Abstract
Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN; CD209) is a human pathogen-attachment C-type lectin with no obvious murine ortholog and for which ligation leads to enhanced anti-inflammatory cytokine release and altered proinflammatory cytokine production. Although induced by IL-4 in monocytes and considered as a DC marker, DC-SIGN expression on human APCs under homeostatic conditions is so far unexplained. We report in this study that M-CSF enhances DC-SIGN expression on in vitro derived anti-inflammatory macrophages and that M-CSF mediates the induction of DC-SIGN by fibroblast- and tumor cell-conditioned media. The M-CSF-inducible DC-SIGN expression along monocyte-to-macrophage differentiation is dependent on JNK and STAT3 activation, potentiated by STAT3-activating cytokines (IL-6, IL-10), and abrogated by the M1-polarizing cytokine GM-CSF. In pathological settings, DC-SIGN expression is detected in tumor tissues and on ex vivo-isolated CD14(+) CD163(+) IL-10-producing tumor-associated macrophages. Importantly, DC-SIGN Abs reduced the release of IL-10 from macrophages exposed to Lewis(x)-expressing SKBR3 tumor cells. These results indicate that DC-SIGN is expressed on both wound-healing (IL-4-dependent) and regulatory (M-CSF-dependent) alternative (M2) macrophages and that DC-SIGN expression on tumor-associated macrophages might help tumor progression by contributing to the maintenance of an immunosuppressive environment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / immunology*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Breast Neoplasms / immunology*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Adhesion Molecules / biosynthesis*
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Cell Adhesion Molecules / genetics
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Cell Differentiation / immunology
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Cell Polarity / immunology*
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Disease Progression
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Gene Expression Regulation / immunology
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Humans
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Immunocompromised Host / genetics
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Immunocompromised Host / immunology
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology
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Interleukin-10 / physiology*
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Interleukin-6 / physiology*
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Lectins, C-Type / biosynthesis*
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Lectins, C-Type / genetics
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Macrophage Colony-Stimulating Factor / physiology*
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / pathology
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Melanoma, Experimental / immunology*
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / pathology
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Neoplasm Proteins / physiology
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Receptors, Cell Surface / biosynthesis*
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Receptors, Cell Surface / genetics
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Tumor Cells, Cultured
Substances
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Cell Adhesion Molecules
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Culture Media, Conditioned
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DC-specific ICAM-3 grabbing nonintegrin
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IL10 protein, human
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IL6 protein, human
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Inflammation Mediators
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Interleukin-6
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Lectins, C-Type
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Neoplasm Proteins
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Receptors, Cell Surface
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Interleukin-10
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Macrophage Colony-Stimulating Factor