Biomedical subjects

M Dy

Publications and source records attributed to M Dy.

At least 19 recordsLinked to original sources

PubMed1992

IL-7 is requisite for IL-1-induced thymocyte proliferation. Involvement of IL-7 in the synergistic effects of granulocyte-macrophage colony-stimulating factor or tumor necrosis factor with IL-1.

In the absence of artificial comitogens murine thymocytes proliferate significantly in response to IL-1 at high but not at low cell densities. This observation has led us to examine a possible indirect mechanism requiring other thymocyte-growth factors, such as IL-2, IL-4, IL-6, and IL-7, in this phenomenon. Our data provide evidence that IL-7 is requisite for the IL-1-induced proliferative response because on the one hand the growth-promoting activity of IL-1 is completely inhibited by an anti-IL-7 mAb, and on the other hand IL-7 synergizes with IL-1 on thymocyte growth. This synergy is observed even at concentrations at which IL-7 is not detected in the pre-B cell proliferation assay, and results, at optimal doses, in TdR incorporation levels similar to those attained in response to IL-1 + IL-2. The anti-IL-7 mAb acts in a dose-dependent manner and does not affect other activities of IL-1, such as its capacity to sustain the growth of the U373 astrocytoma cell line. It is also noteworthy that this mAb does not significantly impair thymocyte growth in response to IL-2 and that the growth-promoting activity of IL-1 is not affected by neutralizing mAb against IL-2, IL-4, and IL-6. In addition, we show that the potentiating effect of granulocyte-macrophage (GM)-CSF and TNF-alpha on IL-1-induced thymocyte growth is dependent on IL-7 because i) the anti-IL-7 mAb abrogates the respective synergistic interactions and ii) both factors potentiate the proliferative response to IL-7. Finally, depletion of thymocyte suspensions for Ia+ Mac-1+ accessory cells results in a considerable decrease in IL-1- and IL-1 + GM-CSF-induced TdR uptake, whereas IL-7-induced growth remains unchanged. Taken together, these results support the notion that, in the absence of artificial comitogens, thymocyte proliferation in response to IL-1 alone or in combination with GM-CSF is dependent on accessory cell-derived IL-7.

Animals↗

PubMed1991

Characterization of murine hematopoietic progenitor subsets involved in interleukin-3-induced interleukin-6 production.

Various murine cell populations were tested for their ability to generate interleukin-6 (IL-6) in response to IL-3. Among these, bone marrow cells exhibit the most prominent IL-6 production. The responder cells in this organ have been further characterized by cell fractionation on a discontinuous Ficoll gradient, fluorescence-activated cell sorting, and in situ hybridization. These procedures have allowed us to ascribe the following features to the cells mainly responsible for IL-3-induced IL-6 production: (1) they possess a low density and a relatively high forward and perpendicular light scatter (FLS/PLS); (2) they are characterized by a high rhodamine (Rh) retention; and (3) their enrichment in various subpopulations is similar to that obtained for progenitors forming colonies in the methylcellulose assay colony-forming units (CFU-C). In contrast, IL-3 target cells in terms of IL-6 production are absent both in the mature and in the most immature bone marrow compartment. Indeed, the Rh-dull population that is enriched for cells with marrow repopulating activity does not respond to the growth factor and mature cells cannot be induced to express IL-6 as assessed by (1) FLS/PLS characteristics, (2) the monoclonal antibody ER-MP 20 recognizing monocytes and granulocytic cells, and (3) in situ hybridization. Taken together, our data support the conclusion that the bone marrow cells generating IL-6 in response to IL-3 belong to a progenitor population with enhanced mitochondrial activity, comprising probably several types of immature cells of the myeloid lineage including macrophage/granulocyte precursors.

Animals↗

PubMed1991

Cascade modulation by anti-tumor necrosis factor monoclonal antibody of interferon-gamma, interleukin 3 and interleukin 6 release after triggering of the CD3/T cell receptor activation pathway.

In addition to being potent immunosuppressants, anti-CD3 monoclonal antibodies (mAb) are powerful mitogens in both humans and mice. The first antibody injection consistently induced an initial monocyte-dependent T cell activation with subsequent release of both monocyte- and T cell-derived cytokines [mainly tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL) 2, IL 3 and IL 6) into the circulation. This cytokine release is associated with a self-limiting, often severe, acute physical reaction in both patients and mice. We report here that a single injection of anti-TNF mAb prior to anti-CD3 administration not only neutralizes the biological activity of TNF but also strongly affects the release of other cytokines, with notably an up-regulation of IFN-gamma release and a down-regulation of IL 3 and IL 6 release. Conversely, pretreatment with anti-IFN-gamma mAb increases IL 3 and IL 6 production but does not affect TNF levels. Taken together, these data point to a pivotal role of IFN-gamma in the anti-CD3-induced cytokine cascade and reveal new regulatory pathways between TNF and IFN-gamma. With regard to the clinical implications of these findings, as anti-TNF mAb prevents anti-CD3-induced sickness in mice, whereas anti-IFN-gamma does not, such a therapeutic approach might be of value in OKT3-treated patients.

Animals↗

PubMed1991

GM-CSF in association with IL-1 triggers day-8 CFU-S into cell cycle: role of histamine.

Our recent evidence for the requirement of endogeneous histamine in IL-3-induced proliferation of day-8 CFU-S has prompted us to investigate whether or not GM-CSF, which shares with IL-3 the ability to stimulate bone marrow histamine synthesis, could also affect the cell cycle status of CFU-S via this mediator. We show herein that recombinant GM-CSF alone fails to trigger day-8 CFU-S into S phase, but supports their survival. However, in the same experimental conditions, GM-CSF in combination with IL-1 induces a CFU-S proliferation similar to that obtained in response to IL-3, while IL-1 by itself has no effect on this biological activity. We further provide evidence that this phenomenon is completely abolished: i) by preventing GM-CSF-induced histamine synthesis by alpha-FMH, the specific inhibitor of histidine decarboxylase (HDC), or ii) by blocking the binding sites of H2 histamine receptors with their specific antagonist oxmetidine. Similar results are obtained when progenitor-enriched bone marrow cells are used instead of the unfractionated population. In addition, we provide an argument in support of a histamine receptor modulation by GM-CSF that could explain the lack of effect of factor-induced histamine on day-8 CFU-S cell cycling. Indeed, the entry of these progenitors into S phase that is normally promoted by dimaprit, a specific histamine H2 receptor agonist, is abolished by a preincubation with GM-CSF. Taken together, our data support the conclusion that IL-1 makes CFU-S sensitive to GM-CSF-induced endogeneous histamine that will trigger them into cell cycle, while GM-CSF alone has no such effect on this biological activity.

Animals↗

PubMed1991

Effect of lipopolysaccharides on histamine synthesis by hematopoietic cells.

We show herein that lipopolysaccharides (LPS), in vitro, synergize with GM-CSF to increase histamine synthesis by murine bone marrow cells. LPS has no effect on its own and does not potentiate histamine synthesis promoted by IL-3, the only other cytokine sharing this biological activity with GM-CSF. Despite the fact that GM-CSF and LPS synergistically increase PGE2 levels, the potentiating effect of LPS does not require PGE2 that have been previously shown to enhance GM-CSF-induced histamine synthesis. We provide evidence that this effect of LPS on histamine production by bone marrow cells is mediated by the intracellular cAMP transduction signal. In addition, LPS and cAMP enhance GM-CSF-induced histidine decarboxylase activity, showing that both substances act on histamine synthesis. Contrary to in vitro results, LPS injection into mice induces an increase in both intracellular histamine and HDC activity in bone marrow cells. Our results support the conclusion that this effect is mediated by GM-CSF. In conclusion, LPS appears to be a powerful HDC inducer in hematopoietic organs because of its ability, on one hand, to induce circulating GM-CSF and, on the other hand, to potentiate GM-CSF induction of HDC.

Animals↗

PubMed1991

Prostaglandin E2 potentiates granulocyte-macrophage colony stimulating factor-induced histamine synthesis in bone marrow cells: role of cAMP.

Histamine synthesis in response to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) by murine hematopoietic cells is strikingly potentiated by prostaglandin E2 (PGE2). This synergy is mediated by an increase in intracellular adenosine 3':5'-cyclic monophosphate (cAMP), since: (a) exogeneous and endogeneous cAMP generated either by forskolin or IBMX potentiate GM-CSF-induced histamine synthesis, (b) the maximal potentiating effects of PGE2 and cAMP are not cumulative, and (c) GM-CSF together with PGE2 enhances intracellular cAMP content in a bone marrow population enriched for GM-CSF target cells. cAMP and PGE2 enhance histidine decarboxylase activity induced by GM-CSF showing that both factors act on histamine synthesis rather than on its release. Conversely, histamine synthesis promoted by Interleukin 3 (IL-3), the unique cytokine sharing this property with GM-CSF, is not modulated by PGE2 or cAMP, suggesting two distinct mechanisms for the induction of this biological activity in hematopoietic cells.

Animals↗

PubMed1991

Inter-mouse strain differences in the in vivo anti-CD3 induced cytokine release.

Triggering of the CD3 molecule by in vivo injection of the hamster anti-murine CD3 monoclonal antibody 145-2C11 in adult BALB/c mice leads to massive although transient T cell activation. High levels of tumour necrosis factor (TNF), interferon-gamma (IFN-gamma), IL-2, IL-3 and IL-6 are released into the circulation 1 to 8 h after a single 10 micrograms 145-2C11 i.v. injection. This release induces an impressive self-limited physical reaction associating hypothermia, hypomotility (as assessed by actimetry), diarrhoea, piloerection and even death when high doses (a single dose of greater than 100 micrograms/mouse injection) are administered. In vivo injection of 145-2C11 to other selected mouse strains, namely NZW, CBA/J and C3H/HeJ, induced both different cytokine release patterns and sickness. 145-2C11 induced significant release of TNF and IL-2 in all four strains. At variance, IFN-gamma was only detected in BALB/c mice sera which, in terms of physical reaction (hypothermia and hypomotility) were the most affected. Higher and long-lasting circulating IL-3/GM-CSF levels were present in CBA/J sera, correlating with a later recovery. These results underline heterogeneity in the in vivo cell activation pattern among different mouse strains, when triggering T lymphocytes via the CD3/Ti molecule as compared to exclusive targeting of monocyte/macrophages by means of lipopolysaccharide.

Animals↗

PubMed1991

Concomitant histamine, interleukin 4, and interleukin 6 production by hematopoietic progenitor subsets in response to interleukin 3.

Murine interleukin 3 (IL-3) induces a strong, concomitant increase in histamine, interleukin 6 (IL-6), and interleukin 4 (IL-4) synthesis by progenitor-enriched bone marrow cell populations, whereas interleukin 2 (IL-2) or interferon-gamma (IFN-gamma) are undetectable. This phenomenon is observed between 4 and 12 h after exposure to the growth factor and attains maximal cytokine and histamine levels within 24 and 48 h, respectively. None of these mediators is produced by lymphoid populations such as lymph node cells or by granulocytes. Splenocytes secrete only low histamine and IL-6 levels, in accordance with the lower incidence of progenitors in the spleen, whereas total bone marrow cells generate substantial amounts of the three mediators even before enrichment. Histamine, IL-4-, and IL-6-producing cells copurify with immature cells and cannot be separated from each other throughout the sorting procedures used herein. They are concentrated in the low-density layers (buoyant density 1.069-1.086 g/cm3) of a discontinuous Ficoll gradient (less than 4% of the total bone marrow) together with the majority of hematopoietic progenitors (marrow-repopulating ability [MRA] cells, spleen colony-forming units [CFU-S] day-8 and day-12, granulocyte-macrophage colony-forming units [CFU-GM], and mast cell precursors). Their lightscatter characteristics are those of relatively large, granular cells. They do not belong to the most primitive stem cell subset (MRA and part of CFU-S day-12), but to a population with high mitochondrial activity identified by their important rhodamine retention (colony-forming unit cells [CFU-C], blast cells). In addition, we provide evidence that histamine, IL-4, and IL-6 do not depend on each other for their respective expression. Taken together, our data are consistent with the notion that in certain conditions, immature hematopoietic cells are a potent source of histamine and cytokines.

Animals↗

PubMed1991

Poly(A)-poly(U) induces circulating colony-stimulating activity resulting from interactions between endogeneous interleukin 6 and serum components.

The immunostimulant poly(A)-poly(U) induces a rapid enhancement of circulating colony-stimulating activity (CSA) in normal mice, culminating 2 h after i.v. injection. A dose of 200 micrograms per mouse is sufficient for a maximal effect. The colonies formed in response to sera from poly(A)-poly(U)-injected mice are mainly granulocytic with few macrophages. These sera are devoid of detectable interleukin 3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF), but contain large amounts of interleukin 6 (IL-6) that are perfectly correlated with circulating CSA levels. Although, in our hands, IL-6 alone induces no colony formation in the standard methylcellulose colony assay, it is nevertheless requisite for this biological activity because 1) monoclonal antibodies against IL-6 strongly diminish colony formation in response to sera from poly(A)-poly(U)-injected mice, and 2) recombinant (r)IL-6 induces colonies when tested in combination with low amounts of normal murine serum. At the concentrations used (0.3%-2.5%), the latter has no or a very slight effect alone. Low amounts of hematopoietic growth factors, that is, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), GM-CSF, or IL-3 that are almost ineffective in the absence of IL-6 can replace normal serum. Taken together, these data suggest that circulating IL-6, induced by i.v. injection of poly(A)-poly(U), promotes colony formation by interacting with serum components that might be identical with hematopoietic growth factors present in normal serum at subliminal concentrations. Finally, the involvement of lipopolysaccharide (LPS) in this phenomenon has been ruled out by the use of the low responder strain of mice (C3H/HeJ) that leads to similar results.

Animals↗

PubMed1990

Antigenic challenge of immunized mice induces endogeneous production of IL-3 that increases histamine synthesis in hematopoietic organs.

Antigenic challenge of Nippostrongylus brasiliensis-infected mice induces a striking increase in histidine decarboxylase (HDC) activity in both spleen and bone marrow cells. This enhancement takes place within 1 h after injection, with a maximum at 4 h and a return to pretreatment values 20 h later. It is associated with the appearance of IL-3 in the sera of these mice. In addition, the intracellular histamine content in both hematopoietic organs is concomitantly increased. A similar injection of worm Ag into normal mice has no significant effect. Comparable enhancement of HDC activity and intracellular histamine content with almost identical kinetics is promoted by i.v. injection of rIL-3 into normal mice. Moreover, HDC levels in infected mice are increased to the same extent in response to either specific antigen or rIL-3 injection. Taken together these results support the conclusion that antigenic challenge of immunized mice induces endogeneous IL-3 which, in turn, promotes a rapid increase in histamine synthesis in hematopoietic organs.

Animals↗

PubMed1990

Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation.

In vivo injection of the hamster anti-murine CD3 monoclonal antibody 145 2C11 into BALB/c mice induces a massive systemic release of several cytokines. Very high circulating levels of tumor necrosis factor are detected both by enzyme-linked immunosorbent assay and L-929 bioassay 90 min following a single injection of 10 micrograms/mouse 145 2C11. Peak circulating levels of exclusively T cell-derived products such as interferon-gamma, interleukin 2 and interleukin 3 are also detected 90 min to 8 h post-injection. Importantly, this cytokine release is transient since none of these cytokines are still present 12 to 24 h post-injection. In parallel to cytokine release, 145 2C11-treated mice (10 micrograms/mouse) exhibit somnolence, hypomotility (quantified by actimetry), hypothermia, diarrhea and piloerection. At this dosage, the physical reaction is not lethal and reverses in all mice by 48 h post-injection. Severe but again reversible anatomopathological changes are also observed: massive cellular depletion, necrosis and edema of lymphoid organs, leakage syndrome and inflammatory cell infiltrates of the lung, cell vacuolization, necrosis and vascular congestion of the liver. All these data are similar to the clinical and immunological manifestations of the OKT3-induced reaction in patients and, thus, provide an invaluable experimental tool to study its mechanisms and explore its prevention.

Animals↗

PubMed1990

New role for histamine in interleukin-3-induced proliferation of hematopoietic stem cells.

This study investigated the effect of histamine generated by murine bone marrow cells in response to IL-3 on one particular biological activity of this growth factor, i.e., triggering of cells forming colonies in spleen (CFU-S) into S phase. Evidence is provided that i) IL-3-induced day-8 CFU-S cell cycling, evaluated by hydroxy-urea suicide, is completely abrogated when the binding of histamine to its H2 receptors is blocked by the specific antagonist oxmetidine, whereas cetirizine, a H1 receptor antagonist, is ineffective; and ii) the entry of day-8 CFU-S into S phase in response to IL-3 is likewise abolished when the histamine synthesis promoted by the growth factor is prevented by alpha-fluoromethylhistidine, a specific inhibitor of the histamine-forming enzyme, histidine decarboxylase. Similar results are obtained with both drugs, when a progenitor-enriched bone marrow population is used instead of total cells. Furthermore, i.v. injection of recombinant (r)IL-3 results within 2 hr in a substantial increase in bone marrow cell histamine synthesis together with triggering of day-8 CFU-S into cycle, the latter being completely abolished by a simultaneous injection of the H2 histamine receptor antagonist oxmetidine. Thus, our findings support the notion that both in vitro and in vivo the proliferation of early CFU-S in response to IL-3 is modulated by histamine via its H2 receptors. This conclusion is also consistent with the observation that dimaprit, a specific agonist of these receptors not only enhances the sensitivity of day-8 CFU-S to HU after a 2 hr incubation with bone marrow cells but also increases, to the same extent as IL-3, the number of colonies formed in irradiated spleens after a 5 hr pretreatment.

Animals↗

PubMed1990

Reduction of morbidity and cytokine release in anti-CD3 MoAb-treated mice by corticosteroids.

In keeping with the in vitro mitogenic properties of anti-CD3 MoAbs, the first injections of anti-CD3 are invariably responsible for an in vivo cellular activation. This activation induces a massive cytokine release in the circulation (TNF, IFN gamma, IL-2, IL-6, and IL-3). Paralleling this release, a severe clinical reaction occurs in OKT3-treated patients and in 145 2C11-treated mice. Corticosteroids both in vitro and in vivo inhibit the production of several cytokines involved in the anti-CD3 reaction. A single 1 mg hydrocortisone dose was administered to 145 2C11-treated mice according to different kinetics schedules. When given 1 hr prior to the anti-CD3 MoAb, hydrocortisone exerted a beneficial effect on the mouse physical reaction. Hypothermia was totally abrogated at the 4-hr time point. Diarrhea decreased by 50%. Hypomotility improved although not significantly. This improvement correlated with a major modification in the anti-CD3 pattern of cytokine release. At the 90-min blood withdrawal time point cytokine serum levels showed a 100% decrease for IFN gamma, an 88% decrease for IL-6, and 85% decrease for IL-2, and a 75% decrease for TNF. At 4 hr IL-2 serum levels were diminished by 65%; IL-6, IL-3, and IFN gamma serum levels were comparable to controls; and, interestingly, TNF was still detected, whereas it has already disappeared when 145 2C11 was administered alone. Importantly, when given more than 1 hr prior to anti-CD3 injection, corticosteroids were ineffective. To conclude, high doses of corticosteroids must be given with a precise kinetics--i.e. 1 hr prior to anti-CD3 MoAb--to achieve their maximal beneficial effect in the prevention of the anti-CD3 reaction.

Adrenal Cortex Hormones↗

PubMed1990

Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy.

In this study, we examined the effect of injecting various cytokines. We report here that tumour necrosis factor (TNF)alpha, gamma-interferon and interleukin 2 (IL-2) can, in some circumstances, increase fetal resorption rates in abortion-prone (CBA/J x DBA/2) and non-abortion prone (CBA/J x BALB/c,C3H x DBA/2) matings: 1000 units TNF enhanced resorptions from 43 to 79% in CBA x DBA/2, from 7 to 89% in CBA x BALB/c, from 5 to 47% in C3H x DBA/2. The effect was both gestational age- and dose-dependent. Gamma interferon and R-IL-2 enhanced resorptions from 38 to 68% and 76% respectively in the CBA/J x DBA/2 mating combination, whereas the rates in CBA/J x BALB/c matings were enhanced from 6 to 44% and 55%. Lipopolysaccharide (LPS), which is known to lead to the release of TNF-alpha, had a similar effect, leading to gestational age- and dose-dependent enhancement of resorptions up to 100%. However, cytokines of the CSF family, including IL-3 and GM-CSF, increased the chances of fetal survival when injected into abortion-prone mice, e.g. reducing resorption rates in the abortion-prone CBA/J x DBA/2 mating combination from 55 to 22% (IL-3), and 47 to 8% (GM-CSF). They also increased fetal and placental weight and, in particular, expanded the spongiotrophoblast zone in the placenta. The latter observations may be due to a direct trophic influence on placental cells, perhaps through a cytokine cascade, or an indirect effect due to inhibition of natural killer (NK)-like cells, or both. Whatever the mechanism, these results may find practical application in influencing reproductive outcome in women and other species.

Animals↗

PubMed1990

Interleukin 3 induces histamine synthesis in the human hemopoietic system.

Recombinant human interleukin 3 (rhIL-3) induces an increase in histamine production by human bone marrow, fetal liver, and cord blood cells. This phenomenon, already significant after 3 days of incubation, is strikingly enhanced following either enrichment in immature cell subpopulations or CD8+ cell depletion. It results from an increase in histamine synthesis because of 1) the low level of histamine cell content before any incubation, 2) the parallel increase in both extra- and intracellular histamine levels in response to rhIL-3, and 3) the early IL-3-induced increase in L-histidine decarboxylase (HDC; EC 4.1.1.22) activity. Moreover, rhIL-3 has no similar activity on adult peripheral blood cells, suggesting that it might be specific to the hemopoietic system.

Adult↗

PubMed1990

Potentiating effect of granulocyte-macrophage colony-stimulating factor on interleukin-1-induced thymocyte proliferation: evidence for an interleukin-2 and tumor necrosis factor-independent pathway.

The effect of Colony-Stimulating Factors (CSFs) on the growth of murine thymocytes was investigated. None among the following factors tested alone, i.e., Interleukin-3 (IL-3), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Granulocyte Colony-Stimulating Factor (G-CSF) or Macrophage Colony-Stimulating Factor (M-CSF) has been found to stimulate thymidine uptake by thymocytes. However, GM-CSF synergistically enhances thymocyte proliferation induced by Interleukin-1 (IL-1). Synergistic responses are obtained at a very pronounced level after 3 days of culture with very low factor concentrations (1.5 to 15 pM) and in the complete absence of mitogen. Similar effects are induced by IL-3, though to a lesser degree. In contrast, neither G-CSF nor M-CSF potentiate thymocyte proliferation promoted by IL-1. Kinetic studies show that the synergy between IL-1 and GM-CSF reaches its maximum after about 72 h of thymocyte culture and that it requires the simultaneous presence of both factors during the first 24 h. In addition, our data suggest that GM-CSF acts in synergy with IL-1 by an Interleukin-2 (IL-2)-independent pathway since: (i) incubation of thymocytes with GM-CSF in the presence of IL-1 does not significantly enhance the expression of the IL-2 receptors (IL-2R) as demonstrated by flow cytometry, and, (ii) specific monoclonal antibodies against murine IL-2 or IL-2R fail to reduce thymocyte proliferation in response to the synergistic combination. Similarly, the potentiating effect of GM-CSF on IL-1 thymocyte growth does not depend on Tumor Necrosis Factor alpha (TNF) since (i) the synergy for IL-1 and GM-CSF and that previously described for IL-1 and TNF cumulate and (ii) anti-TNF antibodies do not abolish the potentiating effect of GM-CSF.

Animals↗

PubMed1989

Interleukin 1 and/or tumor necrosis factor-alpha synergize with granulocyte-macrophage colony-stimulating factor to enhance histamine synthesis in hematopoietic cells: role of prostaglandin E2.

Previously, we have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates histamine synthesis by normal murine hematopoietic cells. Addition of either interleukin (IL) 1 (alpha or beta) or murine recombinant tumor necrosis factor (TNF)-alpha to murine recombinant GM-CSF (at optimal or suboptimal concentrations) enhances its activity on bone marrow histamine synthesis up to 70%. Evidence is provided that these synergies between GM-CSF and IL 1 or TNF-alpha are mediated by prostaglandin E2 (PGE2) production since (a) GM-CSF together with either IL 1 or TNF-alpha stimulates PGE2 synthesis by bone marrow cells, while none of these factors does it alone; (b) exogenous PGE2 (ranging from 10(-6) M to 10(-10) M) potentiates GM-CSF-induced histamine synthesis in a dose-dependent manner; and (c) indomethacin, a cyclooxygenase inhibitor, completely abrogates the synergistic action of IL 1 and TNF-alpha on GM-CSF-induced histamine generation. Conversely, histamine synthesis promoted by IL 3, the unique cytokine sharing this property with GM-CSF, cannot be modulated by IL 1, TNF-alpha or PGE2, suggesting two distinct mechanisms for the induction of this biological activity in hematopoietic progenitor cells.

Animals↗

PubMed1989

[Effects of hematopoietic growth factor (GM-CSF: granulocyte-macrophage colony-stimulating factor) on thymocyte proliferation induced by interleukin-1 (IL-1)].

A semi-purified fraction obtained from P388 D1 cell line conditioned medium (P388 D1 CM) which contains Interleukin-1 (IL-1) and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) stimulates murine thymocyte proliferation both in the absence and the presence of a suboptimal dose of phytohemagglutinin (PHA). Because this effect on thymocyte proliferation is always larger than that obtained with optimal concentrations of pure IL-1, we have investigated the possible involvement of GM-CSF in this semi-purified fraction mediated-thymocyte proliferation. We here show that the maximal level of thymocyte proliferation induced by the semi-purified fraction is comparable to that obtained by the co-addition of recombinant GM-CSF and IL-1. In addition, although GM-CSF alone induces no significant thymocyte proliferation, the presence of an anti-GM-CSF antiserum partially blocks the thymocyte proliferation induced by the semi-purified fraction. Thus, the capacity of the semi-purified fraction of P388 D1 to stimulate thymocyte proliferation appears to result from a synergistic action between GM-CSF and IL-1.

Animals↗