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PubMed1976

Uptake and catabolism of antigen by alvelar macrophages of dogs with respiratory hypersensitivity. Processing of antigen by alveolar macrophages.

The ability of alveolar macrophages of dogs to bind and metabolize two antigens was studied. The antigens were ragweed antigen E (AgE) and keyhole limpet haemocyanin (KLH). These antigens were chosen because of the availability of dogs with respiratory hypersensitivity to them and because they are of very different molecular weights. It was shown that: (1) antigen processing was identical using macrophages from hypersensitive as compared with normal dogs; (2) in comparison with AgE, much more of the higher molecular weight antigen, KLH, was bound to macrophages and much less degraded during subsequent incubation, leaving a greater proportion of the antigen bound to the cell membrane; (3) respiratory cells which had taken up AgE at 0 degrees C instead of 37 degrees C and were then incubated at 37 degrees C were much more active in catabolizing bound antigen with consequently less membrane bound antigen remaining; (4) increases in catabolism of bound AgE were also found in cells from relatively recently lavaged animals; (5) there was no evidence that cytophilic antibody contributed to the uptake of AgE.

Animals↗
PubMed1993

Deregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor in murine macrophage cell line J774A.1.

J774A.1 immortalized macrophage tumor cells display several phenotypes and functional capacities similar to that of murine peritoneal exudate macrophages (PEM). Both populations display comparable number of M-CSF receptors. Yet the number of GM-CSF receptors on J774A.1 cells is only one-fourth that of PEM (1,500 vs. 6,000 per cell). Unlike J774A.1 cells, which constitutively express c-myc transcripts, normal PEM required rMuGM-CSF for the induction of c-myc expression. Nevertheless, the growth of J774A.1 cells can be further enhanced in the presence of exogenous rMuGM-CSF, rHuM-CSF, and rMuIL-3. Treatment with either rMuIL-3 (20 ng/ml) and rHuTGF-beta 1 (1.0 ng/ml) for 24 hr at 37 degrees C, markedly enhanced the expression of GM-CSF receptors on normal PEM but not leukemic J774A.1 cells. J774A.1 cells also did not respond by autologous upregulation of GM-CSF receptors as seen in PEM following treatment with rMuGM-CSF. Treatment with either pertussis toxin (20-100 ng/ml) or H-8 (50 microM) for 24 hr led to an enhanced expression of GM-CSF receptors on J774A.1 cells in a time- and dose-dependent manner but did not result in enhanced receptor expression on normal PEM. These findings suggest that the expression of GM-CSF receptors may be regulated by mechanisms involving Gi-proteins and their downstream elements, which in turn are linked to regulatory pathways of other cytokine receptors. In J774A.1 cells, such regulatory interaction may not exist.

Animals↗
PubMed1992

Biochemical events accompanying macrophage activation and the inhibition of colony-stimulating factor-1-induced macrophage proliferation by tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide.

Agents that can arrest cellular proliferation are now providing insights into mechanisms of growth factor action and how this action may be controlled. It is shown here that the macrophage activating agents tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), and lipopolysaccharide (LPS) can maximally inhibit colony stimulating factor-1 (CSF-1)-induced, murine bone marrow-derived macrophage (BMM) DNA synthesis even when added 8-12 h after the growth factor, a period coinciding with the G1/S-phase border of the BMM cell cycle. This inhibition was independent of autocrine PGE2 production or increased cAMP levels. In order to compare the mode of action of these agents, their effects on a number of other BMM responses in the absence or presence of CSF-1 were examined. All three agents stimulated BMM protein synthesis; TNF alpha and LPS, but not IFN gamma, stimulated BMM Na+/H+ exchange and Na+,K(+)-ATPase activities, as well as c-fos mRNA levels. IFN gamma did not inhibit the CSF-1-induced Na+,K(+)-ATPase activity. TNF alpha and LPS inhibited both CSF-1-stimulated urokinase-type plasminogen activator (u-PA) mRNA levels and u-PA activity in BMM, whereas IFN gamma lowered only the u-PA activity. In contrast, LPS and IFN gamma, but not TNF alpha, inhibited CSF-1-induced BMM c-myc mRNA levels, the lack of effect of TNF alpha dissociating the inhibition of DNA synthesis and decreased c-myc mRNA expression for this cytokine. These results indicate that certain biochemical responses are common to both growth factors and inhibitors of BMM DNA synthesis and that TNF alpha, IFN gamma, and LPS, even though they all have a common action in suppressing DNA synthesis, activate multiple signaling pathways in BMM, only some of which overlap or converge.

Animals↗
PubMed1988

Macrophage cell line B6MP102 resembles peritoneal macrophages in tumor cell recognition and killing.

In this paper we describe the bone marrow-derived macrophage cell line B6MP102. We describe growth characteristics, responsiveness to biological response modifiers known to activate macrophages (MPs), and the ability of B6MP102--comparable to that of peritoneal MPs--to kill and discriminate tumor cells. We demonstrate that B6MP102 is easily maintained in culture in the presence of 15% L-M cell-conditioned media. We have found that the B6MP102 cell line is similar to in vivo-derived peritoneal MPs. These cells are responsive to biological response modifiers but are not spontaneously cytotoxic. They produce O2- in quantities comparable to that produced by peritoneal MPs, and they exhibit target ranges for direct killing similar to those of activated peritoneal MPs. In addition, B6MP102 is similar to MPs in mediating cytostasis. These latter two points are especially significant, suggesting that the mechanisms that MPs may use to distinguish and kill tumor cells are retained in the B6MP102 cell line. This makes the cell line a useful tool for studying MP-tumor cell interactions.

Animals↗
PubMed1992

Tumor growth changes the contribution of granulocyte-macrophage colony-stimulating factor during macrophage-mediated suppression of allorecognition.

Tumor-bearing host (TBH) macrophages (M phi) suppress T cell alloresponses, and this study suggests granulocyte-macrophage colony-stimulating factor (GM-CSF), a molecule associated with suppressive M phi activity during tumor growth, signals more immunosuppression. In the absence of M phi, GM-CSF increased T cell proliferation in response to alloantigen. However, TBH M phi-mediated suppression of allorecogntion was further induced by GM-CSF. Allogeneic mixed lymphocyte reaction (MLR) cultures, containing normal host (NH) M phi, were either unaffected or enhanced. Prostaglandin E2 (PGE2), a highly suppressive monokine that decreases alloreactivity, did not seem to be involved in the suppression caused by the TBH M phi/GM-CSF interaction. M phi-CSF (M-CSF) addition to cultures did not reverse the suppression caused by TBH M phi and GM-CSF, and inhibition of PGE2 synthesis did not change the response to M-CSF. TBH Ia- M phi, a suppressor population that predominates among splenic M phi during tumor growth, demonstrated significantly lower reactivity in the presence of GM-CSF. In contrast, alloresponses suppressed by NH Ia- M phi demonstrated higher reactivity in the presence of GM-CSF. The data collectively suggest that TBH M phi respond differently to GM-CSF, and that tumor-induced changes in GM-CSF responsiveness affect M phi accessory ability.

Animals↗
PubMed1999

Granulocyte macrophage colony-stimulating factor and interleukin-3 regulate chemokine and chemokine receptor expression in bone marrow macrophages.

The beta-chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) and its associated receptors are involved in the regulation of pro-inflammatory and haemopoietic processes. This study was designed to investigate regulation of expression MIP-1alpha and its receptors by other haemopoietic cytokines. Murine bone marrow macrophages (BMM) were treated with or without GM-CSF or IL-3 and expression of MIP-1alpha, other chemokines and their receptors examined by Northern blotting. Receptor levels were also examined using Scatchard analysis and functional tests. Treatment of BMM with GM-CSF revealed a striking increase in MIP-1alpha mRNA levels, relative to untreated cells with a corresponding increase in MIP-1alpha protein. A similar increase in mRNA levels was found when BMM were treated with IL-3. An increase in the expression of three other beta-chemokines namely MIP-1beta, MCP-1 and MCP-3, was also found following treatment with GM-CSF or IL-3. We have additionally examined the expression of the known beta-chemokine receptors in BMM and observed an increase in CCR1 mRNA levels following treatment with GM-CSF and IL-3, but no change was seen in the level of CCR5 expression. The increase in CCR1 expression was reflected in an increase in the number of cell surface receptors for MIP-1alpha on the GM-CSF treated BMM and in an enhanced response of the GM-CSF treated BMM to CCR1 ligands. These data suggest that GM-CSF and IL-3 may be involved in mechanisms regulating expression levels of MIP-1alpha and its receptors.

Animals↗
PubMed1995

Activation-induced apoptosis in human macrophages: developmental regulation of a novel cell death pathway by macrophage colony-stimulating factor and interferon gamma.

Activated macrophages (M phi s) are important participants in host defense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the immune system is programmed cell death, or apoptosis. Monocytes are known to undergo spontaneous apoptosis upon leaving the circulation unless provided with specific survival signals, but mature tissue M phi s are more robust cells, and it was not clear that they could be similarly regulated by apoptosis. We now show that during differentiation monocytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initiates apoptosis after activation with specific stimuli (zymosan and phorbol esters). Sensitivity to activation-induced apoptosis was developmentally determined, being downregulated by the maturation-promoting cytokine macrophage colony-stimulating factor but stably upregulated by even transient exposure to the proinflammatory cytokine interferon gamma (IFN-gamma). Apoptosis began within 2-4 h of activation, occurred in > 95% of susceptible cells, and in mixed cocultures selectively affected only those M phi s with a history of IFN-gamma priming. Consistent with a possible role for protein kinase C in the signaling pathway leading to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosan-induced apoptosis. Our studies describe a novel form of activation-induced M phi apoptosis which is developmentally regulated by two physiologically relevant cytokines. We speculate that apoptosis may serve to restrict the destructive potential of inflammatory M phi s.

Apoptosis↗
PubMed1997

Adoptive immunotherapy with tumor-cytotoxic macrophages derived from recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) mobilized peripheral blood monocytes.

We examined the mobilization of blood monocytes (MO) with recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) with regard to the in vitro generation of MO-derived tumor-cytotoxic macrophages (MAC) for use in adoptive immunotherapy of cancer patients. Eleven patients with progressing metastatic cancer received interferon (IFN)-gamma activated tumor-cytotoxic MAC generated in vitro from autologous MO with and without pretreatment with rhuGM-CSF. RhuGM-CSF was administered subcutaneously at 10 micrograms/kg for 7 days. RhuGM-CSF treatment and adoptive cell transfer were well tolerated, and no toxicity greater than WHO II degrees occurred. Fever was the most common side effect and was seen in all patients during rhuGM-CSF treatment and during 9 of 22 MAC therapies. Bone pain was noted in 5 of 11 patients during rhuGM-CSF therapy. RhuGM-CSF treatment led to a continuous increase in the white blood cell counts and the number of MO within the leukapheresis products. The mean number of transfused MAC was 0.9 x 10(9) without rhuGM-CSF pretreatment and 1.9 x 10(9) after rhuGM-CSF administration. The maximum number of MAC that could be generated was 7.3 x 10(9), but after a dose escalation protocol only up to 2.7 x 10(9) MAC were transfused. Cytotoxicity against U937 cells increased during MO to MAC differentiation, but was decreased in both MO and MAC on treatment with rhuGM-CSF. This study proves the feasibility of reinfusing MAC generated in vitro from rhuGM-CSF mobilized MO.

Adult↗
PubMed1995

Suppressive effects of tranilast on pulmonary fibrosis and activation of alveolar macrophages in mice treated with bleomycin: role of alveolar macrophages in the fibrosis.

We have reported that tranilast, an anti-allergic drug that inhibits chemical mediator release from mast cells, suppresses bleomycin (BLM)-induced pulmonary fibrosis in mice through mechanisms other than inhibiting chemical mediator release from mast cells. The purpose of this paper is to examine the effect of tranilast on alveolar macrophage (AM) activation and on the development of fibrosis in ICR mice instilled with BLM intratracheally. Twenty eight days after the BLM instillation (0.01 mg/mouse), AM often migrated into alveolar spaces surrounding the fibrotic areas. Flow cytometry analysis for the size and density of AM (MAC-1 positive cells) suggested that AM were activated not only in the earlier acute inflammatory phase, but also in the later chronic phase. The p.o. administration of tranilast suppressed an increase of AM activity to produce reactive oxygen species in BLM-instilled mice, and it inhibited the subsequent development of pulmonary fibrosis. In vitro treatment with tranilast suppressed the reactive oxygen species production from murine peritoneal macrophages. However, several different anti-oxidants failed to inhibit the development of fibrosis. These results suggest that the activation of AM plays an important role in the development of fibrosis, and it is likely that tranilast suppresses fibrosis by inhibiting AM activation but not by scavenging reactive oxygen species.

Administration, Oral↗
PubMed2001

IL-10 inhibits granulocyte-macrophage colony-stimulating factor-dependent human monocyte survival at the early stage of the culture and inhibits the generation of macrophages.

We previously demonstrated that IL-10 alone does not stimulate growth and differentiation of human monocytes, but enhances those of monocytes stimulated with M-CSF. We studied here the effect of IL-10 on human monocytes stimulated with GM-CSF. Monocytes stimulated with GM-CSF alone survived and developed into macrophages. Monocytes cultured with GM-CSF plus IL-10, however, died through apoptosis. IL-10 decreased expression of bcl-2, bcl-x(L), and mcl-1- but not bax mRNA in monocytes stimulated with GM-CSF. IL-10 did not change the expression of mRNA of both GM-CSFR alpha-chain and beta-chain, but inhibited tyrosine phosphorylation of STAT5 and extracellular signal-regulated kinases 1 and 2 in the monocytes. The inhibitory effect of IL-10 was restricted to treatment 48 h after stimulation with GM-CSF. Addition of IL-10 after that time induced neither apoptosis nor a decrease in expression of bcl-2, bcl-x(L), and mcl-1 mRNA. IL-10, however, inhibited LPS-induced TNF-alpha production even in these cells, indicating that the cells still possessed responsiveness to IL-10. Monocytes pretreated for >48 h with GM-CSF became resistant to GM-CSF withdrawal, and the cells could survive without GM-CSF. These results indicate that IL-10 selectively inhibits GM-CSF-dependent monocyte survival by inhibiting the signaling events induced by GM-CSF, but the timing of addition of IL-10 is critical, and IL-10 had to be added within 48 h after stimulation with GM-CSF to achieve the inhibitory effect. These results taken together with our previous results indicate that IL-10 plays a pivotal role in monocyte survival and development into macrophages in concert with M-CSF and GM-CSF.

Apoptosis↗
PubMed1989

Interleukin 1 and poly(rI).poly(rC) induce production of granulocyte CSF, macrophage CSF, and granulocyte-macrophage CSF by human endothelial cells.

Electrophoretically pure human interleukin 1 (IL-1) beta was found to stimulate human endothelial cells in monolayer culture to elaborate colony-stimulating activity (CSA). Supernatant fluids from cultures stimulated with increasing concentrations of IL-1 were found to stimulate colony formation of myeloid (CFU-GM), erythroid (BFU-E), and multipotent (CFU-GEMM) progenitor cells in a dose-dependent fashion. The effect on mixed colony formation, however, was less than on CFU-GM and BFU-E growth. Similar to IL-1, the double-stranded RNA polyriboinosinic-polyribocytidilic acid (poly[rI].poly[rC]) also stimulated release of CSA by endothelial cells in a dose-dependent manner. The kinetics of IL-1-induced CSA release as opposed to poly(rI).poly(rC)-induced release were found to be different, in that poly(rI).poly(rC)-induced CSA production occurred more slowly. An anti-IL-1 beta antiserum was able to completely neutralize the IL-1-induced CSA release, but had no effect on poly(rI).poly(rC)-dependent CSA production, indicating that the latter effect was mediated by other mechanisms than intermediate production of IL-1 beta. Using specific immunologic assays, IL-1- as well as poly(rI).poly(rC)-inducible production of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, and macrophage CSF was found. The release of CSF from endothelial cells in response to IL-1 may be a mechanism for stimulating production of neutrophils and mononuclear phagocytes, and for attracting and activating these cells at sites of inflammation.

Bone Marrow↗
PubMed1989

Enhancement of human monocyte function against Candida albicans by the colony-stimulating factors (CSF): IL-3, granulocyte-macrophage-CSF, and macrophage-CSF.

The effect of IL-3, granulocyte-macrophage (GM)-CSF and macrophage (M)-CSF on Candida albicans growth inhibition by human peripheral blood monocytes was investigated. By using a radiolabel microassay developed in our laboratory that makes use of the incorporation of [3H]glucose into residual C. albicans, we demonstrated that rGM-CSF and rIL-3 effectively enhanced human monocyte-mediated anticandidal activity. Incubation for 24 h with either GM-CSF or IL-3 significantly enhanced monocyte antifungal responses down to 0.01 U/ml. M-CSF, at higher concentrations of 10 U/ml, could also enhance monocyte function but to a smaller degree. None of the CSF interfered directly with fungal growth, even up to 1000 U/ml. Because IFN-gamma is also a known monocyte activator, its effect on monocytes was also assessed. Monocytes were first cultured in medium for several days and then further incubated with each of the cytokines. Monocytes aged in medium were found to lose their spontaneous anticandidal activity. Such aged monocytes did not develop anticandidal activity in response to IFN-gamma but did in response to GM-CSF or IL-3. To further elucidate this difference, fresh monocytes were continuously cultured with or without cytokines for 1 to 5 days before assessing their anticandidal activity. Monocytes cultured in IFN-gamma progressively lost their activity by 2 days but monocytes in GM-CSF or IL-3 maintained their high level of anticandidal activity throughout the whole length of culture. Therefore, GM-CSF and IL-3 not only enhanced fresh monocyte anticandidal activity, but maintained monocyte function for a longer period. These results suggest that GM-CSF and IL-3 may act on monocytes via a different pathway than does IFN-gamma.

Candida albicans↗
PubMed1994

Increased sensitivity of tumor-bearing host macrophages to interleukin-10: a counter-balancing action to macrophage-mediated suppression.

Tumor growth causes macrophages (M phi) to suppress T-cell proliferation by inducing M phi production of soluble suppressor molecules. Because interleukin (IL)-10 inhibits production of most M phi-derived molecules, we investigated the effects of IL-10 on murine M phi suppressor function during tumor growth. When acting as accessory cells during alloantigen-induced CD4+ T-cell proliferation, syngeneic tumor-bearing host (TBH) peritoneal M phi suppressed normal host (NH) T-cell proliferation more than their normal counterparts. Exogenous IL-10 suppressed alloantigen-stimulated CD4+ T-cell proliferation in the absence of accessory M phi, but it blocked TBH M phi-mediated suppression. IL-10 pretreatment of M phi reversed suppression mediated by TBH M phi but did not affect NH M phi activity. Supernatant transfer experiments showed that IL-10 blocked TBH M phi-mediated suppression by inhibiting soluble suppressor molecule production. Activated TBH M phi produced greater quantities of the suppressor molecules tumor necrosis factor-alpha, nitric oxide, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor than NH M phi did. Exogenous IL-10 reduced production of these molecules by TBH M phi more than by NH M phi. Activated TBH M phi produced more IL-10 than NH M phi, suggesting that endogenous IL-10 contributes to increased TBH M phi sensitivity to exogenous IL-10's inhibitory action. The antibody-mediated neutralization of endogenous IL-10 activity relieved NH, but not TBH, M phi-mediated suppression of T-cell proliferation. This result supports the idea that TBH M phi are more sensitive to the inhibitory action of IL-10 on suppressor molecule production. IL-10 is known to inhibit M phi antigen-presenting cell-dependent helper T-cell proliferation. We report here that IL-10 restores TBH helper T-cell functions by blocking accessory M phi production of inhibitory molecules. This restoration suggests that IL-10's M phi deactivating activity provides an upregulatory role in immunocompromised individuals where suppressor M phi are abundant.

Animals↗
PubMed1994

Macrophage colony-stimulating factor-induced bone marrow macrophages do not synthesize or release prostaglandin E2.

Previously, we found that murine bone marrow-derived macrophages (MO) induced in vitro by MO-specific colony-stimulating factor (M-CSF) have little capacity to release prostaglandin E2 (PGE2) and other eicosanoids. This work focused on the functional and transcriptional expression of the key enzymes for the PGE2 synthesis in the MO. Nonadherent bone marrow cells were cultured with RPMI1640 plus 10% fetal bovine serum (FBS) further supplemented with either M-CSF or granulocyte-macrophage (GM)-CSF and interleukin-3 (IL-3). Cellular PGG/H synthase (cyclooxygenase) levels were quantified by cytometric analysis with antibodies specific for the two isozymes of PGG/H synthase (PGG/H synthases 1 and 2). The enzyme activity was monitored by adding exogenous arachidonic acid (AA) substrate to the bone marrow MO cultures and to the cell-free particulate fractions. The levels of PGE2 converted were quantitated by radioimmunoassay (RIA). mRNA levels of the enzymes were detected by Northern blot analysis hybridized with mouse PGG/H synthase cDNA probes, 2.7 kb (PGG/H synthase 1) and 4.2 kb (PGG/H synthase 2). In addition, cellular phospholipase A2 (PLA2) activities were detected with sn-2-14C-arachidonyl phosphatidylcholine as a substrate. Cells proliferating in the presence of GM-CSF and IL-3 for more than 4 days showed significant release of PGE2 (> 7 ng/10(6) cells) when stimulated by AA. These cells also expressed significant amounts of PGG/H synthase 1 protein, its mRNA (2.7 kb) and cellular PLA2. M-CSF-induced MO, in sharp contrast, expressed little PGG/H synthase protein, mRNA, cellular enzyme activity, or PGE2 release, despite comparable levels of cellular PLA2 activity. These data suggest that the capacity of differentiating marrow-derived MO to form PGE2 is growth factor-dependent.

Animals↗
PubMed1994

Effect of granulocyte-macrophage colony-stimulating factor on rat alveolar macrophage anticryptococcal activity in vitro.

Cryptococcus neoformans, a pathogenic fungus usually acquired by inhalation, causes the most common lethal mycosis in AIDS. The resident lung phagocytes, alveolar macrophages (AM phi), inhibit growth of C. neoformans poorly unless activated by cytokines such as IFN-gamma. In this study, we examined the effect of rat AM phi of the potent hematopoietic and M phi-activating cytokine, granulocyte-macrophage CSF (GM-CSF), alone and in combination with other cytokines. Rat AM phi monolayers were preincubated with 0.1 to 1000 U/ml GM-CSF without or with other recombinant cytokines, and then were incubated with viable C. neoformans (strain H99/C3D). Growth inhibition was assessed by counting cryptococcal CFU at 24 and 48 h of coculture; AM phi proliferation was assessed by measuring both uptake of [3H]TdR and AM phi numbers. AM phi preincubated with GM-CSF for 5 days (but not for shorter periods) inhibited growth of C. neoformans. Anticryptococcal activity required direct contact of AM phi with C. neoformans, but once induced by preincubation, did not require continued exposure to GM-CSF. Induction of anticryptococcal activity by GM-CSF was dose dependent (maximal induction at 250 U/ml), and was due to both increased ingestion and killing. GM-CSF induced AM phi proliferation, but anticryptococcal activity was not due totally to increases in AM phi numbers, indicating AM phi activation by GM-CSF. GM-CSF-induced AM phi proliferation was increased by IL-6, unchanged by IL-8, and abolished by LPS or IFN-gamma. However, IL-6 did not increase GM-CSF-induced anticryptococal activity. The combination of GM-CSF and IFN-gamma showed rapid and sustained anticryptococcal activity, unlike either cytokine alone. Our in vitro data suggest that the combination of GM-CSF and IFN-gamma may have beneficial effects on host defense against C. neoformans in vivo.

Animals↗
PubMed1996

Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro.

The present study was performed to characterize the immunologic potential of interstitial macrophages (INT) in comparison with alveolar macrophages (AL). The data showed that AL, compared with INT, have a more efficient phagocytic potential. In addition, they have a strong microbicidal activity and secrete large amounts of reactive oxygen radicals, nitric oxides, TNF, and IFN on appropriate stimulation. They also exert strong tumoricidal and parasiticidal activities. In contrast, INT are more efficient in releasing immunoregulatory cytokines such as IL-1 and IL-6. As determined by Ab staining, INT express more MHC class II molecules and are more effective in functioning as accessory cells for mitogen-stimulated lymphocyte proliferation compared with AL. Thus, AL appear to be particularly effective as nonspecific first line defense cells against infectious agents, whereas INT are equipped to cooperate with interstitial lymphocytes in inducing a specific immune reaction.

Animals↗
PubMed1988

Granulocyte-macrophage colony-stimulating factor-cultured bone marrow-derived macrophages reveal accessory cell function and synthesis of MHC class II determinants in the absence of external stimuli.

The antigen-mediated activation of a number of T cell clones by bone marrow (BM) cells cultivated in the presence of various colony-stimulating factor (CSF) preparations was investigated. BM macrophages (BMM phi) grown in L929 cell supernatant as a crude source of macrophage colony-stimulating factor (M-CSF) as well as BM cells propagated in the presence of recombinant M-CSF exhibited transient antigen presentation potential to some T cell clones, being maximal on day 7 and having declined to a low level by day 19 of in vitro culture. Treatment of these long-term-cultivated BMM phi populations with recombinant interferon-gamma (IFN-gamma) resulted in predominant antigen presentation capacity. In contrast, BM cells differentiated in the presence of recombinant granulocyte (G)M-CSF developed highly efficient accessory cell function to all T cell clones examined. This function became apparent earlier, was retained during the time period tested (up to day 19 of continuous culture) and did not require prior stimulation by IFN-gamma. The functionally competent cells were shown to belong to the monocyte/macrophage lineage. These findings are consistent with the demonstration of substantial levels of major histocompatibility complex (MHC) class II molecules synthesized by GM-CSF-cultured BM cells in the absence of exogenous IFN-gamma. In contrast, M-CSF grown BM cells synthesized only minute amounts of Ia antigens unless they were stimulated by IFN-gamma. Because GM-CSF-cultivated BM cells proved clearly superior to M-CSF-grown and IFN-gamma-activated BM cells with respect to antigen-presenting capacity but exhibited lower levels of MHC class II molecules, other properties acting in addition to surface Ia antigens might be responsible for their pronounced T cell accessory function.

Animals↗
PubMed1989

Production of macrophage-, granulocyte-, granulocyte-macrophage- and multi-colony-stimulating factor by peripheral blood cells.

The specific cell sources and signals for induction of various colony-stimulating factors (CSF) in peripheral blood mononuclear cells (PBMC), purified T lymphocyte and monocyte (Mo) populations have been investigated. In the absence of exogenous activating stimuli, human PBMC, T cells and Mo failed to produce stable cytoplasmic mRNA for CSF for macrophages (M-CSF or CSF-1), for granulocytes (G-CSF), for granulocytes and macrophages (GM-CSF) and for multilineage CSF [multi-CSF, interleukin (IL) 3] and thus failed to release CSF proteins. However, after stimulation with phorbol myristate acetate and phytohemagglutinin, M-, G-, GM- and multi-CSF mRNA became detectable in PBMC, resulting in the secretion of the respective proteins. Identical culture conditions resulted in synthesis of only G- and M-CSF by purified Mo, whereas purified T lymphocytes produced GM-CSF and multi-CSF only. When Mo or T lymphocytes were exposed to recombinant human interferon-gamma or were stimulated by triggering the epitopes recognized by the monoclonal antibodies anti-Tll2 and Tll3, respectively, again disparate CSF expression patterns were found to be associated with both cell species. Moreover, IL2-receptive T lymphocytes showed the same distinct pattern of CSF secretion when activated by recombinant human IL2.

Colony-Stimulating Factors↗