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Antimicrob. Agents Chemother. doi:10.1128/AAC.01289-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inmunoferon® modulates dendritic cell pathogen-recognition capabilities by targeting DC-SIGN

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Facultad de Farmacia, Universidad Complutense, Madrid, Spain; R&D Department, Industrial Farmacéutica Cantabria (IFC), Madrid, Spain; IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain

^* To whom correspondence should be addressed. Email: acorbi{at}cib.csic.es.

	Abstract

Inmunoferon® (AM3) is an orally effective immunomodulator that influences regulatory and effector functions of the immune system whose molecular mechanism of action is mostly unknown. We hypothesized that the polysaccharide moiety of AM3 (IF-S) might affect immune responses by modulating 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 ICAM-3 and the HIV-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 dendritic cells without affecting mannose receptor expression, and ¹D saturation transfer difference NMR demonstrated that IF-S directly interacts with DC-SIGN on the cell surface. Therefore, the polysaccharide moiety of AM3 directly influences pathogen recognition of 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 partly, by altering DC-SIGN functional activities.