Susceptibility or resistance toLeishmania infection is dictated by the macrophages evolved under the influence of IL-3 or GM-CSF

Saha, Bhaskar; Saini, Abha; Germond, Rhonda L.; Perrin, Peter J.; Harlan, David M.; Davis, Thomas A.

doi:10.1002/(sici)1521-4141(199907)29:07<2319::aid-immu2319>3.0.co;2-3

Cited by 36 publications

(26 citation statements)

References 56 publications

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“…Recently, Hibbs et al reported that mice lacking M-CSF, GM-CSF, and G-CSF still produce M s (44), and they hypothesized that IL-3 might contribute to M generation in vivo. We show herein that IL-3-derived M s are phenotypically distinct from M-CSF-or GM-CSF-derived M s. This is consistent with studies by Saha et al showing that IL-3-derived M s have unique functions and preferentially activate Th2 responses after Leishmania major infection in BALB/c mice (18). Interestingly, a model has recently been put forward that GM-CSF, which is increased at sites of inflammation, skews to an M1 phenotype while M-CSF, which is produced constitutively, tends to polarize to a more M2-like state (45).…”

Section: Discussionsupporting

confidence: 92%

“…This suggests that enhanced activation of the PI3K pathway facilitates M2 skewing in vivo and, consistent with this, we found that in vivo tumor growth is significantly faster in SHIP Ϫ/Ϫ mice and that tumor-infiltrated M s in these mice display a strong M2 phenotype (16). We (17) and others (18) have also recently found that IL-3 may, under some circumstances, be an important differentiation factor in the development of M2-like M s, and so we investigated whether IL-3 might have substantial M2 skewing ability in the absence of SHIP.…”

supporting

confidence: 88%

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SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

Kuroda

Rüschmann

et al. 2009

The Journal of Immunology

102

100

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There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (Mφs) because of the opposing effects that these two Mφ subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine Mφ progenitors toward an M2 phenotype, especially in the absence of SHIP. Specifically, the addition of these cytokines, with or without M-CSF, to adherence- or lineage-depleted (Lin−) SHIP−/− bone marrow (BM) cells induces high levels of the M2 markers, arginase I, and Ym1 in the resulting mature Mφs. These in vitro-derived mature Mφs also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-γ and low IL-12 and high IL-10 production in response to LPS. Not surprisingly, given that IL-3 and GM-CSF utilize STAT5 to trigger many downstream signaling pathways, this M2 phenotype is suppressed when STAT5−/− BM cells are used. Unexpectedly, however, this M2 phenotype is also suppressed when STAT6−/− BM cells are used, suggesting that IL-4- or IL-13-induced signaling might be involved. Consistent with this, we found that IL-3 and GM-CSF stimulate the production of IL-4, especially from SHIP−/− Lin− BM cells, and that neutralizing anti-IL-4 Abs block IL-3-induced M2 skewing. Moreover, we found that basophil progenitors within the Lin− BM are responsible for this IL-3- and GM-CSF-induced IL-4 production, and that SHIP represses M2 skewing not by preventing skewing within Mφs themselves but by inhibiting IL-4 production from basophils.

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Section: Discussionsupporting

confidence: 92%

supporting

confidence: 88%

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

Kuroda

Rüschmann

et al. 2009

The Journal of Immunology

102

100

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“…The finding that treatment with Candida antigen in vitro was able to inhibit colony formation by bone marrow from CBA/CaH, but not from BALB/c mice, correlates with the relative susceptibility to Candida infection of these two mouse strains, and is consistent with a report that the ability of rhGM-CSF to increase the proliferation of human bone marrow cells was inhibited by a component of C. albicans [24].…”

Section: Discussionsupporting

confidence: 89%

Bone marrow colony-formation in vitro after infection of genetically defined inbred mice with Candida albicans

Wanasaengsakul

Ashman

2004

Microbial Pathogenesis

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The effect of C. albicans infection on the production of haematopoietic precursor cells in the bone marrow of CBA/CaH and BALB/c mice was evaluated by assay of colony formation in vitro. In immunocompetent mice, neither systemic nor oral infection induced significant alterations in colony formation by bone marrow from the two mouse strains, and Candida infection did not alter the proportion of morphological cell types in the colonies. However, the number of neutrophil-like was relatively greater in colonies derived from acutely infected CBA/CaH nude mice than in those from BALB/c nude mice, whereas small mononuclear cells were present in higher proportions in the latter strain. In both strains of nude mice, there was an increase in colony formation at 6 days after oral infection, but at 8 weeks, when the infection had become chronic, the production of bone marrow cells by CBA/CaH nude mice was significantly less than that by BALB/c nude mice. Reconstitution of nude mice with syngeneic lymphocytes enhanced the production of bone marrow precursor cells by BALB/c, but not by CBA/CaH mice, suggesting that T cells can enhance host resistance by promoting the colony-forming response of the bone marrow in BALB/c mice that are genetically resistant to tissue damage, but not in CBA/CaH that are prone to severe lesions. Finally, culture with Candida antigen in vitro decreased the number of colony-forming cells in cultures from CBA/CaH, but not from BALB/c mice.

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“…IL-3 precludes the development of monocytes into DC that secrete the bioactive IL-12 p70 heterodimer in response to a T cell stimulus. A similar phenomenon has been described for other cell types, namely murine macrophages (35) and mast cells (36), but, to the best of our knowledge, not for monocyte-derived DC generated under conditions appropriate for clinical use, i.e., FCSfree and with the help of IL-4.…”

Section: Effects Of Il-3 On DCsupporting

confidence: 79%

A Novel Role for IL-3: Human Monocytes Cultured in the Presence of IL-3 and IL-4 Differentiate into Dendritic Cells That Produce Less IL-12 and Shift Th Cell Responses Toward a Th2 Cytokine Pattern

Ebner¹,

Hofer²,

Nguyen³

et al. 2002

The Journal of Immunology

104

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Dendritic cells (DC) derived from plasmacytoid precursors depend on IL-3 for survival and proliferation in culture, and they induce preferentially Th2 responses. Monocytes express not only GM-CSF receptors, but also IL-3Rs. Therefore, we examined whether IL-3 had an effect on the functional plasticity of human monocyte-derived DC generated in a cell culture system that is widely used in immunotherapy. DC were generated with IL-3 (instead of GM-CSF) and IL-4. Yields, maturation, phenotype (surface markers and Toll-like receptors), morphology, and immunostimulatory capacity were similar. Only CD1a was differentially expressed, being absent on IL-3-treated DC. In response to CD40 ligation DC generated in the presence of IL-3 secreted significantly less IL-12 p70 and more IL-10 compared with DC grown with GM-CSF. Coculture of naive allogeneic CD4+ T cells with DC generated in the presence of IL-3 induced T cells to produce significantly more IL-5 and IL-4 and less IFN-γ compared with stimulation with DC generated with GM-CSF. These data extend the evidence that different cytokine environments during differentiation of monocyte-derived DC can modify their Th cell-inducing properties. A hitherto unrecognized effect of IL-3 on DC was defined, namely suppression of IL-12 secretion and a resulting shift from Th1 toward Th2.

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Susceptibility or resistance toLeishmania infection is dictated by the macrophages evolved under the influence of IL-3 or GM-CSF

Cited by 36 publications

References 56 publications

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

Bone marrow colony-formation in vitro after infection of genetically defined inbred mice with Candida albicans

A Novel Role for IL-3: Human Monocytes Cultured in the Presence of IL-3 and IL-4 Differentiate into Dendritic Cells That Produce Less IL-12 and Shift Th Cell Responses Toward a Th2 Cytokine Pattern

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