title: AM3 modulates dendritic cell pathogen recognition capabilities by targeting DC-SIGN.
abstract: AM3 (Inmunoferon) is an orally effective immunomodulator that influences the regulatory and effector functions of the immune system whose molecular mechanisms of action are mostly unknown. We hypothesized that the polysaccharide moiety of AM3 (IF-S) might affect immune responses by modulating the lectin-dependent pathogen recognition abilities of human dendritic cells. IF-S inhibited binding of viral, fungal, and parasite pathogens by human monocyte-derived dendritic cells in a dose-dependent manner. IF-S specifically impaired the pathogen recognition capabilities of DC-SIGN, as it reduced the attachment of Candida, Aspergillus, and Leishmania to DC-SIGN transfectants. IF-S also inhibited the interaction of DC-SIGN with both its cellular counterreceptor (intercellular adhesion molecule 3) and the human immunodeficiency virus (HIV) type 1 gp120 protein and blocked the DC-SIGN-dependent capture of HIV virions and the HIV trans-infection capability of DC-SIGN transfectants. IF-S promoted DC-SIGN internalization in DCs without affecting mannose receptor expression, and (1)D saturation transfer difference nuclear magnetic resonance demonstrated that IF-S directly interacts with DC-SIGN on the cell surface. Therefore, the polysaccharide moiety of AM3 directly influences pathogen recognition by dendritic cells by interacting with DC-SIGN. Our results indicate that DC-SIGN is the target for an immunomodulator and imply that the adjuvant and immunomodulatory actions of AM3 are mediated, at least in part, by alteration of the DC-SIGN functional activities.
authors: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors: Diego
authors: D
authors: Serrano-Gómez
authors: Rocío T
authors: RT
authors: Martínez-Nuñez
authors: Elena
authors: E
authors: Sierra-Filardi
authors: Nuria
authors: N
authors: Izquierdo
authors: María
authors: M
authors: Colmenares
authors: Jesús
authors: J
authors: Pla
authors: Luis
authors: L
authors: Rivas
authors: Javier
authors: J
authors: Martinez-Picado
authors: Jesús
authors: J
authors: Jimenez-Barbero
authors: José Luis
authors: JL
authors: Alonso-Lebrero
authors: Salvador
authors: S
authors: González
authors: Angel L
authors: AL
authors: Corbí
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001232:Aspergillus fumigatus / Q000187:drug effects; D002130:Calcium Phosphates / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016650:Fluorescein-5-isothiocyanate; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D020014:K562 Cells; D037181:Lectins, C-Type / Q000378:metabolism*; D007891:Leishmania / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000166:cytology; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000276:Adjuvants, Immunologic; D002130:Calcium Phosphates; D015815:Cell Adhesion Molecules; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006020:Glycopeptides; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C038773:Immunoferon