DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production Muñoz Fernández, Pilar Caparrós, Esther Sierra Filardi, E. Serrano Gómez, Diego Puig-Kröger, A. Rodríguez Fernández, J.L. Mellado, M. Sancho, Jaime Zubiaur, Mercedes Corbí, A The generation of pathogen-specific immune responses is dependent on the signaling capabilities of pathogen-recognition receptors. DC-SIGN is a C-type lectin that mediates capture and internalization of viral, bacterial, and fungal pathogens by myeloid dendritic cells. DC-SIGN–interacting pathogens are thought to modulate dendritic cell maturation by interfering with intracellular signaling from Toll-like receptor molecules. We report that engagement of DCSIGN by specific antibodies does not promote dendritic cell maturation but induces ERK1/2 and Akt phosphorylation without concomitant p38MAPK activation. DC-SIGN ligation also triggers PLC phosphorylation and transient increases in intracellular calcium in dendritic cells. In agreement with its signaling capabilities, a fraction of DC-SIGN molecules partitions within lipid raft–enriched membrane fractions both in DC-SIGN–transfected and dendritic cells. Moreover, DCSIGN in dendritic cells coprecipitates with the tyrosine kinases Lyn and Syk. The relevance of the DC-SIGN–initiated signals was demonstrated in monocytederived dendritic cells, as DC-SIGN crosslinking synergizes with TNF- for IL-10 release and enhances the production of LPS-induced IL-10. These results demonstrate that DC-SIGN–triggered intracellular signals modulate dendritic cell maturation. Since pathogens stimulate Th2 responses via preferential activation of ERK1/2, these results provide a molecular explanation for the ability of DC-SIGN– interacting pathogens to preferentially evoke Th2-type immune responses. 2025-01-16T08:58:30Z 2025-01-16T08:58:30Z 2006 journal article https://hdl.handle.net/10481/99338 http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License