-amino acid vasoactive peptides that bind to G-protein-linked transmembrane receptors, ET-RA and ET-RB. As well as modulating vasoconstriction, endothelins regulate growth in several cell types and may also affect differentiation, inflammation and angiogenesis. Both macrophages and endothelins are found in areas of hypoxia in solid tumors and ET-2 expression may be modulated by hypoxia in some tumors. As the peptide structure of mature endothelins is similar to that of CXC chemokines, we asked if endothelins contribute to control of macrophage distribution in tumors. We found that ET-2 is a chemoattractant for macrophages and THP-1 monocytic cells, but not for freshly isolated monocytes. The chemotactic response to ET-2 shows a typical bell-shaped response curve. Experiments with endothelin receptor antagonists showed that migration to ET-2 is mediated via the ET-RB receptor. Moreover, monocytes do not express ET-RB. Chemotaxis towards ET-2 is via the MAPK pathway: p44 and p42 are phosphorylated when THP-1 cells are stimulated with ET-2, and the MAPKK inhibitor PD98059 stops chemotaxis. As with 'classical' chemokines, migration toET-2 is also inhibited by hypoxia and by pertussis toxin. As well as its chemotactic properties, ET-2 leads to activation of macrophages. In human breast tumors that express ET-2, endothelins and ET-RB expressing macrophages often co-localized. While shorter than 'classical' chemokines, ET-2 shares a similar peptide sequence with chemokines and may signal via a similar receptor and MAPK-mediated pathway. Furthermore, ET-2 expression by tumors may modulate the behavior of macrophages such that activated cells accumulate in areas of hypoxia.

Bacterial Proteins↗
PubMed1994

Distribution of macrophages in the mouse uterus from one day to three months after parturition, as defined by the immunohistochemical localization of the macrophage-restricted antigens F4/80 and macrosialin.

BACKGROUND: The morphology of placental detachment sites and the distribution of macrophages were studied in the mouse uterus from day 1 to 3 months post partum. METHODS: Uterine morphology was studied using H&E and Mallory's Trichrome staining. Macrophages were identified using the macrophage-restricted antigens F4/80 and FA/11 and the leukocyte beta 2-integrin CR3 (Mac-1) which is also expressed by neutrophils. RESULTS: The post-partum wound was infiltrated by large numbers of CR3+ F4/80+ FA/11+ macrophages, and CR3+ neutrophils. The wound resolved rapidly and no inflammatory infiltrate or necrotic tissue was seen by day 5 post partum. The area of the detachment wound and the site of the metrial gland of pregnancy resolved into a structure, here called a post-partum nodule, which persisted for at least three months. The post-partum nodule consisted of an outer layer of collagen around a group of nodule-specific cells which could be divided into haemosiderin- and lipid-bearing phenotypes. The lipid-bearing nodule cells were not found after day 20 post partum. Nodule cells were FA/11+ at all times and also expressed leukocyte common antigen. Expression of CR3 and F4/80 was found on nodule cells up to day 9-10 post partum. CR3 expression was found only occasionally after day 10. F4/80 expression was downregulated from day 9-10 to day 20 but was found consistently after day 20. Implantations of second and subsequent pregnancies are known not to occur in the immediate vicinity of post-partum nodules and nodules from successive pregnancies were seen to be separate within the uterus. CONCLUSIONS: Since the endometrial area in the immediate vicinity of nodules is inimical to implantation and nodules consist of a group of macrophages, it can be implied that nodule macrophages are exerting some influence on the endometrium in their vicinity.

Animals↗
PubMed1989

Regulation of systemic macrophage IL-1 gene transcription: the involvement of tumor-derived macrophage growth factor, CSF-1.

Previous data indicated that progressive growth of the C57BL/6J sarcoma, MCA/76-9, was associated with a systemic increase in the level of IL-1 activity in peritoneal and tumor-associated macrophages. In this paper, the hypothesis was tested that macrophage IL-1 alpha and beta gene expression was regulated by the specific macrophage growth factor, CSF-1, produced by tumor cells. The data indicated that all of the nine C57BL/6J, BALB/cJ, and C3H/HeJ sarcomas tested transcribed the CSF-1 gene. The tumor cell culture supernates induced proliferation of bone marrow cells that differentiated into macrophages. Moreover, proliferative activity of conditioned medium and the ability to induce macrophage differentiation were abrograted by neutralization with the 5A1, rat-anti-mouse monoclonal anti-CSF-1 antibody. Conditioned medium from tumor cell cultures, as well as recombinant CSF-1 and L cell-conditioned medium, induced transcription of the IL-1 alpha and beta genes, the latter being more strongly expressed. IL-1 gene transcription was not induced after neutralization of the culture supernates by the monoclonal antibody, 5A1. The overall data would support the hypothesis that the pathway in vivo leading to the increased IL-1 expression by macrophages is regulated by at least one tumor cell product, CSF-1.

Animals↗
PubMed1992

Synergistic interaction of bacterial lipopolysaccharide and the monocyte-macrophage colony-stimulating factor: potential quantitative and qualitative changes in macrophage-produced cytokine bioactivity.

In this brief definitive report, we show that over a 6-h period and under serum-free conditions, recombinant monocyte-macrophage colony-stimulating factor 1 (rCSF-1) and lipopolysaccharide (LPS) synergize and induce macrophages to express higher levels of mRNA for interleukin 1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 and to release more bioactivity than macrophages treated with LPS alone. This synergy was regulated by the amount of LPS in the culture medium. Paraformaldehyde-fixed macrophages like-wise showed augmentation of IL-1 activity, but whereas all of the bioactivity associated with the fixed macrophages could be neutralized by anti-IL-1 alpha antibody only approximately 40% of the supernate activity could be attributed to IL-1 alpha. Preliminary data suggest that the augmenting effect induced by CSF-1 cannot be explained solely on a quantitative basis because the addition of rIL-1 alpha to supernates of macrophages treated with LPS alone or with the combination of LPS and CSF-1 resulted in an increase in thymocyte mitogenic activity to a level that could not be explained on an additive basis. Although the supernates contained TNF and IL-6, antibody neutralization assays made it unlikely that these were directly responsible for the augmenting effect. These results suggest that CSF-1 not only enhances basic genetic responses induced by LPS alone but also may induce a mechanism that amplifies cytokine bioactivity.

Animals↗