AM3 modulates dendritic cell pathogen recognition capabilities by targeting DC-SIGN.
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.
Serrano-Gómez
Diego
D
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Martínez-Nuñez
Rocío T
RT
Sierra-Filardi
Elena
E
Izquierdo
Nuria
N
Colmenares
María
M
Pla
Jesús
J
Rivas
Luis
L
Martinez-Picado
Javier
J
Jimenez-Barbero
Jesús
J
Alonso-Lebrero
José Luis
JL
González
Salvador
S
Corbí
Angel L
AL
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
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