Dendritic cell-specific ICAM-3-grabbing nonintegrin expression on M2-polarized and tumor-associated macrophages is macrophage-CSF dependent and enhanced by tumor-derived IL-6 and IL-10.
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.
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain. ads@cib.csic.es
Angeles
A
Domínguez-Soto
Elena
E
Sierra-Filardi
Amaya
A
Puig-Kröger
Blanca
B
Pérez-Maceda
Fernando
F
Gómez-Aguado
María Teresa
MT
Corcuera
Paloma
P
Sánchez-Mateos
Angel L
AL
Corbí
D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016867:Immunocompromised Host / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D016753:Interleukin-10; D015850:Interleukin-6; D037181:Lectins, C-Type; D016173:Macrophage Colony-Stimulating Factor; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C508609:IL10 protein, human; C508600:IL6 protein, human